The role of metformin in the treatment of infertile women with polycystic ovary syndrome

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1 The role of metformin in the treatment of infertile women with polycystic ovary syndrome Anju Sinha and William Atiomo /toag Keywords infertility, metformin, ovaries, polycystic ovary syndrome (PCOS) Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility and is conventionally treated with clomifene. Recent research shows that insulin resistance and hyperinsulinaemia lead to hyperandrogenism in PCOS. It is thought that this causes anovulation and infertility and is the rationale for the use of insulinsensitising drugs such as metformin. This article explores the role of metformin, which is being increasingly used as first-line therapy to treat infertility with PCOS and potentially avoids the risks of multiple pregnancy and ovarian hyperstimulation associated with clomifene. Introduction Polycystic ovary syndrome (PCOS) affects 5 10% of women in the reproductive age group 1 and is the most common cause of anovulatory infertility. 2 It is characterised by a myriad of symptoms and signs that include menstrual disturbances, hyperandrogenism, hirsutism, obesity, infertility, insulin resistance and the presence of polycystic ovaries on ultrasound.the aetiology of PCOS is uncertain and so far, treatment has been directed mainly at symptom control. Attempts have been made to direct treatment at the underlying mechanisms, which are thought to cause infertility in PCOS. This is reflected by the increasing use of metformin, an insulin-lowering drug conventionally used to treat type 2 diabetes mellitus, in the treatment of infertile women with PCOS, as insulin resistance is thought to underpin infertility in women with PCOS. Metformin also theoretically avoids the risks of multiple pregnancy, ovarian cancer and ovarian hyperstimulation associated with the traditional first-line treatment, clomifene. These theoretical advantages make metformin an attractive firstline option for the treatment of women who are infertile with PCOS, in addition to its use in the treatment of women who are clomifene-resistant and as an adjunct to ovulation induction during assisted conception. Background The key rationale for metformin in women with PCOS who are infertile is the presence of a positive correlation between the degree of insulin resistance and anovulatory infertility. 3 Although the mechanisms linking insulin resistance with anovulatory infertility in PCOS are debatable, proposed mechanisms include a direct stimulation of androgen production from the ovarian stromal cells (thought to directly impair follicle development), impairment of local steroidogenesis mediated via an imbalance in the production of insulin-like growth factors and a direct stimulatory effect on a local (intraovarian) protease inhibitor, plasminogen activator inhibitor-1 (PAI-1), limiting follicle growth. 4 It is thought that metformin, by suppressing hepatic gluconeogenesis and improving peripheral insulin resistance, reduces ovarian hyperandrogenaemia and restores normal ovarian steroidogenesis and PAI-1 levels, thus enhancing ovulation and improving fertility. Metformin has also been shown to reduce systemic luteinising hormone (LH) and PAI-1 levels, both of which have been associated with an increased risk of miscarriage. Therefore, theoretically, metformin use in women who are infertile with PCOS potentially offers real advantages over clomifene by avoiding the increased risk of multiple pregnancies (4 11%) and ovarian cancer (prolonged use more than 12 months). 5 Additionally, as Author details William Atiomo DM MA MRCOG ILTM, Clinical Senior Lecturer and Consultant Gynaecologist, Department of Obstetrics and Gynaecology, School of Human Development, University of Nottingham, University Hospital, Queen s Medical Centre, Nottingham, NG7 2UH, UK. william.atiomo@nottingham.ac.uk (corresponding author) Anju Sinha MRCOG, Specialist Registrar in Obstetrics and Gynaecology, Department of Obstetrics and Gynaecology, University Hospital, Queen s Medical Centre, Nottingham, UK. 145

2 metformin reverses the adverse endocrine and metabolic risk factors for miscarriage in PCOS (insulin resistance, raised PAI-1 and raised androgens), pregnancy loss could be reduced in these women. First-line use of metformin could also potentially avoid the risks and costs associated with second- and third-line therapies for women with PCOS who are infertile, such as gonadotrophin ovulation induction, laparoscopic ovarian drilling and in vitro fertilisation. However, although there is evidence from a systematic review supporting the first-line use of metformin in inducing ovulation, 6 there is an absence of robust data indicating the true live birth rates in women with PCOS when metformin is used as a first-line treatment. Table 1. Summary of published RCTs on the effect of metformin in PCOS Ref. Design Criteria used Women BMI Dose, Effect on Effect on Effect on to diagnose (n) (kg/m 2 ) duration menstruation and pregnancy BMI, T, PCOS ovulation FI 10 R, SB, Clinical features, mg t.i.d. for 5/12(42%) M vs. 1/13(8%) NA BMI PC hyperandrogenism (all BMI 4 weeks Pl ovulated; P NS T > 27.5) FI 11 R, SB, Clinical features, mg t.i.d. for 12/35 (34%) M vs. NA M alone: PC hyperandrogenism (all BMI 34 days (M alone) 1/26 (4%) Pl ovulated; BMI > 28.0) If anovulatory by P S T day 34, add CC 19/21 (90%) M + CC FI 50 mg for 1 cycle vs. 2/25 (8%) P + CC; (M + CC) P S 8 R, DB, Clinical features, mg t.i.d. for 5 M vs. 0 Pl (total M or P NA) NA BMI PC hyperandrogenism 6 months 37% _ in frequency of menses T on M vs. 0% on P; P S FI 9 R, DB, Clinical features, 40 ( All given hypocalorie Numbers NA but improved NA M + diet: PC hyperandrogenism PCOS vs. (all BMI diet for 1 month then frequency of menstrual cycles BMI and US criteria 20 non- > 28.0) added either M 850 mg b.d. in obese PCOS group with T PCOS) for 6 months (M + diet) both M + diet & Pl + diet, but FI or Pl for 6 months effects of M significantly higher (Pl + diet group) compared to Pl; P S 12 R, DB, Clinical features, mg b.d. for 16 weeks 37/45 (82%) M vs. 30/47 Pregnancy BMI PC hyperandrogenism (64%) Pl ovulated; P S was not 1 o T NA and US criteria endpoint but FI 4/23 (17.4%) M vs. 1/19 (5.3%) Pl; P NS 13 RCT Clinical features, Both CC alone and CC Ovulation rate 13/45 (29%) CC + M: hyperandrogenism (all BMI + M groups received CC CC + M (80%) vs. CC + M vs. FI and US criteria > 28.0) mg daily for 5 days (65%) CC alone; P S 4/45 (8%) CC CC alone: for up to 6 cycles, depending alone; P S FI on ovulatory response. CC+M group also received treatment with M 500 mg t.i.d. for 6 months 14 R, DB, US criteria only 20 a mg t.i.d. for 3 months 3/10 (30%) M alone 1/10 (10%) w M alone: PC (M alone) If anovulatory on vs. 3/10 (30%) Pl alone on M alone vs. BMI M alone, add CC 100 mg for ovulated; P NS 2/10 (20%) w T 1 cycle (M + CC) 1/7 (14%) M + CC vs. on P alone; P NS FI 4/7 (57%) Pl + CC; P NS Results NA with addition of CC to M & P. 15 R, DB, Clinical features, 56 a mg b.d. for 28 days 21/27 (78%) ovulated on 3/27(11%) w M + CC: PC hyperandrogenism (M alone). If no menses, add M + CC vs. 4/28 (14%) on M+CC vs. BMI and US criteria CC 100 mg to M for 1 cycle Pl + CC; P S 0/28(0%) on T (M + CC) P+CC; P NS FI 16 R, DB, Clinical features, 27 a mg t.i.d. for 7 weeks 1/12 (8%) M alone vs. 1/15 6/11(55%) M alone: PC hyperandrogenism (M alone) a If anovulatory (7%) Pl alone ovulated; M + CC vs. BMI and US criteria on M alone, add CC 50 mg P NS 9/12 (75%) 1/14 (7%) T to 150 mg for up to 6 M + CC vs. 4/15 (27%) P + CC; P S FI ovulatory cycles (M + CC) Pl + CC; P S b.d. = twice daily; BMI = mean body mass index; CC = clomifene citrate; DB = double blind; FI = mean fasting insulin; M = metformin; NA = not available; PC = placebo controlled; Pl = placebo; P S = statistically significant; P NS = not statistically significant; R = randomised; RCT = randomised controlled trial; SB = single blind;t = testosterone; US = ultrasound; = increased with treatment; = unchanged with treatment; = decreased with treatment; t.i.d. = three times daily a All women were clomifene citrate resistant 146

3 How effective is metformin therapy? Although there have been many studies which have demonstrated the effectiveness of metformin use in PCOS, none has directly addressed the question of live birth rates when metformin is used as a first-line therapy.the first study on metformin in PCOS to be published was an uncontrolled study in 1994, 7 in which 26 obese women with PCOS were treated with metformin at a dose of 500 mg three times daily for 8 weeks. In this study, metformin resulted in three spontaneous pregnancies and menstrual cycles were normalised in another seven women. Metformin also improved insulin sensitivity, lowered serum LH, total and free testosterone concentrations and caused an elevation in serum follicle-stimulation hormone and sex hormonebinding globulin. This study paved the way for many more trials on the metabolic and clinical effects of metformin in PCOS. To specifically address the question of the effectiveness of metformin use as first-line therapy in women with PCOS, we looked at nine randomised controlled trials in which the effect of metformin (alone or with clomifene) on menstrual function, ovulation and pregnancy had been evaluated (Table 1) and a systematic review from the Cochrane Collaboration. There was convincing evidence that metformin alone improved menstrual cyclicity 8,9 and ovulation rates, 10,11,12 indirectly supporting its first-line use. Although there were no data to support an improved pregnancy rate when metformin was used as a single agent, the addition of metformin to clomifene improved ovulation and pregnancy rates in obese women with PCOS. 11,13 This effect was also seen when metformin was added to clomifene in women who were clomifene resistant. 14,15,16 More indirect support for first-line use of metformin in PCOS can also be found in the results of the systematic review. 6 In a metaanalysis of 13 randomised controlled trials, metformin was shown to be effective in achieving ovulation in women with PCOS, with an odds ratio of 3.88 (95% CI ) for metformin compared with placebo and 4.41 (95% CI ) for metformin and clomifene compared with clomifene alone.with regard to clinical pregnancy rates, the systematic review stated that five trials comparing metformin with placebo did not show any significant difference, although questions were raised about the possibility of publication bias. When all five trials comparing metformin with clomifene were analysed, there was a significant benefit from metformin and clomifene compared with clomifene alone (OR 4.88, 95% CI ). However, four of these five trials recruited women who were previously resistant to clomifene and thus not pure first-line users of metformin. An appraisal of the evidence on metformin in PCOS would therefore suggest that, although there is no direct evidence that first-line use leads to increased live birth rates, indirect evidence from increased ovulation and pregnancy rates when used in women who are clomifene resistant, or in combination with clomifene, supports a role for metformin therapy as a firstline treatment of anovulatory PCOS. The following sections provide some practical guidelines for how it should be used in practice. Table 2. Basic investigations in couples with infertility where PCOS may be a contributory factor, prior to metformin therapy Investigation History Details Duration of infertility Type of infertility (primary or secondary) Menstrual history (dysmenorrhoea, dyspareunia, discharge) Sexual history (coital frequency) Drug history Social history (alcohol, smoking, occupation) Physical examination Assess body mass index Perform Chlamydia screen Cervical smear if needed Assess pelvic organs in the woman and testicular volume and penile urethra in the man Baseline investigations FSH and LH level, day 2 4 Progesterone, day 21 Rubella titre Test of tubal patency (hysterosalpingogram, hysterocontrast sonography or laparoscopy and dye test) Two semen analyses 147

4 Investigating couples with infertility where PCOS may be a contributory factor Basic investigations in couples with infertility where PCOS may be a contributory factor, prior to metformin therapy, are listed in Table 2. To confirm the diagnosis of PCOS in anovulatory women, a hormonal profile including testosterone, sex hormone-binding globulin, prolactin, thyroid function tests, 17-hydroxyprogesterone and pelvic ultrasound should be taken. Anovulatory infertility due to PCOS should be diagnosed if two of the following three criteria are present, after exclusion of other causes of androgen excess according to the new joint European Society of Human Reproduction and Embryology/ American Society for Reproductive Medicine-sponsored PCOS consensus definition. 17 These three criteria are: oligoand/or anovulation, clinical and/or biochemical signs of hyperandrogenism and polycystic ovaries morphology on ultrasound scan, defined as the presence of 12 or more follicles in each ovary (with one ovary sufficient for diagnosis) measuring 2 9 mm in diameter and/or increased ovarian volume (greater than 10 ml). A clear definition of PCOS is especially important prior to first-line therapy with metformin in anovulatory women with infertility, as there is no evidence for metformin use in women with the other types of anovulatory infertility (WHO type I and type III anovulation). Patient selection for metformin treatment Metformin can theoretically be offered as a firstline drug to all women (obese and non-obese) with anovulatory infertility due to PCOS who have been trying to conceive for a year or more. Although there have been concerns expressed about the risk of hypoglycaemia in lean anovulatory women with PCOS on metformin treatment, this risk is low. Theoretically, hypoglycaemia should be extremely unlikely, particularly as insulin resistance is linked with anovulation in PCOS, even in women who are not obese. It would, however, be prudent to recommend that all women going on metformin are advised to look out for signs of hypoglycaemia and stop treatment if this is suspected. As with all other ovulation induction therapy, it is preferable to ensure that other major causes of infertility (male factor and tubal disease) have been ruled out. However, logically, first-line metformin treatment could be started without a formal test for tubal patency, provided there are no symptoms suggestive of any co-morbidities such as endometriosis, past history of pelvic inflammatory disease, history of miscarriage or termination or previous abdominal surgery. Strictly speaking, there is no agreed upper body mass index cut-off as is the case with clomifene. However, weight loss by exercise and diet modification should be advised at the outset of management, particularly as weight loss in women with PCOS who are obese results in a striking improvement in ovulatory function and hyperandrogenism, largely related to amelioration of obesity-related hyperinsulinaemia. 18 Furthermore, even a relatively minor weight loss of 5% of body weight often leads to the restoration of normal cycles 19 and improved pregnancy rates. 20 Many pregnancy complications are also linked to obesity and it makes sense to advise women to lose weight, as this reduces the occurrence of obesity-related pregnancy complications. 21 Baseline investigations Before prescribing metformin, renal and hepatic function should be checked as metformin may rarely cause lactic acidosis in the presence of even mild renal impairment. Annual testing of renal and hepatic function is mandatory during metformin therapy. An oral glucose tolerance test and fasting lipids should also ideally be checked, as women with PCOS are at higher risk of diabetes and atherogenic lipid profile. An oral glucose tolerance test should also be rechecked during any successful pregnancies following metformin treatment, as women with PCOS are more likely to develop gestational diabetes. 22 Dose and regimen for metformin treatment The usual dose of metformin is 500 mg three times daily, whether offered as first-line treatment or to women with PCOS who are clomifene resistant. To minimise the mainly gastrointestinal adverse effects, women are commonly advised to take the medication prior to meals and to increase the dosage gradually from once daily, in increments of 500 mg/day each week. Alternatively, it can be prescribed at a dose of 850 mg twice daily to improve compliance. A higher dose (850 mg three times daily) in women with PCOS who are obese does not appear to confer any further benefit. 23 A slow-release form of metformin (metformin XR) given once daily is now available in North America (currently not available in the UK) and its effectiveness is being evaluated in a 148

5 multicentre randomised trial, comparing the effects of clomifene, metformin and combined clomifene and metformin on live birth rates in women with PCOS. Although the results of this trial will be useful, they will not provide clear evidence of the effectiveness of first-line metformin therapy, as treatment is not being restricted to first-line ovulation induction. General advice to couples General advice about optimising fertility, written information and information about useful websites covering PCOS (such as i8.com) should be made available. Couples should also be given advice on stopping or reducing smoking and alcohol intake, pre- and periconceptional folic acid and weight loss (particularly if the body mass index is greater than 30). Parallel referral to a dietician should be encouraged in women who are obese, if facilities are available. Period of therapy The optimal period of first-line metformin monotherapy for fertility is debatable, given its theoretical safer adverse-effect profile (fewer risks compared with clomifene). Although the care of each woman should be individualised it seems prudent to suggest that where metformin is used as stand-alone first-line therapy, it is continued for 6 months if regular ovulation is documented. However, if it has not been effective after 6 months of treatment, clomifene should be added for a further 6 months. This suggestion is based on the results of studies that have shown a rapid return to spontaneous ovulation and normal menstrual rhythm within 3 months of the start of therapy. 9,11 Metformin should be stopped once pregnancy is confirmed, as it is not licensed for use in pregnancy. Where pregnancy has not occurred after 1 year of either metformin alone or metformin clomifene combination therapy then alternative treatment, namely laparoscopic ovarian drilling, gonadotrophins or in vitro fertilisation, should be considered. There are currently no clear guidelines on the role of follicle tracking in women on metformin monotherapy as, in theory, the risks of multiple pregnancy and ovarian hyperstimulation are absent. We would, however, recommend that some evidence of successful induction of ovulation be obtained early on in the treatment course (serum progesterone or ultrasound) as this will inform the need to progress to combined clomifene metformin treatment. Adverse effects and contraindications of metformin The main immediate adverse effects of metformin are gastrointestinal in nature and include anorexia, nausea, vomiting and diarrhoea. These adverse effects are usually transient. They are quite common with metformin and may persist in some women, particularly with high doses such as 3 g daily.there is no evidence as to the safety of metformin in long-term use in young women but no trial has reported a serious adverse effect with up to six-months use. Longterm use may however interfere with vitamin B 12 absorption. Thus, it is important to counsel the woman regarding the adverse effects before starting treatment. Metformin may provoke lactic acidosis, which is most likely to occur in women with renal impairment. Metformin must therefore not be used in women with even mild renal impairment.the increased blood lactate concentrations are probably caused by metformin-induced conversion of glucose to lactate by intestinal mucosa. It is also contraindicated in other situations that predispose to lactic acidosis, e.g. severe dehydration, infection, shock, heart failure, recent myocardial infarction, severe peripheral vascular disease, hepatic impairment, alcohol dependency and use of X-ray contrast media. Therefore, metformin should be discontinued one week before a woman is about to have a hysterosalpingogram to check for tubal patency and resumed after one week s rest. Use of metformin in pregnancy Metformin therapy should be discontinued once pregnancy is confirmed, whether it is being used as a first-line treatment or in women who are clomifene resistant, as it is not licensed for use in pregnancy. There is, however, no evidence of animal or human fetal teratogenicity with metformin. For example, metformin has been used in the treatment of type 2 diabetes mellitus in pregnant women, with no increase in the incidence of major congenital anomalies when compared with untreated pregnant women with type 2 diabetes. 24 Metformin therapy has been advocated to reduce miscarriage rates in women with PCOS, although the basis of the link between miscarriage and PCOS is controversial. Evidence in support of a reduction in miscarriage rates can be found in two retrospective analyses which showed that metformin reduced first-trimester spontaneous miscarriages in women with PCOS. 25,26 In both these studies, the women con- 149

6 INITIAL ASSESSMENT History Physical examination Baseline investigations GENERAL ADVICE Folic acid Stop smoking and alcohol Weight loss (BMI>30) METFORMIN MONOTHERAPY Start metformin if renal function normal Titrate dose to reduce GI side effects NOT EFFECTIVE Continue metformin: 6 12 months EFFECTIVE Stop metformin once pregnancy confirmed Add clomifene for 6 ovulatory cycles Ultrasound monitoring EFFECTIVE Stop metformin clomifene therapy once pregnancy confirmed NOT EFFECTIVE Stop metformin clomifene combination therapy after 12 cycles Consider gonadotrophin or ovarian drilling In vitro fertilisation Key GI = gastrointestinal Figure 1. Suggested algorithm for the management of infertility in women with PCOS ceived while taking metformin and continued the treatment during the pregnancy with no associated fetal anomalies. On the other hand, a prospective trial by Heard et al. 27 did not find the same beneficial effect of metformin in reducing early pregnancy losses. Metformin therapy has also been shown to reduce the risk of gestational diabetes in women with PCOS. In a retrospective study, Glueck et al. 28 showed that metformin use throughout pregnancy was associated with a ten-fold decrease in the development of gestational diabetes in nondiabetic women with PCOS. However, metformin therapy should not be recommended to reduce miscarriage rates and gestational diabetes in infertile women with PCOS until more robust research data are available. Suggested algorithm for the use of metformin in the management of infertility in women with PCOS There are various existing algorithms for the management of ovulation induction in women with PCOS. 29,6 The National Institute of Clinical Excellence (NICE) 30 has developed guidelines on assessment and treatment for couples with infertility problems.these guidelines suggest that metformin is considered as a second-line therapy, after the use of clomifene for up to

7 cycles. However, given the drawbacks of clomifene and the reported effectiveness of metformin in the induction of ovulation, firstline use as illustrated in Figure 1 potentially reduces the number of clomifene cycles to which women with PCOS are exposed. Following 6 months of metformin monotherapy, clomifene can be added to metformin and combined treatment offered for another 6 months. Decisions on lengthening the duration of therapy should be individualised, taking into account the risks of ovarian cancer with longterm clomifene use. Following 12 months of metformin and combined metformin clomifene use, second-line therapies such as gonadotrophins and ovarian drilling should be considered. Conclusion Indirect evidence from improved ovulation rates, when metformin is either used alone or in combination with clomifene, would suggest that first-line metformin use is reasonable, particularly in the context of the hazards of firstline clomifene use (ovarian cancer and multiple pregnancy). Metformin can be offered to women with PCOS who are anvolulatory, whether obese or non-obese. The daily dose of metformin should be titrated to minimise gastrointestinal adverse effects and improve compliance. Where ovulation is documented, metformin can be used for 6 12 months but, if not successful, combined treatment with clomifene should be considered. Metformin should be stopped as soon as pregnancy is confirmed, as it is currently not licensed for use during pregnancy. A large and properly conducted randomised controlled trial is required to determine clearly whether first-line metformin monotherapy results in equal or better pregnancy and live birth rates compared with clomifene. 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