Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome.

OBJECTIVE: To evaluate the effect of metformin therapy on hyperandrogenism, insulin resistance, cervical scores, ovulation, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome (PCOS). DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: Infertility clinic of a tertiary referral center. PATIENT(S): Fifty-six women with clomiphene citrate-resistant PCOS. INTERVENTION(S): Two cycles of oral metformin therapy (850 mg, twice daily) in group I and placebo therapy (twice daily) in group II. Clomiphene citrate (100 mg/day) on cycle days 3-7 of the second cycle in both groups. MAIN OUTCOME MEASURE(S): Insulin, T, DHEAS, FSH, LH, body mass index (BMI), waist-to-hip ratio, endometrial thickness, cervical score, ovulation, and pregnancy rates in clomiphene-induced cycles after metformin therapy. Result(s): Metformin therapy resulted in a significant decrease in total T, LH level, LH/FSH ratio, insulin resistance, and mean BMI. No difference in waist-to-hip ratio, DHEAS level, and fasting insulin level was observed. Clomiphene citrate induction resulted in higher ovulation rates and thicker endometrium in the metformin group than in the placebo group. There was higher cumulative pregnancy rate in the metformin group; however, there was no significant difference in the pregnancy rate between the two groups. CONCLUSION(S): Metformin therapy not only decreases hyperandrogenism and insulin resistance but also improves ovulation rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with PCOS.     

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.     

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.     

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.     

Association of metformin and pregnancy in the polycystic ovary syndrome. A report of three cases

BACKGROUND: Infertility is a common manifestation of the polycystic ovary syndrome (PCOS), a condition characterized by chronic anovulation, hyperinsulinemia and hyperandrogenism. Hyperinsulinemia leads to increased ovarian androgen production, resulting in follicular atresia and anovulation. Metformin, a medication that improves insulin sensitivity and decreases serum insulin levels, restores menstrual cyclicity and ovulatory function and may improve fertility rates in women with PCOS. We present three consecutive cases from our clinic that support this premise. CASES: Three patients were seen in the reproductive endocrinology clinic with documented PCOS, long-standing infertility and clinically diagnosed insulin resistance. The first patient had hyperandrogenic, insulin-resistant acanthosis nigricans syndrome and had been resistant to multiple courses of clomiphene citrate; the second exhibited hypertension, hyperlipidemia and glucose intolerance along with anovulation; and the third presented with poorly controlled type 2 diabetes and a desire to conceive. Each patient received metformin, which led to restoration of menstrual cyclicity and conception in all three cases. CONCLUSION: These three patients reflect the heterogeneous nature of PCOS, and treating their underlying insulin resistance with metformin resulted in pregnancy. These findings suggest that metformin may be a useful adjunct for treatment of infertility in patients with PCOS.     

二甲双胍用于多囊卵巢综合征患者促排卵治疗有效性的系统性评价

目的:系统性评价二甲双胍对多囊卵巢综合征(PCOS)促排卵治疗的有效性。方法:计算机检索CBMDISC(中国生物医学文献数据库,1979～2011年)、万方(1994～2011年)、CNKI(中国学术期刊网专题全文数据库,1994～2011年)、维普(中国生物医学期刊数据库,1989～2011年),PubMed(1997～2011年)、ProQust Medical Libraray(PML,1997～2011年)、外文生物医学期刊文献数据库(FMJS,2000～2011年),读秀学术搜索(www.duxiu.com),并手检9种相关杂志。纳入二甲双胍与氯米芬用于PCOS促排卵治疗的随机对照试验,质量评价后进行Meta分析。结果:共纳入8篇RCT,合计1168例。Meta分析结果显示:与氯米芬组比较,二甲双胍组排卵率低于氯米芬组[OR 0.48(0.26～0.87)],两组差异有统计学意义;妊娠率[OR 0.94(0.26～3.43)],流产率[OR 0.63(0.06～6.47)],活产率[OR 0.90(0.11～7.32)],两组差异无统计学意义。氯米芬联合二甲双胍组妊娠率较高,与氯米芬组的差异有统计学意义[Peto OR 1.56(1.16～2.08)];排卵率[OR 1.54(0.96～2.49)],流产率[Peto OR 1.40(0.79～2.48)],活产率[Peto OR1.26(0.83～1.91)],两组差异无统计学意义。结论:较之氯米芬用于PCOS患者促排卵治疗,二甲双胍可能促进排卵、有利于妊娠,二甲双胍与氯米芬联合用药的治疗效果要好于单一用药。     

The effectiveness of metformin ovulation induction treatment in patients with PCOS: a systematic review and meta-analysis

Objective: To evaluate of metformin effectiveness of ovulation induction treatment in polycystic ovary syndrome (PCOS) women. Methods: Eight databases and nine related journals were searched for randomized controlled trails (RCTs) on the comparison between metformin and clomiphene citrate used for PCOS women. Meta analysis was performed after quality assessment. Results: Ovulation rate in metformin group compared with clomiphene citrate group was lower with a significant difference [OR = 0.48 (0.26–0.87), p = 0.01]; no significant difference was found for pregnancy rate [OR = 0.94 (0.26–3.43)], miscarriage rate [OR = 0.63 (0.06–6.47)] between two groups. Compared with the combination of metformin and clomiphene citrate group, pregnancy rate in metformin group was significantly lower [Peto OR = 1.56 (1.16–2.08), p = 0.003], but there was no significant difference in the two groups about ovulation rate [OR = 1.52 (0.95–2.45)], miscarriage rate [Peto OR = 1.40 (0.79–2.48)]. Conclusions: Compared with clomiphene citrate, metformin used for ovulation induction treatment in PCOS women, can promote ovulation induction and pregnancy rate, the effect of the combination treatment is better than that of a single drug use.     

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.     

Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone

OBJECTIVE: To determine whether metformin treatment increases the ovulation and pregnancy rates in response to clomiphene citrate (CC) in women who are resistant to CC alone. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Multicenter environment. PATIENT(S): Anovulatory women with the polycystic ovary syndrome (PCOS) who were resistant to CC. INTERVENTION(S): Participants received placebo or metformin, 500 mg three times daily, for 7 weeks. Information on reproductive steroids, gonadotropins, and oral glucose tolerance testing was obtained at baseline and after treatment. Metformin or placebo was continued and CC treatment was begun at 50 mg daily for 5 days. Serum P level > or =4 ng/mL was considered to indicate ovulation. With ovulation, the daily CC dose was not changed, but with anovulation it was increased by 50 mg for the next cycle. Patients completed the study when they had had six ovulatory cycles, became pregnant, or experienced anovulation while receiving 150 mg of CC. MAIN OUTCOME MEASURE(S): Ovulation and pregnancy rates. RESULT(S): In the metformin and placebo groups, 9 of 12 participants (75%) and 4 of 15 participants (27%) ovulated, and 6 of 11 participants (55%) and 1 of 14 participants (7%) conceived, respectively. Comparisons between the groups were significant. CONCLUSION(S): In anovulatory women with PCOS who are resistant to CC, metformin use significantly increased the ovulation rate and pregnancy rate from CC treatment.     

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.     

二甲双胍/CC/HMG序贯用药治疗胰岛素抵抗PCOS患者的临床研究

目的 :探讨二甲双胍对胰岛素抵抗多囊卵巢综合征 (PCOS)患者的治疗效果及作用机理。方法 :随机将 69例胰岛素抵抗PCOS患者分为A、B两组。A组 34例用Diane 35治疗 3个周期后用CC +HMG促排卵 ;B组 35例用二甲双胍治疗 3个月后用CC +HMG促排卵。观察两组患者治疗前后的BMI、T、FINS、TNF α及排卵率。结果 :两组患者治疗后BMI及T差异无显著性(P >0 .0 5) ;FINS、TNF α及排卵率差异有显著性 (P <0 .0 5)。结论 :胰岛素抵抗PCOS患者治疗的关键是应用胰岛素增敏剂降低FINS ,二甲双胍对于PCOS合并不孕的治疗效果优于Diane 35。     

Therapeutic strategies for ovulation induction in infertile women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by hirsutism, obesity, hyperandrogenism and insulin resistance. The syndrome is often accompanied by infertility because of anovulation. Many approaches have been proposed to solve this problem, with the most commonly used therapies being ovarian drilling and pharmacological ovulation induction. Ovarian drilling is a procedure in which a laser fiber or electro-surgical needle punctures the ovary four to ten times. Side-effects are rare and often related to surgery itself. Pharmacological strategies include administration of metformin and insulin-sensitizing agents, clomiphene citrate (CC), gonadotropins and aromatase inhibitors. Metformin appears valuable in increasing ovulation rate, menstrual cyclicity and pregnancy rate. CC is an oral estrogen antagonist that raises circulating concentrations of follicle-stimulating hormone (FSH) and induces follicular growth in most women with PCOS and anovulation. Failure to respond is associated with high body mass index and high androgen levels. Aromatase inhibitors mimic the central reduction of negative feedback through which CC works. Ovulation induction with recombinant FSH has proved successful, but treatment requires skill and experience to avoid multiple pregnancies and ovarian hyperstimulation syndrome. The hypothetical deleterious effects of the high luteinizing hormone concentrations observed in PCOS patients seem to be related to the concomitant hyperinsulinemia (and/or insulin resistance). A thorough understanding of the syndrome and a careful assessment of each patient are the mainstays for choosing an appropriate treatment regimen.     

Metformin therapy in women with polycystic ovary syndrome.

OBJECTIVE: To determine the clinical, biochemical, hormonal, and ultrasonographic effects of 6 months of metformin therapy in women with polycystic ovary syndrome (PCOS) and compare with pretherapy parameters. METHOD: 50 Indian women with PCOS, 25 unmarried and 25 married, infertile women, were enrolled in this prospective clinical study. After a baseline workup, including body mass index (BMI), waist hip ratio (WHR), Ferriman Gallwey hirsutism scoring, menstrual pattern, levels of fasting insulin, lipids, oral glucose tolerance test (OGTT), serum gonadotropins, estradiol (E2), testosterone, androstenedione, sex hormone binding globulin (SHBG), and dehydroepiandrosterone sulphate (DHEAS), patients were given 1000 gm of metformin for 6 months and then reevaluated. RESULT: In 41 of 50 women who completed treatment, significant improvement in BMI, WHR, menstrual cyclicity (80.5%), ovulation rate (66%), and pregnancy rate (28%) was noted. Statistically significant decrease in lutenising hormone (LH) and LH/FSH ratio with an increase in follicle stimulating hormone (FSH) levels were seen. Levels of high-density lipoprotein (HDL) cholesterol (Chol) increased along with a decrease in total cholesterol. Improvement was noted in ovarian volume, stromal thickness, and number of follicles. There was no change in hirsutism, acne, levels of other sex steroid hormones, and lipids. CONCLUSION: A 6-month course of metformin therapy may improve menstrual cyclicity and fertility in women with PCOS.     

l-Carnitine plus metformin in clomiphene-resistant obese PCOS women,reproductive and metabolic effects: a randomized clinical trial

To evaluate the reproductive and metabolic effects of L-carnitine plus metformin in clomiphene citrate (CC) resistant obese polycystic ovary syndrome (PCOS) women. A double-blinded randomized controlled clinical trial, clomiphene-citrate resistant obese women were allocated randomly to receive CC plus metformin and L-carnitine (n?=?138) or CC plus metformin and placebo (n?=?136). The primary outcome was clinical pregnancy rate. The secondary outcomes were hormonal and metabolic profile changes in addition to ovulation and first trimester (13 weeks) miscarriage rates. Clomiphene-citrate, L-carnitine, and metformin group showed significant improvement in the menstrual regularity, ovulation rate, and pregnancy rate compared to CC plus metformin and placebo group (29% vs. 9%, 34.7% vs.11%, and 28.2% vs. 6.6%, respectively). No statistically significant difference in the miscarriage rate between the two groups (p?=?.08). After three months of treatment, the reduction in body mass index (BMI) was non-significant (p?=?.061) between both groups. The hormonal and metabolic parameters were more significantly improved in the L-carnitine group compared with the placebo group. l-Carnitine may act synergistically with metformin for improvement of reproductive performance, insulin resistance, and lipid profile in clomiphene-resistant obese PCOS women.     

二甲双胍治疗耐克罗米酚多囊卵巢综合征23例临床分析

目的探讨二甲双胍在多囊卵巢综合征(PCOS)治疗中的作用.方法对23例耐克罗米酚PCOS患者的临床资料进行回顾性分析,比较二甲双胍治疗前后各项内分泌代谢指标的变化及其对恢复月经、促排结局及妊娠的影响.结果二甲双胍治疗前后比较,血清睾酮、空腹胰岛素水平下降,胰岛素敏感性指数上升(P<0.01).6例(26.09%)的患者恢复月经,4例(17.39%)恢复自然排卵,2例妊娠. 二甲双胍加促排治疗共26个周期,排卵周期率为61.54%(16/26),妊娠周期率为23.08%(6/26). 结论二甲双胍可以降低雄激素水平及胰岛素水平,改善PCOS妇女对克罗米酚促排的反应.     

Predictive value of glucose–insulin ratio in PCOS and profile of women who will benefit from metformin therapy: Obese,lean, hyper or normoinsulinemic?

OBJECTIVE: The aim of the present study is to evaluate sub-groups of PCOS patients who will benefit from metformin therapy and to find out any predictors of ovulation in PCOS sub-groups. METHOD: In the current prospective-randomized, placebo-controlled, double-blind study, PCOS patients (n = 116) were divided into six main groups according to glucose to insulin ratio (G-I ratio mg/10(-4) U) and body mass index (BMI kg/m2) as: Group 1: normoinsulinemic (G-I ratio > or = 4.5 mg/10(-4) U), lean (BMI < 25) (n = 37); Group 2: normoinsulinemic, overweight (BMI: 25-29.9) (n = 19); Group 3: normoinsulinemic, obese (BMI > or = 30) (n = 18); Group 4: hyperinsulinemic (G-I ratio < 4.5 mg/10(-4) U), lean (n = 28); Group 5: hyperinsulinemic, overweight (n = 17); Group 6: hyperinsulinemic, obese (n = 20). Patients in each group were randomized onto placebo or metformin treatments (850 mg two to three times per day according to BMI). The rate of ovulation, biochemical profile, hormonal profile and clinical symptoms of hyperandrogenism were evaluated before and after 6 months of metformin and placebo treatments. RESULT(S): We observed a significant decrease in WHR following metformin therapy in the normoinsulinemic overweight sub-group (P < 0.05). The duration of the menstrual cycle significantly decreased in the normoinsulinemic obese sub-group on metformin therapy (P < 0.05). Metformin had a significant effect on hirsutism scores in hyperinsulinemic lean women (P < 0.05) and decreased DHEAS levels significantly in the lean hyperinsulinemic and normoinsulinemic groups (P < 0.05). Metformin had significant effects on ovulation in only lean hyperinsulinemic women (P < 0.05). CONCLUSIONS: Clinical outcomes of metformin therapy may be categorized on the basis of basal BMI and insulin levels in PCOS patients.     

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.     

Metformin therapy in polycystic ovary syndrome

Polycystic ovarian syndrom (PCOS) affects 5% to 10% of women of reproductive age, and is the most common reason of anovulation in infertile women. It is multi-symptom disease. A drug which is used to induce ovulation in women with PCOS is clomiphene citrate. After clomiphene treatment, ovulation is achieved in 56%-73% of women. The rest of them has different level of opportunity to therapy. Clomiphene does not have influence on elementary factor in PCOS which seems to be opportunity to insulin. The drug which can have positive effect is metformin, derivative from biguanid. Its influence on percent of ovulation, pregnancy and live births was evaluated based on randomized trials. Many trials have reserched this so far, but their results are divergent. In this article, we are aiming to systemize results of randomized trials concerning the role of metformin in PCOS therapy.     

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.