Raoul Orvieto, MD
Happy are those who dream dreams and are ready to pay the price to make them come true.
—Leon Suenes
Key Points
• Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among women of reproductive age, associated with reproductive and metabolic dysfunction
• PCOS is associated with increased risk of impaired glucose tolerance (IGT) and type 2 diabetes (T2D)
• PCOS women are at increased risk for adverse pregnancy outcomes, that is, gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), preeclampsia, and preterm birth
• Metformin does not improve live birth rates in PCOS patients undergoing infertility treatment and should therefore be restricted for only those with IGT
• Although metformin does not improve pregnancy outcome in nonhyperinsulinemic PCOS patients, a beneficial effect was demonstrated in those with IGT
INTRODUCTION
Polycystic ovary syndrome (PCOS) is the most common endo- crinopathy among women of reproductive age, associated with reproductive and metabolic dysfunction.1 The clinical presentation varies from eumenorrhea and a sonographic picture of polycystic ovaries but with subtle phenotypic abnormalities or signs of hyperandrogenism, to advanced Stein and Leventhal syndrome2 with clinical heterogeneity as the rule. Moreover, most women with PCOS also exhibit features of the metabolic syndrome, including impaired glucose tolerance (IGT), obesity, and dys- lipidaemia3-5 with their associated long-term sequelae namely endometrial carcinoma, hypertension, type 2 diabetes (T2D), and cardiovascular disease.
The pathophysiology of PCOS is not completely understood and its etiology remains an enigma. Moreover, until 2004, there was no single acceptable definition, though the most widely used indicator is the presence of typical ultrasound features of the polycystic ovaries6 in association with hyperandrogenism and/or chronic anovulation in women without specific underlying disease of the adrenal or pituitary glands. The recognition of the controversies surrounding the diagnostic criteria of PCOS has led to the Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group that revised the diagnostic criteria and addressed the long-term health risks related to PCOS.1 The Rotterdam ESHRE/ASRM PCOS consensus recommended that PCOS be defined when at least two of the following three criteria are present: (1) polycystic ovaries, (2) oligo and/or anovulation, and (3) clinical and/or biochemical signs of hyperandrogenism. Accordingly, the estimated prevalence of PCOS varies from 3% to 20% depending on the diagnostic criteria used.7
PCOS, IGT, AND T2D
IGT, or insulin resistance, are defined as decreased insulin-mediated glucose utilization. It has long been recognized as a major risk factor for diabetes.8 Moreover, it was shown that lifestyle intervention or metformin in patients with IGT may reduce the prevalence of T2D.9
The cellular and molecular mechanisms of insulin action in PCOS have been widely investigated. It was demonstrated that insulin-dependent receptor tyrosine autophosphorylation was significantly decreased, while insulin-independent receptor serine phosphorylation was markedly increased resulting in normal receptor signaling inhibition.10,11 This increased insulin-independent serine phosphorylation in PCOS insulin receptors appears to be a unique disorder of insulin action, not presented in other insulin-resistant states such as T2D, obesity, and so forth.10,12 and acts synergistically with obesity to detrimentally affect insulin action.13
Several dynamic invasive tests and calculated indices are currently available for detecting IGT. Although the euglycemic clamp technique is considered the most accurate test for the assessment of insulin resistance, this cumbersome test is frequently replaced by the simple measurement of the ratio of fasting glucose to fasting insulin, or the two-hour glucose level after a 75-g oral glucose tolerance test (OGTT) (WHO criteria, IGT > 140-199 mg/ dL).14 As a result, reports of the prevalence on IGT in women with PCOS vary depending on the sensitivity and specificity of the tests employed and the heterogenic phenotypes of PCOS.
There is now convincing evidence that PCOS is associated with increased risk of IGT and T2D.15,16 Studies published before the 2003 Rotterdam ESHRE/ASRM PCOS consensus on diagnostic criteria for PCOS have reported 23%-35% and 4%-10% prevalence for IGT and T2D, respectively, in PCOS women.17-19 Moreover, the prevalence of IGT and T2D were respectively 2- to 3-fold and 7.5- to 10-fold, higher in PCOS compared to age- and weight-comparable to reproductively normal control wom- en.17,18IGT was mainly evident in post-glucose challenge glucose levels and the prevalence was highest in obese affected women; lean PCOS women showed increased rates of IGT and T2D.17 Similar figures were also observed following the 2003 Rotterdam ESHRE/ASRM PCOS consensus. Moran et al.15 in their comprehensive meta-analysis have demonstrated that PCOS women had increased prevalence of IGT (odds ratio [OR] 2.48), T2D (OR 4.43), and metabolic syndrome (OR 2.88) as compared to body mass index (BMI)-matched controls. Moreover, using the gold standard clamp techniques, Stepto et al.20 have recently confirmed that PCOS women, irrespective of BMI, are more IGT and report that the prevalence of IGT in PCOS based on the World Health Organization (WHO) definition (<25th centile of glucose infusion rate in healthy lean controls) is 75% in lean PCOS, 62% in overweight controls, and 95% in overweight PCOS in a largely Caucasian population.
The different phenotypes of PCOS present similarities but also important differences in their clinical and endocrine pattern. Although the risk of IGT or diabetes is highest in women who have both oligo/anovulation and hyperandrogenism and is further amplified by obesity,21 most of the normoandrogenic PCOS do not exhibit the two main components of PCOS: hyperandrogenism and IGT.22,23
PCOS AND ADVERSE PREGNANCY AND NEONATAL COMPLICATIONS
Women with PCOS, who desire a pregnancy may be at increased risk for adverse pregnancy outcomes. This may be exacerbated by obesity and/or IGT (Amsterdam). Boomsma et al.24 have conducted a meta-analysis aiming to evaluate the risk of pregnancy and neonatal complications in women with PCOS. Of the 15 eligible studies, involving 720 PCOS women and 4505 controls, PCOS women demonstrated a significantly higher risk of developing GDM (OR 2.94), PIH (OR 3.67), preeclampsia (OR 3.47), and preterm birth (OR 1.75). Moreover, their babies had a significantly higher risk of admission to a neonatal intensive care unit (NICU) (OR 2.31) and a higher perinatal mortality (OR 3.07). These observations were recently confirmed by Qin et al.25 evaluating 27 studies involving 4982 women with PCOS and 119,692 controls. They also demonstrated a significantly higher risk of developing GDM (OR 3.43), PIH (OR 3.43), preeclampsia (OR 2.17), preterm birth (OR 1.93), and caesarean section (OR 1.74) in PCOS patients compared to controls. Moreover, PCOS babies had a marginally significant lower birth weight and higher risk of admission to NICU compared to controls. They, therefore, concluded that women with PCOS should be followed closely during pregnancy and parturition in an attempt to prevent or ameliorate these complications.
Pregnancy-associated risks are greater in women diagnosed by more classic National Institute of Health (NIH) criteria as opposed to nonhyperandrogenic women.26 This probably reflects the well-known observation that PCOS phenotypes had different hormonal and metabolic patterns, in particular, a full-blown phenotype associated with IGT in contrast with the ovulatory pheno- type.23,27,28 In their prospective controlled study, Palomba et al.29 evaluated the clinical impact of the main features of PCOS in 97 pregnant PCOS women and 73 healthy pregnant controls. The relative risk for adverse obstetric or neonatal outcomes was increased in PCOS patients and varied according to the PCOS phenotype, as defined by the ESHRE/ASRM consensus on PCOS diagnostic criteria.1 They observed a higher relative risk for adverse outcomes in patients with the full-blown and non-PCO phenotypes than in those with the nonhyperandrogenic and ovulatory phenotypes (1.93, 2.23, 0.54, and 0.48, respectively). The risk for adverse obstetric or neonatal outcomes was affected significantly by ovarian dysfunction and biochemical hyperandrogenism, whereas no significant effect was detected for clinical hyperandrogenism and PCO.
METFORMIN FOR PCOS PATIENTS
Women with the PCOS are at increased risk for the metabolic syndrome and its associated health risks.26 One of the cardinal components of metabolic syndrome is insulin resistance and its compensatory hyperinsulinemia, which are considered prominent features of PCOS and have a cardinal role in the pathophysiology of the syndrome.30
Metformin, an orally active biguanide, enhances insulin sensitivity by the inhibition of hepatic glucose production and by increasing glucose uptake and utilization into muscle tissue. It has been commonly used for the treatment of T2D. Moreover, for approximately two decades, metformin has been also used in PCOS patients to improve insulin resistance and reduce hyperin- sulinemia with the subsequent improvement in PCOS metabolic and hyperandrogenic disturbances.31,32
With regard to its use during pregnancy, according to the Federal Drug Administration, metformin is a category B drug. This means that either animal studies have shown an adverse effect not confirmed by controlled studies in women, or animal studies have not shown a fetal risk but there are no controlled studies in women. A systematic review and meta-analysis conducted by Gilbert et al.33 based on eight small eligible studies revealed that metformin treatment in the first trimester does not appear to be unsafe for use during pregnancy with respect to major malformations.
Prompted by the aforementioned observations, subsequent studies reported the beneficial effects of metformin on ovulation rate,32 abortion rate,34 and improvement of pregnancy outcome35 in PCOS patients.
METFORMIN AND INDUCTION OF OVULATION
PCOS women with insulin resistance undergoing ovulation induction with gonadotropin have a longer duration of treatment, use a higher total follicle-stimulating hormone (FSH) dose, and have an elevated cancellation rate and a lower conception rate.36,37Im- proving insulin sensitivity through both lifestyle and pharmacological intervention were suggested to ameliorate the aforementioned abnormalities, restore ovulation, and enhance pregnancy in women with PCOS.
However, a systematic review by Costello et al.38 demonstrated that although the coadministration of metformin to gonadotropin ovulation induction and in vitro fertilization (IVF) does not improve ovulation, pregnancy, or live birthrates, it does consistently affect ovarian response during ovulation induction with variable effects on the length of ovarian stimulation, total dose of FSH used, peak serum E2 level, the number of oocytes collected, and reduces the risk of ovarian hyperstimulation syndrome. Following two randomized controlled studies that could not demonstrate an increase in live birthrate with metformin as compared to clomiphene treatment for ovulation induction,39,40 a recently published ESHRE/ASRM consensus,41 that addressed the therapeutic challenges raised in women with infertility and PCOS, concluded that there is no evidence for improved live birthrates with the use of metformin, and metformin should be, therefore, restricted only to those patients with glucose intolerance.
METFORMIN AND SPONTANEOUS ABORTION
The associations between abortion or malformations and poor glycemic control in the periconceptional period are well estab- lished.42 According to the Amsterdam ESHRE/ASRM consensus, miscarriage rates are not increased in natural conceptions in women with PCOS, independent of obesity, while after induction of ovulation, the rate mirrors those found in other infertile popu- lations.26 However, in most of the published studies, miscarriage rates were significantly higher in PCOS patients who had one or more pregnancies (44%) or in those conceiving following IVF treatment (35.8%),29,43,44 and appeared to be threefold higher compared to controls.45
The suggested mechanisms by which PCOS could cause miscarriage are hypersecretion of luteinizing hormone (LH); elevated androgen concentrations, which may lead to abnormally developed endometrium; reduction in endometrial glycodelin A expression and its known detrimental effect on oocyte quality/ embryo viability; and hyperinsulinaemia with the consequent decrease in serum glycodelin and insulin-like growth factor-binding protein-1 levels, and elevation in plasminogen activator inhibitor-1 (PAI-1) and homocysteine concentrations (summarized by Cocksedge et al.46).
Considering the potential beneficial effects of metformin, which was shown to reduce body weight, LH, androgens, and PAI-1 levels (summarized in Palomba et al.47), it was offered to PCOS patients, in an attempt to prevent abortions to increase uterine blood flow,48 and to reduce insulin resistance and hyperinsu- linaemia that protect against development of miscarriage, as was already established in pregestational diabetic patients undergoing strict euglycemic control.
However, data related to metformin and abortion risk are conflicting.49,50 When the miscarriage rate was compared in the same group of PCOS women before and after metformin therapy, the reported reduction in miscarriage rates ranged from 62%-73% to 8.8%-26%.34,51,52
Moreover, a closer analysis of the data reveals that the majority of the available studies are observational, uncontrolled, and of short duration and women were not necessarily selected or tested for hyperinsulinemia. For example, in Palomba et al.49 meta-analysis, of the 17 eligible studies, in only three studies were patients insulin resistant. In these results, 2 out of 16 (8%) of women aborted in the metformin arm versus 3 out of 16 (18.8%) in the control; these small sample sizes make it impossible to draw reasonable conclusions.
METFORMIN AND PREGNANCY COMPLICATIONS
As described above, PCOS women are at increased risk for adverse pregnancy outcomes, that is, GDM, PIH, preeclampsia and preterm birth. In women with GDM, no differences were seen between metformin- and insulin-treatment groups at different levels of glucose control. Moreover, metformin (alone or with supplemental insulin) was not associated with increased perinatal complications as compared with insulin.53,54
Metformin administration to PCOS patients during pregnancy was suggested to reduce the risk of gestational diabetes.35,52 Among PCOS patients receiving metformin, only 3%-4% were reported to develop gestational diabetes compared to 26%-27% in their previous untreated pregnancies.35,52 However, while in De Leo et al.55 study of hyperinsulinemic overweight PCOS patients, metformin eliminated gestational diabetes, in the randomized, placebo-controlled, double-blind, multicenter study by Vanky et al.56 of 274 singleton pregnancies, receiving either metformin or placebo, the prevalence of GDM was17.6% versus 16.9%, respectively. Of note, in contrast to the study by De Leo et al.,55 according to patients mean fasting and two-hour glucose levels, patients in the Vanky et al.56 study were not hyperinsulinemic with the consequent relatively low prevalence of GDM. Therefore, Vanky et al.56 observations cannot reflect the preventive role of metformin in insulin-resistant PCOS patients, as shown elsewhere.57,58
Since metformin modulates blood pressure, lipid profile, insulin resistance, and fibrinolytic activity, it is reasonable to assume that it may prevent PIH.59 Glueck et al.60 have prospectively compared the prevalence of preeclampsia in metformin-treated PCOS women to healthy controls. No difference was observed between the two groups (5.2% vs. 3.6%, respectively). In the study by De Leo et al,55 none of the PCOS women treated with metformin developed hypertensive disorders or preeclampsia while the gestational hypertension was demonstrated in 11% (P < 0.05) and preeclampsia in 3% (P = 0.24) of the control group. Again, in Vanky et al.56 study of noninsulin-resistant PCOS patients, preeclampsia prevalence was 7.4% in the metformin group and 3.7% in the placebo group. These observations confirm the protective role of metformin against PIH in insulin-resistant pregnant PCOS patients, presumably due to the aforementioned beneficial effects and its ability to induce weight loss and to control weight gain during pregnancy.
SUMMARY
PCOS is the most common endocrinopathy among women of reproductive age associated with reproductive and metabolic dysfunction. PCOS phenotypes have different hormonal, metabolic, and clinical patterns, some of which are at increased risk of IGT and T2D. PCOS women are also at increased risk for adverse pregnancy outcomes, that is GDM, PIH, preeclampsia, and preterm birth that may be ameliorated by metformin administration.
In our practice, we screen all PCOS patient for IGT by fasting glucose to insulin ratio and 75-g OGTT. Metformin is offered only to insulin-resistant PCOS patients starting at a dose of 850 mg bid preconceptionally.
According to the Thessaloniki ESHRE/ASRM PCOS Consensus Workshop Group, decisions about continuing metformin during pregnancy in women with glucose intolerance should be left to obstetricians providing care and based on a careful evaluation of risks and benefits.41 Two commonly used protocols are either to stop metformin with pregnancy confirmation or to continue metformin throughout the first trimester and then to halve the dose and continue metformin up to the 37th week of gestation.
REFERENCES
1. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and longterm health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81:19-25.
2. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol. 1935;29:181-191.
3. Dunaif A, Graf M, Mandeli J, et al. Characterization of groups of hyperandrogenic women with acanthosisnigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab. 1987;65:499-507.
4. Robinson S, Kiddy D, Gelding SV, et al. The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries. Clin Endocrinol. 1993;39:351-355.
5. Franks S. Genetic and environmental origins of obesity relevant to reproduction. Reprod Biomed Online. 2006;12:526-531.
6. Adams J, Franks S, Polson DW, et al. Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotrophin releasing hormone. Lancet. 1985;2:1375-1378.
7. Carmina E, Azziz R. Diagnosis, phenotype, and prevalence of polycystic ovary syndrome. Fertil Steril. 2006;86:S7-S8.
8. Norman RJ, Masters L, Milner CR, et al. Relative risk of conversion from normoglycemia to impaired glucose tolerance or noninsulin dependent diabetes mellitus in polycystic ovary syndrome. Hum Reprod. 2001;9:1995-1998.
9. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.
10. Dunaif A, Xia J, Book CB, et al. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. J Clin Invest. 1995;96:801-810.
11. Li M, Youngren JF, Dunaif A, et al. Decreased insulin receptor (IR) autophosphorylation in fibroblasts from patients with PCOS: effects of serine kinase inhibitors and IR activators. J Clin Endocrinol Metab. 2002;87:4088-4093.
12. Caro JF, Dohm LG, Pories WJ, Sinha MK. Cellular alterations in liver, skeletal muscle, and adipose tissue responsible for insulin resistance in obesity and type II diabetes. Diabetes Metab Rev. 1989;5:665-689.
13. Ehrmann DA, Sturis J, Byrne MM, et al. Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus. J Clin Invest. 1995;96:520-527.
14. Bloomgarden ZT. American Association of Clinical Endocrinologists (AACE) consensus conference on the insulin resistance syndrome. Diabetes Care. 2003;26:1297-1303.
15. Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2010;16:347-363.
16. Solomon CG, Hu FB, Dunaif A, et al. Long or highly irregular menstrual cycles as a marker for risk of type 2 diabetes mellitus. JAMA. 2001;286:2421-2426.
17. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999;84:165-169.
18. Ehrmann DA, Barnes RB, Rosenfield RL, et al. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999;22:141-146.
19. Ehrmann DA, Kasza K, Azziz R, et al. for the PCOS/Troglitazone Study Group. Effects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:66-71.
20. Stepto NK, Cassar S, Joham AE, et al. Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic- hyperinsulaemic clamp. Hum Reprod. 2013;28:777-784.
21. Barber TM, Wass JA, McCarthy MI, Franks S. Metabolic characteristics of women with polycystic ovaries and oligo-amenorrhoea but normal androgen levels: implications for the management of polycystic ovary syndrome. Clin Endocrinol (Oxf). 2007;66:513-517.
22. Guastella E, Longo RA, Carmina E. Clinical and endocrine characteristics of the main polycystic ovary syndrome phenotypes. Fertil Steril. 2010;94:2197-2201.
23. Shroff R, Syrop CH, Davis W, et al. Risk of metabolic complications in the new PCOS phenotypes based on the Rotterdam criteria. Fertil Steril. 2007;88:1389-1395.
24. Boomsma CM, Eijkemans MJ, Hughes EG, et al. A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum Reprod Update. 2006;12:673-683.
25. Qin JZ, Pang LH, Li MJ, et al. Obstetric complications in women with polycystic ovary syndrome: a systematic review and meta-analysis. Reprod Biol Endocrinol. 2013;11:56.
26. Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Consensus on women's health aspects of polycystic ovary syndrome (PCOS). Hum Reprod. 2012;27(1):14-24.
27. Chang WY, Knochenhauer ES, Bartolucci AA, Azziz R. Phenotypic spectrum of polycystic ovary syndrome: clinical and biochemical characterization of the three major clinical subgroups. Fertil Steril. 2005;83:1717-1723.
28. Carmina E, Chu MC, Longo RA, et al. Phenotypic variation in hyperandrogenic women influences the findings of abnormal metabolic and cardiovascular risk parameters. J Clin Endocrinol Metab. 2005;90:2545-2549.
29. Palomba S, Falbo A, Russo T, et al. Pregnancy in women with polycystic ovary syndrome: the effect of different phenotypes and features on obstetric and neonatal outcomes. Fertil Steril. 2010;94:1805-1811.
30. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38:1165-1174.
31. Velazquez EM, Mendoza S, Hamer T, et al. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism. 1994;43:647-654.
32. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med. 1998;338: 1876-1880.
33. Gilbert C, Valois M, KorenG. Pregnancy outcome after first-trimester exposure to metformin: a meta-analysis. Fertil Steril. 2006;86:658-663.
34. Glueck CJ, Phillips H, Cameron D, et al. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril. 2001;75:46-52.
35. Glueck CJ, Wang P, Kobayashi S, et al. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertil Steril. 2002;77:520-525.
36. Homburg R, Orvieto R, Bar-Hava I, Ben-Rafael Z. Serum levels of insulin-like growth factor-1, IGF binding protein-1 and insulin and the response to human menopausal gonadotrophins in women with polycystic ovary syndrome. Hum Reprod. 1996;11:716-719.
37. Dale O, Tanbo T, Haug E, Abyholm T. The impact of insulin resistance on the outcome of ovulation induction with low-dose follicle stimulating hormone in women with polycystic ovary syndrome. Hum Reprod. 1998;13:567-570.
38. Costello MF, Chapman M, Conway U. A systematic review and meta-analysis of randomized controlled trials on metformin co-administration during gonadotrophin ovulation induction or IVF in women with polycystic ovary syndrome. Hum Reprod. 2006;21:1387-1399.
39. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356:551-566.
40. Moll E, Bossuyt PM, Korevaar JC, et al. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ. 2006;332:1485-1489.
41. Thessaloniki ESHRE/ASRM- Sponsored PCOS Consensus Workshop Group.Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril. 2008;89:505-522.
42. Rosenn B, Miodovnik M, Combs CA, et al. Glycemic thresholds for spontaneous abortion and congenital malformations in insulin-dependent diabetes mellitus. Obstet Gynecol. 1994; 84:515-520.
43. Glueck CJ, Wang P, Fontaine RN, et al. Plasminogen activator inhibitor activity: an independent risk factor for the high miscarriage rate during pregnancy in women with polycystic ovary syndrome. Metabolism. 1999;48(12):1589-1595.
44. Balen AH, Tan SL, MacDougall J, Jacobs HS. Miscarriage rates following in-vitro fertilization are increased in women with polycystic ovaries and reduced by pituitary desensitization with. Hum Reprod. 1993;8:959-964.
45. Regan L, Braude PR, Trembath PL. Influence of past reproductive performance on risk of spontaneous abortion. Br Med J. 1989;299:541-545.
46. Cocksedge KA, Li TC, Saravelos SH, Metwally M. A reappraisal of the role of polycystic ovary syndrome in recurrent miscarriage. Reprod Biomed Online. 2008;17:151-160.
47. Palomba S, Falbo A, Zullo F, Orio F. Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review. Endocr Rev. 2009;30:1-50.
48. Palomba S, Russo T, Orio F Jr, et al. Uterine effects of metformin administration in anovulatory women with polycystic ovary syndrome. Hum Reprod. 2006;21(2):457-65.
49. Palomba S, Falbo A, Orio F, Zullo F. Effect of preconceptional metformin on abortion risk in polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials. Fertil Steril. 2009;92:1646-1658.
50. Palomba S, Falbo A, La Sala GB. Effects of metformin in women with polycystic ovary syndrome treated with gonadotrophins for in vitro fertilisation and intracytoplasmic sperm injection cycles: a systematic review and meta-analysis of randomised controlled trials. BJOG. 2013;120:267-276.
51. Jakubowicz DJ, Iuorno MJ, Jakubowicz S, et al.Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87:524-529.
52. Glueck CJ, Wang P, Goldenberg N, Sieve-Smith L.Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod.2002;17:2858-2864.
53. Rowan JA, Hague WM, Gao W, et al. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008;358:2003-2015.
54. Rowan JA, Gao W, Hague WM, McIntyre HD. Glycemia and its relationship to outcomes in the metformin in gestational diabetes trial. Diabetes Care. 2010;33:9-16.
55. De Leo V, Musacchio MC, Piomboni P, et al. The administration of metformin during pregnancy reduces polycystic ovary syndrome related gestational complications. Eur J Obstet Gynecol Reprod Biol. 2011;157(1):63-66.
56. Vanky E, Stridsklev S, Heimstad R, et al. Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study. J Clin Endocrinol Metab. 2010;95:448-455.
57. Simmons D. Metformin treatment for Type 2 diabetes in pregnancy? Best Pract Res Clin Endocrinol Metab. 2010;24:625-634.
58. Nicholson W, Bolen S, Witkop CT, et al. Benefits and risks of oral diabetes agents compared with insulin in women with gestational diabetes: a systematic review. Obstet Gynecol. 2009;113(1):193-205.
59. McCarthy EA, Walker SP, McLachlan K, et al. Metformin in obstetric and gynecologic practice: a review. Obstet Gynecol Surv. 2004;59:118-127.
60. Glueck CJ, Bornovali S, Pranikoff J, et al.Metformin, pre-eclampsia, and pregnancy outcomes in women with polycystic ovary syndrome. Diabet Med. 2004;21:829-836.