Laparoscopic treatment of polycystic ovaries: is its place diminishing?

PURPOSE OF REVIEW: The purpose of this review is to provide a critical discussion on the place of laparoscopic ovarian drilling and medical treatment with metformin for polycystic ovary syndrome. RECENT FINDINGS: Laparoscopic ovarian drilling remains popular. It is associated with an ovulation rate of approximately 80% and a pregnancy rate of 50-60% within 1 year of the procedure. The technique results in a decrease in ovarian stromal blood flow. An increasing amount of data, however, suggests that treatment with metformin is equally as effective. The use of metformin in pregnancy appears to be safe; it decreases the miscarriage rate and possibly the incidence of gestational diabetes. SUMMARY: Laparoscopic ovarian drilling and metformin improve ovulatory dysfunction and pregnancy rate to a similar extent. The advantages of metformin continue beyond conception. It reduces the miscarriage rate and also decreases the likelihood of developing gestational diabetes. A randomized trial comparing the effects of metformin and laparoscopic ovarian drilling in women with polycystic ovary syndrome is recommended.     

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.     

Polycystic ovary syndrome

Women with polycystic ovarian syndrome have chronic anovulation and androgen excess not attributable to another cause. This condition occurs in approximately 4% of women. The fundamental pathophysiologic defect is unknown, but important characteristics include insulin resistance, hyperandrogenism, and altered gonadotropin dynamics. Inadequate follicle-stimulating hormone is hypothesized to be a proximate cause of anovulation. Obesity frequently complicates polycystic ovarian syndrome but is not a defining characteristic. The diagnostic approach should be based largely on history and physical examination, thus avoiding numerous laboratory tests that don't contribute to clinical management. Women with polycystic ovarian syndrome typically present because of irregular bleeding, hirsutism, and/or infertility. These conditions can be treated directly with oral contraceptives, oral contraceptives plus spironolactone, and ovulation induction, respectively. However, women with polycystic ovarian syndrome also have a substantially higher prevalence of diabetes and increased risk factors for cardiovascular disease. They should also be screened, therefore, for these conditions and followed closely if any risk factors are uncovered. For obese women with polycystic ovarian syndrome, behavioral weight management is a central component of the overall treatment strategy.     

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.     

Polycystic ovarian syndrome--prognosis and outcomes

Polycystic ovarian syndrome (PCOS) is a condition that is present in 5-6% of women of reproductive age. It has potentially profound implications for women with regard to anovulatory infertility and symptoms related to elevated androgen levels. In addition, in later life women are prone to significant health problems related to hyperinsulinaemia, with an excess risk for diabetes and cardiovascular risk factors. Evidence suggests that the adverse features of PCOS can be ameliorated with lifestyle intervention, such as diet and exercise, while further short-term benefits related to ovulation and cardiac risk factors may be derived from medication with metformin. Evidence for the long-term use of metformin to protect against adverse cardiovascular outcomes and for the use of metformin throughout pregnancy to reduce the risk of miscarriage, gestational diabetes, pre-eclampsia and fetal macrosomia is still lacking.     

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.     

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 in obstetric and gynecologic practice: a review

Metformin is a common treatment for women who have insulin resistance manifesting as type 2 diabetes or polycystic ovarian syndrome (PCOS). With an increasing number of these patients conceiving, it is expected that the use of metformin in and around the time of pregnancy will increase. This article reassesses the mechanisms, safety, and clinical experience of metformin use in obstetrics and gynecology. Metformin is an attractive therapeutic option because administration is simple, hypoglycemia rare, and weight loss promoted. There is a large volume of research supporting the use of metformin treatment in diabetes mellitus, androgenization, anovulation, infertility, and recurrent miscarriage. Although metformin is known to cross the placenta, there is, as yet, no evidence of teratogenicity. Metformin has an array of complex actions, accounting for the varied clinical roles, many of which are still to be fully evaluated. Much research is still needed.     

Laparoscopic treatment of polycystic ovaries: is it time to relinquish the procedure?

OBJECTIVE: To evaluate the role of laparoscopic ovarian drilling and treatment with metformin in the management of the polycystic ovary syndrome (PCOS). DESIGN: A literature search was conducted using the keywords laparoscopy, laparoscopic ovarian drilling, laparoscopic ovarian diathermy, PCOS, metformin, and ovulation. The MEDLINE and EMBASE databases and the Cochrane Database of Systematic Reviews were searched. RESULTS: No randomized comparisons have been done between laparoscopic ovarian drilling and metformin therapy. However, the ovulation and pregnancy rates appear to be similar for both techniques. Both treatments decrease the incidence of ovarian hyperstimulation and the cancellation rate of IVF cycles. However, unlike laparoscopic ovarian drilling, metformin may decrease the incidence of type 2 diabetes and coronary heart disease. CONCLUSION(S): Given the similar magnitude of the results without the potential risks and complication of surgery, we propose that laparoscopic ovarian drilling should be used sparingly in favor of less invasive treatment with metformin.     

Therapeutic options in the polycystic ovary syndrome.

The polycystic ovary syndrome is the most common endocrine disorder affecting women. It is a heterogeneous familial condition of uncertain aetiology. The diagnosis is made by the detection of polycystic ovaries on ultrasound examination and the occurrence of single or multiple clinical features such as menstrual cycle disturbances, obesity, acne, hirsutism, alopecia and biochemical abnormalities such as hypersecretion of luteinising hormone and testosterone. In a significant number of women with this condition there is impaired insulin metabolism. Women with the polycystic ovary syndrome are at an increased risk of developing diabetes and possibly cardiovascular disease in later life. The management should be symptom-orientated. Menstrual cycle regulation may be attained with the combined oral contraceptive pill or cyclical progestogen therapy. In obese women, with the loss of weight, the symptoms and endocrine profile are generally improved. Short-term treatment with metformin may be useful in women with insulin resistance. Hyperandrogenism may be treated with the contraceptive pill containing cyproterone acetate or with short-term low-dose anti-androgen therapy, together with effective contraception. Ovulation may be induced with clomiphene citrate with careful monitoring, failing which low-dose gonadotrophin therapy or laparoscopic ovarian diathermy are effective options.     

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.     

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.     

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.     

Preventing endometrial cancer risk in polycystic ovarian syndrome (PCOS) women: Could metformin help?

Current data indicate that there is a significant risk of endometrial cancer (EC) in women with polycystic ovarian syndrome (PCOS), although further research needed to clarify the exact molecular mechanisms. Endometrial hyperplasia is a premalignant condition that usually heralds EC and it shares identical risk factors with EC. Metabolic syndrome with a triad of obesity, hyperinsulinaemia and diabetes, which is commonly observed in PCOS appears to be a key mechanism in EC pathogenesis. Measures to improve insulin resistance could therefore play a role in reducing the risk of EC in women with PCOS. Metformin is an insulin sensitising agent which is safe, widely available and currently licensed for type-2 diabetes. It has been clearly shown in both animal and human studies that metformin is of value in reversing endometrial hyperplasia. Metformin may therefore prevent EC in PCOS. This article reviews the use of metformin in reducing EC risk in PCOS and makes a case for future research on this topic.     

Insulin resistance and metformin in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder with widespread systemic manifestations affecting 5-10% of women of reproductive age. The accompanying insulin resistance and hypeinsulinemia mark this syndrome as a prediabetic state, with high incidence of impaired glucose tolerance, gestational diabetes, and overt diabetes. Other metabolic and biochemical changes, such as hypertension and dyslipidemia, increase the risk of cardiovascular disease. Fertility may also be impaired due to anovulation, impaired implantation, and higher rates of spontaneous abortions. All of these effects may also be related to hyperinsulinemia. Metformin, as insulin-sensitizing drug, is being evaluated for its potential long-term disease-modifying effect, such as prevention of diabetes. Its use may also help restore spontaneous ovulation and improve menstrual cyclicity, improve the success rate of induction of ovulation with clomiphene citrate and FSH, and decrease the high rate of ovarian hyperstimulation and early pregnancy loss. Nevertheless, these new exiting potential benefits of metformin should be evaluated in large randomized controlled studies, and clinicians must counsel women appropriately before the initiation of metformin therapy.     

复方口服避孕药对多囊卵巢综合征患者糖代谢的影响

多数多囊卵巢综合征(polycystic ovary syndrome,PCOS)患者存在糖代谢、脂代谢、代谢综合征等代谢障碍,罹患糖尿病、心血管疾病的风险增高。口服避孕药作为PCOS患者抗雄激素和调经治疗的一线药物取得令人满意的临床效果,但是这类可能导致糖代谢、脂代谢异常的药物,在应用于有代谢障碍的PCOS患者时可能会加剧其代谢障碍问题,而具有抗雄激素和抗盐皮质激素作用的含屈螺酮的复方口服避孕药——优思明,由于对糖代谢影响极小,有望成为这类PCOS患者的备选药物。     

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.     

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.     

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.     

Long-term consequence of polycystic ovarian syndrome

Polycystic ovarian syndrome (PCOS) is one of the most common hormonal disorders affecting women, although the true incidence and pathophysiology have yet to be determined. A diagnosis of PCOS is likely to be associated with an increased long-term risk of developing cardiovascular disease and type 2 diabetes, especially in obese women. The evidence base for a causal relationship between cancer risk and PCOS is weak. Lifestyle changes leading to weight loss is the most effective treatment in these patients. There is insufficient evidence for the use of metformin or surgical interventions such as ovarian drilling in preventing the long-term effects of PCOS.