Should we continue or stop insulin sensitizing drugs during pregnancy?

PURPOSE OF REVIEW: The use of insulin sensitizing drugs such as metformin in polycystic ovary syndrome has been increasingly popular and validated by systematic reviews. There has also been an interest in the use of metformin for gestational diabetes. However, administration of metformin to prevent miscarriage is controversial and widespread use of this drug in early pregnancy requires investigation. RECENT FINDINGS: There are claims that miscarriage and gestational diabetes are more common in polycystic ovary syndrome and that use of insulin sensitizers improves outcomes dramatically. This review suggests there is no evidence for increased risk of miscarriage solely due to polycystic ovary syndrome and that there are insufficient data for promoting therapy with metformin. There is some reason for use of metformin in mid-pregnancy for gestational diabetes but better evidence from randomized controlled trials is urgently needed. SUMMARY: The use of metformin in early pregnancy for reducing the risk of miscarriage should be avoided outside of the context of properly designed prospective randomized trials. Safety in early pregnancy appears to be reassuring but not completely proven. The use of metformin in mid-pregnancy for gestational diabetes appears more logical but also needs adequate trials before general use is advocated.     

Use of metformin in polycystic ovary syndrome: a meta-analysis

OBJECTIVE: To update the state of evidence on the efficacy of metformin, used either alone or in combination with clomiphene citrate in women with polycystic ovary syndrome, by examining three outcomes: ovulation, pregnancy, and live birth. Sources of heterogeneity among the published randomized controlled trials are systematically assessed. DATA SOURCES: An electronic literature search was performed using MEDLINE, EMBASE, SCOPUS, CENTRAL, Cochrane, and U.S. Food and Drug Administration databases, restricted to studies conducted on humans and published in English. METHODS OF STUDY SELECTION: Of the 406 potentially relevant articles identified, 17 met criteria for inclusion in the meta-analysis, rendering a total sample of 1,639 women. Study quality was examined in terms of randomization scheme, masking process, adequacy of allocation concealment, statistical power, and loss to follow-up; publication bias was also assessed. Meta-analytic procedures were used to compare metformin with placebo, and metformin plus clomiphene with clomiphene alone, for all study outcomes. Exploratory analyses were conducted to assess differences in treatment effects between clomiphene-resistant and nonresistant patients, obese and nonobese patients, and trials with long and short durations of follow-up. TABULATION, INTEGRATION, AND RESULTS: Metformin improved the odds of ovulation in women with polycystic ovary syndrome when compared with placebo (odds ratio [OR] 2.94; 95% confidence interval [CI] 1.43-6.02; number-needed-to-treat 4.0) and appears more effective for non-clomiphene-resistant women. Metformin and clomiphene increased the likelihood of ovulation (OR 4.39; 95% CI 1.94-9.96; number-needed-to-treat 3.7) and pregnancy (OR 2.67; 95% CI 1.45-4.94; number-needed-to-treat 4.6) when compared with clomiphene alone, especially in clomiphene-resistant and obese women with polycystic ovary syndrome. These treatment effects were greater for trials with shorter follow-up. CONCLUSION: Using all available evidence, this meta-analysis suggests that metformin increases the likelihood of ovulation and, in combination with clomiphene, increases the odds of both ovulation and pregnancy in women with polycystic ovary syndrome.     

The role of metformin in the management of polycystic ovary syndrome

PURPOSE OF REVIEW: The purpose of this review is to provide a critical summary of recent studies on the clinical effects of metformin in polycystic ovary syndrome. RECENT FINDINGS: After the recognition that hyperinsulinaemia is a fundamental disturbance in polycystic ovary syndrome, a novel and promising form of therapy in the form of insulin-sensitizing drugs has been introduced. Among these, metformin is the most widely used. This therapeutic intervention has been shown to exert beneficial effects on the endocrine and metabolic disturbances that characterize the syndrome and, more recently, to improve the reproductive outcome in women with polycystic ovary syndrome. With rapid progress in this area, metformin use has also been extended to the management of lean polycystic ovary syndrome patients. SUMMARY: Although most studies are nonrandomized trials, current data provide a rationale for metformin as first-line management for women with polycystic ovary syndrome, alone or in combination with conventional treatments. Controversy still exists, however, regarding the mechanisms by which metformin exerts its beneficial effects in polycystic ovary syndrome.     

Homocysteine levels are unaffected by metformin treatment in both nonpregnant and pregnant women with polycystic ovary syndrome

BACKGROUND: Women with polycystic ovary syndrome have elevated homocysteine levels. Elevated homocysteine levels associate with pregnancy complications. Women with polycystic ovary syndrome are often treated with metformin, a drug that may increase homocysteine levels. Hence, we investigated the effect of metformin treatment on homocysteine levels in nonpregnant and pregnant women with polycystic ovary syndrome. METHODS: Two prospective randomized placebo-controlled studies included women with polycystic ovary syndrome in a university hospital setting. Sixty-three infertile women were treated with metformin 1,000 mg bid or placebo for 16 weeks and 38 pregnant women with metformin 850 mg bid or placebo from the first trimester and throughout pregnancy. All the women had polycystic ovary syndrome and all participants received diet and lifestyle advice, and oral folate and vitamin B12 substitution, and a daily oral multivitamin tablet. The main outcome measures were serum levels of homocysteine, folate, and vitamin B12. RESULTS: Serum homocysteine levels were unaffected by metformin treatment both in nonpregnant and pregnant women with polycystic ovary syndrome. However, in nonpregnant women both serum folate and vitamin B12 levels decreased with treatment. At inclusion in nonpregnant women, serum homocysteine levels associated negatively with serum levels of folate and methyl malonic acid and positively with free testosterone index. No such associations were seen in pregnant women. CONCLUSIONS: Metformin treatment in women with polycystic ovary does not increase serum homocysteine levels in the nonpregnant or the pregnant state.     

Surgical treatment in polycystic ovary syndrome

PURPOSE OF REVIEW: The purpose of this review is to provide a critical summary of current knowledge on the role and effectiveness of ovarian surgery in the treatment of polycystic ovary syndrome. RECENT FINDINGS: Clomiphene citrate is used as a first-line treatment for ovulation induction in infertile anovulatory patients with polycystic ovary syndrome. In clomiphene citrate-resistant women, other treatment modalities such as laparoscopic electrocautery or ovulation induction with gonadotropins have been proposed as alternative therapies. Although gonadotropin treatment and laparoscopic ovarian drilling have demonstrated similar reproductive outcomes, laparoscopic ovarian drilling has some advantages over gonadotropin treatment such as lower cost per pregnancy, improvement in menstrual regularity, and better long-term reproductive performance. On the other hand, knowledge about the pathogenesis of polycystic ovary syndrome has been growing and insulin-sensitizing drugs have gained popularity as a new treatment option. SUMMARY: According to current data, metformin has gained popularity as first-line management in clomiphene citrate-resistant women with polycystic ovary syndrome. If ovulation does not occur within several months after treatment with metformin, after the evaluation of all pros and cons related to each treatment, laparoscopic ovarian drilling or gonadotropins may be considered as an effective option according to patient choice.     

Increase of multiple pregnancies caused by ovulation induction with gonadotropin in combination with metformin in infertile women with polycystic ovary syndrome

Metformin appears to be an effective medicine to induce ovulation in women with polycystic ovary syndrome and insulin resistance. After the introduction of metformin treatment for such cases, the use of gonadotropin in combination with metformin significantly increased the incidence of multiple pregnancies.     

The effect of metformin on fat distribution and the metabolic syndrome in women with polycystic ovary syndrome--a randomised, double-blind, placebo-controlled trial

OBJECTIVE: To establish whether metformin has a significant action in reducing visceral fat and improving other metabolic parameters in women with polycystic ovary syndrome (PCOS). DESIGN: Randomised, double-blind, placebo-controlled trial. SETTING: Reproductive medicine clinic. POPULATION: Forty women with anovulatory PCOS. METHODS: Participants were randomised into receiving metformin 500 mg three times a day or placebo for 3 months. MAIN OUTCOME MEASURES: Fat distribution was measured by computed tomography scan. Secondary outcome measures included serum indices of the metabolic syndrome and evidence of ovulation. RESULTS: We found no significant differences in any of the measures of fat distribution between the placebo and metformin groups. The metformin group had significantly lower total cholesterol (P= 0.02), low-density lipoprotein cholesterol (P= 0.02) and cholesterol:high-density lipoprotein cholesterol ratio (P= 0.05), but there was no statistically significant treatment effect on androgens, insulin, insulin resistance, triglycerides, ovulation or pregnancy. CONCLUSIONS: Metformin has no clinically significant effect in reducing visceral fat mass, although it does have a beneficial effect on lipids. This trial lends support to the growing evidence that metformin is not a weight loss drug. Metformin might therefore be used as an adjunct to lifestyle modification in women with PCOS, but not as a substitute for it.     

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.     

Polycystic ovary syndrome and metformin in pregnancy

The diagnostic criteria of polycystic ovary syndrome incorporate hyperandrogenism, polycystic ovaries, anovulation and irregular menstrual bleeding and the syndrome is a recognized reason behind infertility. The biguanide metformin has encouraging effects on several metabolic aspects of the syndrome, including insulin sensitivity, plasma glucose concentration and lipid profile. Moreover, metformin improves the ovarian function in women diagnosed with polycystic ovary syndrome. Hence, metformin is considered an agent for ovulation induction among these patients. However, even higher ovulation frequencies have been observed when metformin has been adjuvant to clomifene therapy. Metformin-induced ovulation presumably brings about resumption of regular menstrual cycles and improved conception rates. Polycystic ovary syndrome patients are presumably more likely than healthy women to suffer from pregnancy-related problems like early pregnancy loss, gestational diabetes mellitus and hypertensive states in pregnancy. Recent data suggest sparing effects of continued metformin therapy throughout pregnancy on early pregnancy loss and gestational diabetes mellitus, but its impact on hypertensive complications to pregnancy appears less evident. Instead, metformin might even induce pre-eclampsia or exert no effect on blood pressure. CONCLUSION: So far, evidence for safety of continued therapy throughout gestation is insufficient, and existing papers are limited in design and might mask for fetal toxic outcomes due to metformin therapy. Prior to a recommendation of sustained metformin therapy throughout pregnancy, randomized placebo-controlled double-blinded clinical trials are awaited with interest, so that present assumptions on efficiency can be clarified, in order to assure efficient and safe management of pregnant polycystic ovary syndrome patients.     

Adolescent androgen abnormalities

PURPOSE OF REVIEW: Polycystic ovary syndrome is one of the most common endocrinopathies affecting premenopausal women. This review focuses on this major cause of hyperandrogenism in adolescents and young women, highlighting new diagnostic and therapeutic strategies that are under investigation. The pathophysiologic role in the disorder are the subject of several recent reports. RECENT FINDINGS: Recent studies have found a 33% prevalence of abnormal glucose tolerance in a cohort of affected adolescents, higher fasting insulin levels and lower insulin sensitivity, and that glucose tolerance testing appears to be necessary for routine screening. The effects of hyperinsulinism may be counteracted by insulin sensitizing agents. In adult women with polycystic ovary syndrome, metformin treatment reduced hyperinsulinemia and hyperandrogenemia. In some obese adolescents, metformin therapy resulted in declines in body mass index, insulin, and glucose. Restoration of regular menses may also occur after metformin treatment. Thus, data is accumulating that insulin-sensitizing agents may be helpful in decreasing the pathophysiologic effects of hyperinsulinism and insulin resistance associated with polycystic ovary syndrome. Other hormonal alterations in polycystic ovary syndrome have also been the subject of recent reports. Leptin secretion was found to be markedly irregular in these women. Elevated LH secretion may be secondary to accelerated gonadotropin-releasing hormone pulse generator activity, although the etiology of the pulse alterations is unclear. SUMMARY: Although polycystic ovary syndrome is the most common endocrine disorder affecting young women, it is one of the least understood, reflected by the wealth of research in this area. One area of focus has been the pathophysiologic link between insulin resistance and this disorder, including the effects of promising new agents to counteract these effects.     

No more surrogate end-points in randomised trials: the PCOSMIC trial protocol for women with polycystic ovary syndrome using metformin for infertility with clomiphene

Current data supporting the effectiveness of metformin as a fertility treatment for women with polycystic ovary syndrome have been misinterpreted. Still unproven for women with polycystic ovary syndrome is, first, whether metformin adds to the standard first-line fertility management in all women, second, whether metformin is an effective fertility treatment for overweight women, and third, the relative fertility efficacy of metformin and clomiphene citrate as a first-line treatment in women with a lower body weight. The PCOSMIC (polycystic ovary syndrome: metformin for infertility with clomiphene) trial is an ongoing New Zealand multicentre double-blind placebo-controlled parallel randomised trial assessing these questions.     

Metformin for the treatment of polycystic ovary syndrome

OBJECTIVE: To familiarize obstetrician-gynecologists with the use of metformin for the treatment of polycystic ovary syndrome (PCOS). DATA SOURCES: Using OVID, 94 English-language articles published after 1966 indexed with the key words "metformin" and "polycystic ovary syndrome" were identified. METHODS OF STUDY SELECTION: Studies were excluded if they did not have a control group, did not use the National Institutes of Health definition of PCOS, did not have a clinical outcome as an end point, and were not in the English language. Reviews were also excluded, leaving 21 articles for inclusion. TABULATION, INTEGRATION, AND RESULTS: Three clinical trials reported that for the treatment of anovulatory infertility caused by PCOS, metformin plus clomiphene is more effective than clomiphene alone in inducing ovulation. For the treatment of irregular menses caused by PCOS in women not attempting conception, metformin therapy may restore ovulatory menses in the majority of women. However, most women will require 4-6 months of metformin therapy before they achieve ovulatory menses. In obese women, metformin plus a low-calorie diet may be associated with more weight loss than a low-calorie diet alone. CONCLUSION: Polycystic ovary syndrome is a common gynecologic endocrine disorder. Obstetrician-gynecologists should be familiar with the indications and contraindications for the use of metformin in their practice.     

Outlook: metformin use in infertile patients with polycystic ovary syndrome: an evidence-based overview

Metformin is an insulin sensitizer currently used for treating type-2 diabetes mellitus and recently administered for inducing ovulatory menstrual cycles in oligo-amenorrhoeic patients with polycystic ovary syndrome (PCOS). The aim of the present review is to describe the efficacy of metformin as an ovulation inducer on the basis of the most important evidence-based medicine supported data, including meta-analyses and randomized controlled trials. Specifically, we reviewed the uses of metformin as first- and second-step treatment for PCOS related anovulatory infertility and as co-treatment in infertile PCOS patients who receive gonadotrophins. To date, there is evidence that metformin is effective for restoring normal menstrual cycles in anovulatory PCOS patients, and that it is more effective and cheaper than laparoscopic ovarian drilling as the second therapeutic step in PCOS patients previously defined as resistant to clomiphene citrate. Co-administration of metformin in PCOS patients treated with gonadotrophin improves the mono-ovulation rate and can prevent ovarian hyperstimulation syndrome in patients treated with gonadotrophins for IVF cycles.     

Should infertile women with polycystic ovarian syndrome be treated with metformine?

Polycystic ovary syndrome is a frequent endocrine disorder often associated with insulin resistance and hyperinsulinaemia which may play a role in hyperandrogenism and anovulation. The use of "insulin sensitizing" agents has been suggested to reduce insulin resistance and hyperandrogenism. In that respect, the use of metformin in polycystic ovary syndrome is reviewed. Although its mechanism of action is still unclear, metformin proved to be effective to restore cyclicity and spontaneous ovulation. The synergistic effect of clomiphene citrate and metformin was demonstrated in some studies, suggesting that metformin could be helpful for women with clomiphene citrate resistance. However, the potential effect of metformin administration for reducing hyperstimulation in women treated with exogenous FSH, or for preventing early miscarriages has to be confirmed. Here, we propose a guideline for the use of metformin, as an adjuvant therapy, to restore cyclicity and ovulation in women with polycystic ovary syndrome.     

Optimizing ovulation induction in women with polycystic ovary syndrome

Recent developments in our understanding of the pathophysiology of polycystic ovary syndrome led to the introduction of new therapeutic approaches. It is apparent that a significant proportion of women with polycystic ovary syndrome have insulin resistance and compensatory hyperinsulinemia. Growing evidence indicates that elevated serum insulin induces hyperandrogenism, which in turn leads to anovulation and infertility. Hyperinsulinemia also contributes to the increased risk for cardiovascular disorders and type 2 diabetes mellitus. These concepts provide rationale for therapies focused on treatments of insulin resistance. In particular, weight loss and exercise have been shown to increase insulin sensitivity and improve ovulatory function. Metformin, an insulin-sensitizing agent, is particularly effective in women with polycystic ovary syndrome who have significant insulin resistance. Metformin use leads to a decrease in serum insulin and androgen levels as well as an improvement in ovulatory function. Moreover, it appears to ameliorate cardiovascular risk factors. Other approaches to ovulation induction in women with polycystic ovary syndrome include traditional therapies using clomiphene citrate or gonadotropins. In clomiphene-resistant subjects, one can consider laparoscopic ovarian drilling and other forms of partial ovarian resection or destruction.     

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.     

Does metformin induce ovulation in normoandrogenic anovulatory women?

OBJECTIVE: This study was undertaken to evaluate the efficacy of metformin in women with anovulation who do not have evidence for hyperandrogenism and classic polycystic ovary syndrome. STUDY DESIGN: A randomized trial of metformin (1500 mg daily) and placebo in 24 anovulatory women was undertaken for 3 months. Assessments of changes in hormone levels and insulin sensitivity were carried out. Abnormal hormonal values were defined by levels exceeding the range in normal ovulatory controls. RESULTS: Anovulatory women had normal androgen levels and luteinizing hormone but had higher serum insulin and lower insulin sensitivity compared with controls. Over 3 months, there were 16 ovulatory cycles with metformin and only 4 with placebo ( P < .05). Success of ovulation did not correlate with changes in androgen, insulin, or insulin sensitivity parameters. CONCLUSION: Metformin may be useful for inducing ovulation in anovulatory women who do not have hyperandrogenism. This effect may be independent of a lowering of androgen or insulin levels.     

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.     

Role of metformin in patients with polycystic ovary syndrome: the state of the art

Metformin, an insulin sensitizer widely used for the treatment of patients with type-2 diabetes mellitus (DM), was recently introduced in the clinical practice to treat women with polycystic ovary syndrome (PCOS). The aim of the current review was to evaluate the current role of metformin in the treatment of the PCOS-related disorders. The Authors analyze here the administration of metformin for treating the ovarian dysfunction due to PCOS, and show the evidences available in literature regarding its alternative uses.     

Polycystic ovarian syndrome--prognosis and treatment outcomes

PURPOSE OF REVIEW: Polycystic ovarian syndrome is the commonest endocrine disorder of reproductive-age women. It may have implications for women with regard to anovulatory infertility, insulin resistance and elevated androgens. Furthermore, patients are prone to health problems in later life, including diabetes and cardiovascular risk. This review provides an update of recent findings for the management of polycystic ovarian syndrome. RECENT FINDINGS: Studies have been performed to determine the best first-line medication for ovulation induction in polycystic ovarian syndrome. Meta-analyses have been performed to determine whether metformin should be used as an adjunct in IVF in women with this syndrome and to determine whether metformin or the oral contraceptive pill should be used for symptom control. Adverse features of this syndrome can be improved by diet and exercise. Evidence for the longer-term use of metformin to protect against adverse cardiovascular outcomes, and for its pregnancy use to reduce gestational diabetes, preeclampsia, and fetal macrosomia is lacking, although evidence for a reduction in miscarriage in insulin-resistant patients is accumulating. SUMMARY: Recent studies have sought to clarify the serious short-term clinical problems faced by women with polycystic ovarian syndrome; however, studies looking to the long term to address cardiovascular and diabetic conversion are still required.