METFORMIN IN THE TREATMENT OF INFERTILITY IN PCOS
THE ROLE OF METFORMIN IN THE TREATMENT OF INFERTILE WOMEN WITH POLYCYSTIC OVARY SYNDROME
THE ROLE OF METFORMIN IN THE TREATMENT OF INFERTILE WOMEN WITH POLYCYSTIC OVARY SYNDROME
Anju Sinha & Mr William Atiomo. 2004.
Polycystic ovary syndrome (PCOS) affects 5-10% of women in the reproductive age group (1) and is the commonest cause of anovulatory infertility (2). It is characterised by a myriad of symptoms and signs which include menstrual disturbances, hyperandrogenism, hirsuitism, obesity, infertility, insulin resistance and the presence of polycystic ovaries on ultrasound. The aetiology of PCOS is uncertain and hitherto, treatment has mainly been directed at symptom control. Attempts have however been recently made to direct treatment at the underlying mechanisms which are thought to cause infertility in PCOS. This is reflected in the increasing use of metformin, an insulin lowering drug, conventionally used to treat non-insulin 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 (clomiphene). This article argues that these theoretical advantages make metformin use a very attractive first line option for the treatment of infertile women with PCOS in addition to its use in the treatment of clomiphene resistant women and as an adjunct to ovulation induction during assisted conception. The aim of this article is to therefore provide some guidelines for metformin use by practicing gynaecologists. The article starts by briefly reviewing the background literature on metformin before going on to discuss patient selection, indications for treatment, duration of treatment, side-effects and use in pregnancy. The article however concludes by calling for adequately powered trials to evaluate the role of metformin in the first line treatment of women with PCOS. A management algorithm is also provided.
The key rationale for metformin in infertile women with PCOS is the presence of a positive correlation between the degree of insulin resistance and anovulatory infertility in these women (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 ( which is 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 (intra-ovarian) protease inhibitor, plasminogen activator inhibitor-one (PAI-1) limiting follicle growth (4). It is thought that Metfomin 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 infertile women with PCOS, potentially, offers real advantages over clomifene the conventional first line treatment by avoiding the increased risk of multiple pregnancies (4-11%), and ovarian cancer (prolonged use more than 12 months) associated with clomiphene . In addition, as metformin reversing 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 use could also in theory potentially avoid the risks and costs associated with second and third line therapies for infertile women with PCOS 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 metfomin in inducing ovulation (5) there is an absence of robust data indicating the true live birth rates in women with PCOS when metformin is used as first line treatment.
How effective is metformin therapy?
Although there have been many studies which have demonstrated the effectiveness of the use of metformin in PCOS, none has directly addressed the question of live birth rates when metformin is used as first-line therapy. The results from the previous studies on metformin use in PCOS and the recent systematic review from the Cochrane collaboration showing improved menstrual cyclicity (6,7) and ovulation rates (8,9) do however indirectly support first-line use. Historically, the first study on metformin in PCOS to be published was an uncontrolled study (10) in 1994, where 26 obese women with PCOS were treated with metformin at a dose of 500 mg three times daily for 8 weeks. In the study, metformin resulted in three spontaneous pregnancies and menstrual cycles were normalized in another seven women. Metformin also improved insulin sensitivity, lowered serum LH, total and free testosterone concentrations and caused an elevation in serum FSH and sex hormone-binding globulin. This study however paved the path for many more trials on the metabolic and clinical effect 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 11 randomised controlled trials where the effect of metformin (alone or with clomiphene) on menstrual function, ovulation and pregnancy had been evaluated (table 1) and a recent systematic review from the Cochrane Collaboration. Although there was 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 patients with PCOS (11,12). This effect was also seen when metformin was added to clomifene in clomifene resistant women (13,14,15) . More indirect support for the first-line use of metfomin in PCOS can also be found in the results of the systematic review published by the Cochrane collaboration (subsequently published in the British Medical Journal in October last year 5 . In a meta-analysis of 13 randomised controlled trials, metformin was shown to be effective in achieving ovulation in women with PCOS, with odds ratio of 3.88 (95% confidence interval 2.25 to 6.69) for metformin compared with placebo and 4.41 (2.37 to 8.22) for metformin and clomifene compared with clomifene alone. With regard to clinical pregnancy rates, although five trials, which compared metformin to placebo did not show any significant difference, there were questions raised about the possibility of publication bias. When all of the five trials comparing metformin with clomifene were analysed, there was significant benefit from metformin and clomifene compared to clomifene alone (OR 4.88, 95% CI 2.46 to 9.67). However four of these five trials recruited women who were previously resistant to clomifene, 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 clomiphene resistant women and or combination with clomiphene support a role for metformin therapy as first-line treatment of anovulatory PCOS. The following sections therefore provide some practical guidelines for how it should be used in practice.
General principles of investigating couples with infertility where PCOS may be a contributory factor, prior to metformin therapy.
Prior to commencing first-line metformin therapy in infertile women with PCOS, the general principles of management include a careful synthesis and analysis of the information obtained from a detailed history, physical examination and the results of investigations undergone by the couple. The history should as a minimum assess the duration of infertility, type of infertility (primary or secondary infertility), menstrual history (dysmenorrhoea, dyspareunia, discharge), sexual history (coital frequency), medical and surgical history, drug history and social history (alcohol, smoking, occupation). A physical examination of the couple should be performed to assess the body mass index, perform a chlamydia screen or cervical smear if needed and assess the pelvic organs in the female and testicular volume and penile urethra in the male.
The following baseline investigations, should be encouraged as a minimum: follicle stimulating hormone (FSH) and luteinising hormone (LH) level on day 2-4, a day 21 progesterone, a rubella titre, a test of tubal patency (hysterosalpingogram, Hystero-Contrast-Sonography (HyCoSy) or laparoscopy and dye test) and two semen analysis. To confirm the diagnosis of PCOS in anovulatory women, a hormonal profile including testosterone, sex hormone binding globulin, prolactin, thyroid function tests, 17-hydroxy-progesterone and pelvic ultrasound should be performed. 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 Rotterdam ESHRE/ASRM sponsored PCOS consensus definition. These three criteria are Oligo-and/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 is sufficient for diagnosis) measuring 2-9 mm in diameter, and/or increased ovarian volume (ƒ® 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).
Baseline investigations required in infertile women with PCOS going on metformin:
Before prescribing metformin, renal and hepatic function should be checked as metformin can very rarely cause lactic acidosis in the presence of even mild renal impairment. Annual testing of renal and hepatic function is also indicated, once on metformin therapy. An oral glucose tolerance test and fasting lipids should also ideally be checked as women with PCOS are at higher risk of being diabetic and having an atherogenic lipid profile. The oral glucose tolerance test should be repeated during any successful pregnancies following metformin treatment as women with PCOS are more likely to develop gestational diabetes (20)
Use of metformin in pregnancy:
Metformin therapy, treatment should be discontinued once pregnancy is confirmed whether it is being used as first line treatment or in clomiphene resistant women, as it is strictly speaking 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 non-insulin dependent diabetes mellitus (NIDDM) in pregnant women with no increase in the incidence of major congenital anomalies when compared with untreated pregnant women with NIDDM (22) .
Metformin therapy has actually been advocated to reduce miscarriage rates in women with PCOS although the exact basis of this link between miscarriage and PCOS is controversial (23 ,24) . 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 (23,25) . In both these studies, the women conceived 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., did not find the same beneficial effect of metformin in reducing early pregnancy losses (26). Metformin therapy has also been shown to reduce the risk of gestational diabetes in women with PCOS. In a retrospective study, Glueck et al., 2002 showed that metformin use throughout pregnancy was associated with a ten fold decrease in the development of gestational diabetes in non-diabetic women with PCOS (27). We do not however recommend that metformin therapy is to reduce miscarriage rates and gestational diabetes in infertile women with PCOS until more robust research data is available.
Suggested method for the use of metformin in the management of infertility in women with PCOS:
There are various algorithms already existing for the management of ovulation induction in women with PCOS( Nestler2002, Lord 2003). The national institute of clinical excellence (NICE) (28) has developed guidelines on the assessment and treatment for couples with infertility problems and suggest that metformin is considered second line, after the use of clomiphene for up to 12 cycles. However, given the drawbacks of clomiphene and the reported effectiveness of metformin in the induction of ovulation, first-line use as illustrated in our algorithm potentially reduces the number of clomiphene cycles women with PCOS are exposed to. Following six months metformin monotherapy, clomiphene can be added to metfomin 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 long term clomiphene use. However following 12 months metformin and combined metformin clomiphene use, second-line therapies such as gonadotrophins and ovarian drilling should be considered.
Side effects of MetforminThe main immediate side effects of metformin are gastro-intestinal in nature and include anorexia, nausea, vomiting, diarrhoea. These unwanted side-effects are usually but not always transient. They are quite common with metformin and may persist in some patients, particularly when very high doses such as 3 g daily are given. 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. Long term use may however interfere with vitamin B12 absorption. Hence, it is very important to counsel the patient regarding the side effects before starting treatment.
Metformin may provoke lactic acidosis which is most likely to occur in patients with renal impairment. Metformin must therefore not be used in patients 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 which 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 patient is about to have a hysterosalpingogram to check for tubal patency and resumed after one weeks rest.
This article has explored the background and clinical role of metformin use in women with PCOS and argued for a role in the first-line treatment of women with PCOS Although there is no direct evidence in support of this argument from a randomised controlled trial showing improved live birth rates, indirect evidence from improved ovulation rates when metformin is either used alone or in combination with clomiphene would suggest that first line metformin use is reasonable particularly in the context of the hazards of first-line clomiphene use (ovarian cancer and multiple pregnancy). Metformin can be offered to obese and non-obese anovulatory women with PCOS. The daily dose of metformin should be titrated to minimize gastrointestinal side effects and improve compliance. Where ovulation is documented, metformin can be used for 6-12 months, however if not successful, combined treatment with clomiphene should be considered. Metformin should be stopped as soon as pregnancy is confirmed, as it is currently not licensed for use in pregnancy. A large and properly conducted randomised controlled trial is however required to clearly determine whether first line metformin monotherapy results in equal or better pregnancy and live birth rates compared to clomiphene.
A recent clinical trial in the USA comparing extended release Metformin (once a day) with Clomiphene or combined Metformin and Clomiphene showed that Metformin was not as effective as originally thought when used as first line treatment in women with PCOS trying to conceive. In the study of 626 infertile women, the live birth rates in women on extended release (once a day) Metformin was 7.2% compared to 22.5% in the Clomiphene group and 26.8% in women who were treated with a combination of Clomiphene and Metformin. (Reference: Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Giudice LC, Leppert PC, Myers ER; Cooperative Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007 Feb 8;356(6):551-66.)
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Dose and treatment regimen of metformin treatment.
Recently, a slow release form of metformin (metformin XR) given once a day, has become available in North America (currently not available in the UK) and its effectiveness is being evaluated in a multicenter-randomised trial comparing the effect of clomiphene, metformin and combined clomiphene and metformin on live birth rates in women with PCOS . Although the results of this trial would be very useful (see update below article), it unfortunately will not provide clear evidence of the effectiveness of first-line metformin use as treatment is not being restricted to first-line ovulation induction. In addition, general advice about optimising fertility and written information or useful websites about PCOS should be made available. Couples should be given advice on stopping (or reducing smoking and alcohol intake), pre and peri-conceptional folic acid and weight loss (particularly if the body mass index is greater than 30). Parallel referral to a dietician if facilities are available should be encouraged in obese women.
The optimal period of first-line metformin monotherapy for fertility is debatable given its theoretical safer side effect profile (fewer risks compared with clomiphene). Although the care of each patient 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 six months treatment, clomifene should be added for a further 6 months. This suggestion is based on the results of studies which have shown a rapid return to spontaneous ovulation and normal menstrual rhythm within three months of the start of therapy (7,9) . There also appears to be no correlation between length of trial and proportion ovulating with metformin alone (5) .
Metformin should be stopped once pregnancy is confirmed as it is not licensed for use in pregnancy. Where pregnancy has not occurred, after a year of either metformin alone or metformin-clomifene combination therapy, then alternative treatment namely, laparoscopic ovarian drilling, gonadotrophins or invitro 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 is obtained (serum progesterone or ultrasound) early on in the treatment course as this will inform the need or not to progress to combined clomifene metformin treatment.