Polycystic ovary syndrome (PCOS): metformin

Abstract

Introduction

Polycystic ovary syndrome (PCOS) is classically characterised by an accumulation of incompletely developed follicles in the ovaries due to anovulation. However, since the publication of the Rotterdam criteria, there is acceptance that menstrual cycle and endocrine dysfunction with hyperandrogenism is more important in reaching the diagnosis than ultrasound findings. It is diagnosed in up to 10% of women attending gynaecology clinics, but the prevalence in the population as a whole varies from 10% to 20%, depending on which diagnostic criteria are used. PCOS has been associated with hirsutism, infertility, acne, weight gain, type 2 diabetes, cardiovascular disease (CVD), and endometrial hyperplasia.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of metformin on hirsutism and menstrual frequency in women with PCOS? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2014 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 14 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: metformin compared with placebo/no treatment, metformin compared with weight loss intervention, or metformin compared with cyproterone acetate-ethinylestradiol.

Key Points

Polycystic ovary syndrome (PCOS) is a syndrome of ovarian dysfunction together with established features of hyperandrogenism and morphological polycystic changes in the ovary. It is a condition for which there are disputed diagnostic criterion to confirm clinical diagnosis. However, since the publication of the Rotterdam criteria, there is acceptance that menstrual cycle and endocrine dysfunction with hyperandrogenism are more important in reaching the diagnosis than ultrasound findings.

• Prevalence in the population as a whole varies from 10% to 20%, depending on which diagnostic criteria are used.

• Clinical manifestations of PCOS include infrequent or absent menses and signs of androgen excess, including acne or seborrhoea.

• PCOS has been associated with hirsutism, infertility, insulin resistance, elevated serum luteinising hormone levels, weight gain, type 2 diabetes, CVD, and endometrial hyperplasia.

In this review, we have reported on the effects of metformin on hirsutism and menstrual frequency in people with PCOS compared with placebo/no treatment, weight loss intervention, or cyproterone acetate-ethinylestradiol.

• We have reported on clinical outcomes, such as hirsutism scores, rather than laboratory-based outcomes (such as effects on hormone levels).

In general, we found evidence mainly from small RCTs of limited methodological quality.

Many RCTs reported effects on infertility as their primary outcome, and any data on hirsutism and menstrual effects were more sparingly reported.

We found limited evidence that metformin may improve menstrual frequency compared with placebo.

• Many of the trials also included a diet or a diet plus exercise intervention in both groups.

We found insufficient evidence on the effects of metformin on hirsutism compared with placebo.

Metformin may be associated with an increase of gastrointestinal adverse effects compared with placebo.

We don’t know whether metformin is more effective than a weight loss intervention (diet or diet plus exercise) at improving hirsutism or menstrual frequency.

• We found insufficient evidence from two small RCTs to draw reliable conclusions.

We don’t know how metformin amd cyproterone acetate-ethinylestradiol compare at improving hirsutism and menstrual frequency, as we found little high-quality evidence.

• Metformin may increase gastrointestinal effects (including nausea and diarrhoea) compared with cyproterone acetate-ethinylestradiol, resulting in the need to stop medication.

• However, cyproterone acetate-ethinylestradiol may increase other adverse effects (such as weight gain, high blood pressure, chest pain, and headache) compared with metformin, also resulting in the need to stop medication.

About this condition

Definition

Polycystic ovary syndrome (PCOS; Stein-Leventhal syndrome; sclerocystic ovarian disease) is, by definition, a condition for which there are disputed diagnostic criteria to confirm clinical diagnosis. It is a syndrome of ovarian dysfunction together with established features of hyperandrogenism and morphological polycystic changes in the ovary. The nomenclature of the condition is somewhat misleading, as the ultrasound findings are not a key part of the diagnostic criteria. Clinical manifestations include infrequent or absent menses and signs of androgen excess, which include acne or seborrhoea. Women with PCOS commonly have insulin resistance and elevated serum luteinising hormone (LH) levels, and are at an increased risk of type 2 diabetes and cardiovascular events. In this review, we have included studies in women aged 18 to 45 years, or where the majority of participants are aged 18 to 45 years.

Incidence/ Prevalence

PCOS is diagnosed in 4% to 10% of women attending gynaecology clinics in resource-rich countries, but this figure may not reflect the true prevalence as the criteria used for diagnosis vary. Depending on the diagnostic criteria used, prevalence in the population as a whole varies from 10% to 20%. An international consensus definition of PCOS defined a set of agreed criteria used for diagnosis. Studies since then suggest a greater than 20% incidence and prevalence of PCOS in overweight and obese women.

Aetiology/ Risk factors

The aetiology is unknown. Genetic factors play a part, but the exact mechanisms are unclear. Two studies found some evidence of familial aggregation of hyperandrogenaemia (with or without oligomenorrhoea) in first-degree relatives of women with PCOS. In the first study, 22% of sisters of women with PCOS fulfilled diagnostic criteria for PCOS. In the second study, of the 78 mothers and 50 sisters evaluated clinically, 19 (24%) mothers and 16 (32%) sisters had PCOS. In a study of Dutch women, there was a doubling of the incidence of PCOS in monozygotic twins (though the prevalence was no different to dizygotic twins and the PCOS definition was non-standard). Diagnosis The diagnosis excludes secondary causes, such as androgen-producing neoplasm, hyperprolactinaemia, and adult-onset congenital adrenal hyperplasia. It is characterised by irregular menstrual cycles, scanty or absent menses, multiple small follicles on the ovaries (polycystic ovaries), mild hirsutism, and infertility. Many women also have insulin resistance, acne, and weight gain. Until recently, there was no overall consensus on the criteria for diagnosing PCOS. In some studies, it has been diagnosed based on the ultrasound findings of polycystic ovaries rather than on clinical criteria. An international consensus definition of PCOS has now been published, which defines PCOS as at least two of the following criteria: reduced or no ovulation; clinical and/or biochemical signs of excessive secretion of androgens; and/or polycystic ovaries (the presence of at least 12 follicles measuring 2–9 mm in diameter, an ovarian volume in excess of 10 mL, or both).

Prognosis

There is some evidence that women with PCOS are at increased risk of developing type 2 diabetes and cardiovascular disorders secondary to hyperlipidaemia, compared with women who do not have PCOS. A meta-analysis found a twofold increase in the risk of coronary heart disease and stroke in women with PCOS. However, although there is a higher risk of cardiovascular disorders, there is no apparent increase in risk of mortality. There is some evidence that oligomenorrhoeic and amenorrhoeic women are at increased risk of developing endometrial hyperplasia and, later, endometrial carcinoma.

Aims of intervention

To reduce hirsutism and restore regular menstrual cycle, with minimal adverse effects.

Outcomes

Hirsutism in women with hirsutism, measured by objective scales of reduction in hirsutism such as the Ferriman-Gallwey Scale, which quantifies the extent of hair growth in nine anatomical sites, scoring 0 (no hair) to 4 (maximal growth), with a maximum score of 36; personal perception of reduction in hirsutism. Menstruation frequency in women with oligomenorrhoea. Adverse effects. We have also reported on clinical outcomes that matter to people, rather than laboratory-based outcomes such as effects on hormone levels.

Methods

BMJ Clinical Evidence search and appraisal May 2014. The following databases were used to identify studies for this review: Medline 1966 to May 2014, Embase 1980 to May 2014, and The Cochrane Database of Systematic Reviews 2014, issue 5 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts of the studies identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were: published RCTs and systematic reviews of RCTs in the English language, at least single-blinded for drug interventions. Interventions to achieve weight loss could be unblinded/open. The trials contained 20 or more individuals (10 in each arm), of whom more than 90% were followed up. There was a 3-month minimum length of follow-up for hirsutism outcomes, but no minimum length for other outcomes. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as RRs and ORs. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Polycystic ovary syndrome (PCOS): metformin.

Important outcomes	Hirsutism, Menstrual frequency
Studies (Participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of metformin on hirsutism and menstrual frequency in women with PCOS?
4 (unclear; no more than 190)	Hirsutism	Metformin versus placebo (with or without lifestyle intervention)	4	–2	0	–2	0	Very low	Quality points deducted for sparse data and incomplete reporting of results; directness points deducted for no direct statistical analysis between groups and for co-intervention (diet)
9 (546)	Menstrual frequency	Metformin versus placebo (with or without lifestyle intervention)	4	–1	–1	–1	0	Very low	Quality point deducted for incomplete reporting of results; consistency point deducted for statistical heterogeneity among RCTs; directness point deducted for co-intervention (diet)
2 (117)	Hirsutism	Metformin versus cyproterone acetate-ethinylestradiol	4	–2	0	–1	0	Very low	Quality points deducted for sparse data and incomplete reporting of results; directness point deducted for no statistical analysis between groups
2 (unclear; no more than 140)	Menstrual frequency	Metformin versus cyproterone acetate-ethinylestradiol	4	–2	0	–2	0	Very low	Quality points deducted for sparse data and incomplete reporting of results; directness points deducted for no statistical analysis between groups in 1 RCT and unclear outcome in 1 RCT
1 (46)	Hirsutism	Metformin versus weight loss intervention	4	–2	0	–2	0	Very low	Quality points deducted for sparse data and incomplete reporting of results; directness points deducted for no direct statistical analysis between groups and unclear outcome measurement
2 (unclear)	Menstrual frequency	Metformin versus weight loss intervention	4	–2	0	–1	0	Very low	Quality points deducted for incomplete reporting of results and weak methods; directness point deducted for unclear outcome measurement

We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Ferriman-Gallwey Scale

Hirsuitism scale that quantifies the extent of hair growth in nine anatomical sites, scoring 0 (no hair) to 4 (maximal growth), with a maximum score of 36.

Hirsutism

The presence of excessive male-pattern hair growth in women on the face, chest, linea alba, or lower back. It usually occurs in women with polycystic ovary syndrome (PCOS), but 'idiopathic hirsutism' may occur in women with regular menstrual cycles and normal circulating androgen levels.

Oligomenorrhoea

Infrequent or scanty menstruation.

Very low-quality evidence

Any estimate of effect is very uncertain.

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