1 Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada, 2 Center for Reproductive Medicine, Weill Sanford Medical College of Cornell University, New York Presbyterian Hospital, New York, NY 10021, USA and3 Ottawa Health Research Institute (OHRI)
4 To whom correspondence should be addressed. Email: skashyap{at}ottawahospital.on.ca
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Abstract |
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Key words: clomiphene citrate/insulin sensitizers/meta-analysis/metformin/polycystic ovarian syndrome
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Introduction |
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Theoretically, metformin reduces the insulin response by decreasing hepatic gluconeogenesis and reducing androgen levels, which allow resumption of normal menstrual cyclicity. Metformin should not confer the same risks of ovarian hyperstimulation and multiple pregnancy as CC since metformin returns patients to spontaneous ovulation not super ovulation. Also, metformin should not have the same negative effects on the cervical mucus and endometrium as CC. Metformin was first suggested as a treatment for ovulation induction in women with PCOS in the early 1990s. The first reports demonstrated resumption of menstrual cyclicity in 21 of 22 patients with PCOS (Velazquez et al., 1994). Since then, many studies have been conducted on small samples of women with PCOS, with the primary outcomes ranging from alteration of metabolic profiles to reinstitution of ovulation (Glueck et al., 1999
). Most of these studies were observational and many retrospective. Several studies have demonstrated positive effects on the surrogate outcomes of metabolites such as androgen level and fasting insulin levels as well as ovulation (Moghetti et al., 2000
). Also, none of the previous studies used pregnancy as a primary outcome.
The objective of this systematic review is to evaluate the available literature, RCT and cohort studies, regarding the use of CC versus metformin for induction of ovulation and achievement of pregnancy. A quantitative summary is provided only where appropriate. This study was done in preparation for an RCT investigating CC versus metformin which was started at our centre in August 2002. Subsequently, our study has been terminated but the Reproductive Medicine Network (funded by the NICHD) has been conducting a RCT investigating metformin, CC, and metformin plus CC. Thirteen centres are involved in the recruitment of 768 patients with oligomenorrhoea, elevated testosterone, normal semen parameters and regular intercourse (23 times/week) who desire pregnancy.
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Materials and methods |
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Search strategy
We used an Ovid vendor and Polaris interface to conduct a computerized literature search of the following seven bibliographic databases: Medline, Premedline, Current Contents, Biological Abstracts, Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and EMBASE. The databases were searched for the last 25 years. MeSH headings and textwords, for databases without MeSH headings, were used. Adjacency operators and truncation were used. A preliminary search was conducted to maximize potential key words. We did not apply a study filter and the search was not limited by language or year of publication (Moher et al., 1996, 2000
; Juni et al., 2002
). The search was run every 3 weeks between August, 2002 and September, 2003 to identify new articles.
A hand search of the following journals was also completed: Fertility and Sterility, Human Reproduction, New England Journal of Medicine, Journal of Clinical Endocrinology, and The Lancet. Online indexing facilitated this process.
To avoid publication bias, we attempted to search for grey literature (McAuley et al., 2000). Two content experts were contacted. No completed alternative studies were identified but an ongoing RCT was identified Results are not available (private communication, Reproductive Medicine Network, http://rmn.dcri.duke.edu/).
Ten years of conference proceedings for the American Society of Reproductive Medicine were also searched. The proceedings for the Canadian Fertility and Andrology Society were searched from 1998 onward. One abstract for a RCT was found (Singh et al., 2001).
The Cochrane Database was also searched for relevant papers. One protocol for a systematic review on the same topic was identified, but no completed review was found (Flight, 2002). The objective of the protocol was to assess multiple drugs of the same family and their effects on PCOS symptoms, sequelae (glucose intolerance, hypertension, cardiovascular disease), and adverse side-effects. This paper has, however, been published subsequently in both the Cochrane Database and the British Medical Journal and is considered in depth and compared to our review in the discussion (Lord et al., 2003
).
Titles and abstracts were screened and articles retrieved if they passed the relevance filter or if there was uncertainty as to whether or not they were relevant. Bibliographies of review articles, systematic reviews and retrieved studies were also searched for candidate articles (Jadad et al., 1998). Retrieved articles were then reviewed for inclusion/exclusion criteria. Those articles that met the criteria were then kept for critical appraisal and data collection.
Reviewers were not blinded at any point to the authors or sources of publication as the evidence for such blinding is weak and the reviewers were likely to be previously familiar with some of the literature (Berlin, 1997).
Inclusion/exclusion criteria
Randomized controlled trials
Study population. The study population consists of women with primary or secondary infertility, between the ages of 18 and 40 years, who have been diagnosed with PCOS by the following characteristics: chronic oligo-ovulation (menstrual cycles less frequent than every 35 days or fewer than six periods per year); infertility; and one or more of the following characteristics: chronic hyperandrogenism (biochemical elevated testosterone, dehydroepiandrosterone, or androstenesdione levels or clinical hirustism or acne); increased LH/FSH ratio >2.5; or ultrasound criteria of PCOS. The study and control groups should have no other infertility diagnosis and preferably would have a documented normal semen analysis.
Intervention: We looked for the following comparisons: Metformin versus placebo; metformin versus CC; metformin plus CC versus placebo plus CC.
Outcome: Two outcomes are assessed: ovulation as determined by serum progesterone level, and pregnancy as determined by urinary or serum hCG.
Cohort studies
Similar inclusion/exclusion criteria were applied but no cohort studies were found that met the criteria.
For studies that resulted in multiple publications, only the most recent or most complete publication was used. Relevant data were collected onto a pre-formed, standard data extraction sheet. The following were recorded: study characteristics (source, language, year, and design); subject characteristics (definition and selection of controls, study subjects, available information on confounders); intervention/exposure information (drug doses and duration); and outcome assessment (methods of ascertainment of exposure or outcome, and time to assessment of outcome).
The Jadad scale was used for quality assessment of RCT (Jadad et al., 1996). Quality assessment involves evaluation of patient selection, assessment of exposure or outcomes, administration of interventions, and controls for confounding factors.
Quantitative data synthesis
Where appropriate, Rev-man 4.1 and Metaview 4.0 have been used to analyse data. A relative risk (RR) estimate, with confidence intervals (CI), was extracted from RCT. We reported the fixed effects model since results did not differ from a random effects model. A 2-test was done to determine the significance of the association. Heterogeneity is determined by the Cochran Q-test. These results are illustrated graphically in the form of a Forrest plot. Funnel plots have been constructed to represent the likelihood of publication bias. The precision of the search is determined by the formula of Normand.
Where appropriate, sensitivity analysis and subgroup analysis were done to determine the significance of contributing factors to the overall results.
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Results |
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Year of publication
All included RCT were published between 1998 and 2002 (Nestler et al., 1998; Moghetti et al., 2000
; Ng et al., 2001
; Singh et al., 2001
; Sturrock et al., 2001
; Vandermolen et al., 2001
; Fleming et al., 2002
; Kocak et al., 2002
).
Quality of publication
The Jadad quality scale for RCTs was applied to all included studies and is shown in Table I (Clark et al., 1999).
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All studies, except Singh et al. (2001), investigated metformin versus placebo. All studies except three used pregnancy as an outcome but only one abstract assessed pregnancy as a primary outcome (Nestler et al., 1998
; Moghetti et al., 2000
; Ng et al., 2001
). All studies except three had infertile, PCOS women as their study population (Nestler et al., 1998
; Moghetti et al., 2000
; Fleming et al., 2002
). Several studies tried to compare metformin plus CC to CC alone or with placebo (Nestler et al., 1998
; Ng et al., 2001
; Vandermolen et al., 2001
; Kocak et al., 2002
). However, all of these studies did so in a sequential manner in those patients who failed to conceive or ovulate with metformin. The duration of intervention and follow-up varies from 1 to 6 months. Table IITable II illustrates the characteristics of these studies. Table III outlines objectives for each study.
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Discussion |
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The evidence that hyperinsulinaemia causes hyperandrogenism, which in turn affects fertility, is more convincing than arguments that hyperandrogenism causes hyperinsulinaemia. Following insulin infusion, adrenal androgen levels rise (Elkind-Hirsch et al., 1991). Conversely, treatment of hyperinsulinaemia with insulin-sensitizing agents or weight loss [5% or body mass index (BMI) <27 kg/m2] decreases androgen levels (Loverro et al., 2002
; Mitkov et al., 2002
). Medically or surgically induced menopause decreases circulating androgen levels without any effect on serum insulin levels (Nagamani et al., 1986
).
Previously, primary therapy PCOS patients involved ovarian drilling, possibly followed by ovulation induction with CC or gonadotrophins (Farquhar et al., 2001). Ovarian drilling was hypothesized to decrease ovarian androgen production. Currently, standard treatment for ovulation induction in these patients is CC. The success rate of CC varies; 80% ovulation and 3040% pregnancy rates have been reported (Gorlitsky et al., 1978
; Lunenfeld et al., 1991
; Kousta et al., 1997
; Imani et al., 1998
, 1999
). Seventy-five per cent of pregnancies are achieved within the first 3 months of an ovulatory dose of CC (Imani et al., 1998
). Some authors have suggested that ovulation induction with CC for a period >6 months in properly selected patients with PCOS can provide a cumulative pregnancy rate >90% (Messinis and Milingos, 1997
). The proposed mechanism of action is that CC is an anti-estrogen which leads to increased production of pituitary production of gonadotrophins (FSH and LH). CC does not address the hyperandrogenic or hyperinsulinaemic environment. CC also has an anti-estrogenic effect on the endometrial lining and cervical mucus. The incidence of multiple pregnancy (mostly twins) with CC is 410% (Kousta et al., 1997
; Eijkemans et al., 2003
). Although the 1% risk of ovarian hyperstimulation sydrome (OHSS) after gonadotrophin therapy may be much less with CC, it may still occur.
Metformin is a biguanide insulin sensitizer. It is labelled as class B in pregnancy. Sufficient human data are not available but the drug has not been associated with congenital defects in animals. It has been used in the treatment of women with diabetes mellitus II without negative effects on the fetus. Recently, small series of women who have taken metformin throughout pregnancy to prevent miscarriage and gestational diabetes have been published and there were no reported defects (Glueck et al., 2002; Jakubowicz et al., 2002
). The mechanism of action is mainly the inhibition of hepatic gluconeogenesis. Metformin also increases peripheral glucose utilization and insulin sensitivity, but it is not associated with hypoglycaemia.
Recently, Lord et al. (2003) published meta-analyses with similar results in both the Cochrane Collaboration and the British Medical Journal. The protocol for their paper was identified during our search but the papers were published after the last search date. While their results concerning ovulation and pregnancy were similar to those reported here, six studies were included in both papers, our paper included two different studies and their paper included five different studies (Nestler and Jakubowicz, 1996
; Moghetti et al., 2000
; El-Biely and Habba, 2001
; Jakubowicz et al., 2001
; Sturrock et al., 2001
; Malkawi and Qulban, 2002
; Yarali et al., 2002
). Two of these five papers were not available to us (El-Biely and Habba, 2001
; Malkawi and Qulban, 2002
). Another evaluated co-administration of metformin during recombinant (r) FSH treatment of patients with CC-resistant PCOS (Yarali et al., 2002
). Two other papers had been initially identified but nothing in their title, abstract or methods suggested relevance (Nestler and Jakubowicz, 1996
; Jakubowicz et al., 2001
). Nevertheless, our results are quite similar (Table IV).
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No RCT directly compared metformin to CC for induction of ovulation and/or attainment of pregnancy. Cohort studies were insufficiently homogeneous to allow quantifiable summary. This review provides level 1a evidence regarding metformin versus placebo for ovulation induction and pregnancy. This study suggests that metformin is superior to placebo for ovulation induction in patients with PCOS but that this benefit is not more pronounced with longer therapy (i.e. >3 months). The definition of PCOS is very important in determining the group of patients who will have an optimal response. Ng et al. (2001) did not find a benefit with metformin. The patients in their study were not overweight (BMI <23 kg/m2) and also were not hyperandrogenaemic as opposed to the other studies where a benefit was found. In a well-defined group of PCOS patients who do not complain of infertility, metformin also has significant advantage over placebo for resumption of ovulation and regulation of menstrual cycles.
Nevertheless, the data so far do not demonstrate a benefit of metformin versus placebo when the outcome considered is pregnancy. The follow-up time to pregnancy was short and, in the quantitatively summarized studies, pregnancy was not the primary outcome nor were these studies powered to assess pregnancy as an outcome. When we compared metformin plus CC to CC or metformin alone, however, there appeared to be a significant benefit of the combination treatment for both ovulation and pregnancy in patients with PCOS who were both hyperandrogenemic and overweight. However, the comparison of metformin with CC versus placebo with CC was done in each of these studies as a sequential study rather than a true RCT or cross-over study.
A need still exists to compare directly metformin and CC as first-line agents for ovulation induction and achievement of singleton pregnancy in patients with well-defined PCOS. PCOS patients may gain more than ovulation induction from metformin therapy, including reduced miscarriage rates, lower incidences of multiple pregnancies, gestational diabetes, and ovarian hyperstimulation, and longer term cardiovascular health benefits. The currently ongoing study (Pregnancy in Polycystic Ovarian Syndrome: PPCOS) is designed to answer the first question and has the potential to provide valuable insight into the clinical management of this elusive syndrome.
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Submitted on February 9, 2004; resubmitted on May 4, 2004; accepted on July 6, 2004.