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Cochrane Database of Systematic Reviews Protocol - Intervention

Lifestyle changes in women with Polycystic Ovary Syndrome

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effectiveness of lifestyle treatment that aims to achieve weight loss in improving reproductive, metabolic, anthropometric and quality of life factors in overweight women with polycystic ovary syndrome (PCOS).

Background

Polycystic ovary syndrome (PCOS) is a common endocrine condition affecting women of reproductive age. Clinically, women can present with variable reproductive and metabolic abnormalities. These include abnormalities with menstruation (anovulation or lack of ovulation and menstrual irregularity), clinical and biochemical hyperandrogenism (elevated circulating androgens and clinical effects of androgens on peripheral tissues) and infertility (Hart 2004). There is also an increase in risk factors for Type 2 Diabetes Mellitus and cardiovascular disease including impaired glucose tolerance, hyperlipidaemia, hypertension, inflammation and subclinical vascular disease (Paradisi 2001; Solomon 1999; Hart 2004; Meyer 2005). The diagnosis of PCOS was previously based on the National Institute of Health (NIH) criteria (Zawdaki 1992) comprising biochemical or clinical hyperandrogenism and anovulatory irregular cycles with the exclusion of related reproductive disorders. According to these criteria, 4‐8% of women exhibit PCOS worldwide (Diamanti‐Kand. 1999; Knochenhauer 1998; Asuncion 2000; Azziz 2004). In 2003, the ESHRE/ASRM international consensus workshop group developed guidelines for a diagnosis of PCOS to be based on presentation with any two of the following three criteria; hyperandrogenism, irregular anovulatory periods or polycystic ovaries on ultrasound, with exclusion of related reproductive disorders (ESHRE/ASRM 2004).

The aetiology of PCOS is unknown although abnormalities in steroidogenesis (the production of steroid hormones including reproductive hormones) and gonadotrophin action (the action of hormones that control reproductive hormone production) are implicated. Insulin resistance (IR) and compensatory hyperinsulinaemia are proposed as significant aetiological factors and are present in a high proportion of lean and overweight women with PCOS (DeUgarte 2005). These play a key role in PCOS through insulin stimulated androgen production by ovarian thecal cells (Barbieri 1986) and decreasing hepatic production of sex hormone‐binding globulin (SHBG) (Plymate 1988) resulting in increased concentrations of total and free androgens. Insulin resistant women with PCOS present with worsened reproductive and metabolic features compared to insulin sensitive women with PCOS (DeUgarte 2005). IR is also further worsened by the presence of overweight (defined as a body mass index (BMI) > 25 kg/m2) and obesity (defined as a BMI > 30 kg/m2) such that women with PCOS are generally more insulin resistant than BMI‐matched control women and IR in lean women with PCOS is further worsened by the presence of IR associated with obesity (Acien 1999). Obese and overweight women with PCOS display worsened clinical reproductive (Balen 1995; Kiddy 1990) and metabolic features (Legro 1999; Ehrmann 2006).

Treatment of PCOS includes normalising biochemical and clinical hyperandrogenism, restoring reproductive function, improving reproductive outcomes and managing metabolic (diabetic and cardiovascular) morbidity and mortality. Treatment of PCOS includes combination oral contraceptives to suppress luteinising hormone and enhance SHBG production, anti‐androgens (spironolactone and flutamide) to inhibit androgen binding to peripheral androgen receptors, 5 alpha‐reductase inhibitors (finasteride) for treatment of hirsutism, glucocorticoids to reduce adrenal androgen levels, ovulation induction agents (clomiphene citrate) and gonadotrophins for the treatment of anovulatory infertility and laparoscopic ovarian surgery (Ehrmann 2005). Where the clinical features of PCOS are worsened by IR or obesity, preventative and therapeutic interventions and use of insulin sensitising agents, including the glitazones and metformin, have increasingly been adopted as preferable pharmacological strategies both in isolation or in combination with other pharmacological options to improve treatment response.

However, use of lifestyle (dietary and/or exercise) interventions to reduce the features of obesity, IR or hyperinsulinaemia are preferable and cost‐effective initial treatment strategies (Clark 1998) compared to surgical and pharmacological options. Furthermore, there is some evidence that women with PCOS have a greater incidence of overweight and obesity compared to the general population (Glueck 2005). As such, weight loss and lifestyle management may be feasible treatments options for a large proportion of women with PCOS.

There are a large number of small uncontrolled trials demonstrating that weight loss achieved through lifestyle management decreases abdominal fat, hyperandrogenism and IR, and improves lipid profiles, menstrual cyclicity, fertility and risk factors for diabetes and cardiovascular disease in overweight women with PCOS (Moran 2003; Clark 1998; Huber‐Buchholz 1999). There is additionally some evidence that exercise interventions can improve metabolic risk factors associated with PCOS, including hypertension, IR and elevated blood glucose, even when no weight loss occurs (Poehlman 2000; Ross 2000). However, there is currently no systematic review assessing the evidence for the effectiveness of lifestyle management in improving reproductive and metabolic features in PCOS. Provision of this evidence has significant implications for the treatment of both short‐term reproductive abnormalities and long‐term metabolic morbidity and mortality in PCOS. The aim of this review was therefore to assess the effect of lifestyle treatment (defined as a dietary, exercise and/or behavioural intervention designed to induce weight loss through an energy deficit) on reproductive, metabolic, anthropometric and quality of life factors in overweight women with PCOS.

Objectives

To assess the effectiveness of lifestyle treatment that aims to achieve weight loss in improving reproductive, metabolic, anthropometric and quality of life factors in overweight women with polycystic ovary syndrome (PCOS).

Methods

Criteria for considering studies for this review

Types of studies

Randomised Controlled Trials (RCT’s) that compare lifestyle intervention to minimal treatment will be considered for inclusion in the review. Cross‐over trials will not be included as the interventions under study are anticipated to have lasting effects. Quasi‐randomised trials will not be included.

Types of participants

Overweight females of reproductive age (postmenarcheal and premenopausal) with PCOS.

Studies using any definition of PCOS or overweight will be included in this review with the trialists definition of PCOS and overweight described.

Exclusion criteria: Conditions with reproductive symptoms similar to PCOS including: congenital adrenal hyperplasia, Cushing Syndrome, hyperprolactinaemia, thyroid disease and androgen‐secreting tumours. Subjects will not be excluded based on ethnicity, Type 2 Diabetes, co‐morbidities or medication use for clinical or metabolic features of PCOS as long as this medication use was not a primary component of the intervention or control arms. Type 2 Diabetes, co‐morbidities or medication use will be noted and the effects on outcome measures assessed.

Types of interventions

Randomised controlled trials (RCT’s) comparing a weight loss lifestyle intervention to minimal treatment. Lifestyle intervention is defined as a weight loss intervention achieved through a structured dietary, exercise or behavioural intervention while minimal treatment is defined as either no treatment or standard unstructured minimal dietary, exercise or behavioural advice. A structured program refers to more than 1 study visit allocated to implementation of the dietary, exercise or behavioural treatment.

This will include trials examining:

  • Weight loss dietary intervention versus minimal treatment

  • Exercise intervention (resistance or aerobic exercise) versus minimal treatment

  • Behavioural management techniques for modifying diet or exercise versus minimal treatment

  • Combination of dietary, exercise and/or behavioural intervention versus minimal treatment.

All study duration lengths over 2 weeks will be included.

Types of outcome measures

Reproductive factors

  • Primary: Fertility outcomes (pregnancy, live birth, miscarriage), menstrual regularity (an initiation of menses or significant shortening of cycle length) and ovulation (number of ovulatory menstrual cycles).

  • Secondary: Total testosterone, sex hormone binding globulin, estimates of free testosterone, and clinical hyperandrogenism (hirsutism assessed clinically and subjectively).

Metabolic factors

  • Primary: Oral glucose tolerance test glucose

  • Secondary: Lipid profile (total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglycerides), fasting glucose and insulin, surrogate measures of IR (oral glucose tolerance test insulin).

Anthropometric factors

  • Primary: Weight, body mass index, adiposity distribution (by measures including waist circumference, waist‐to‐hip ratios)

Quality of life and patient satisfaction (secondary outcome)

Search methods for identification of studies

See: Methods of the review Appendix 1; Appendix 2; Appendix 3; Appendix 4

This review will follow the Cochrane Menstrual Disorders and Subfertility Group Trials Register. The literature search will aim to locate randomised controlled trials reported in all languages.

(1) We will search the Cochrane Menstrual Disorders and Subfertility Group Trials Register. The search strategy was as follows:

Keywords CONTAINS "PCOS" or "polycystic ovary syndrome" or "Polycystic Ovary Syndrome" or Title CONTAINS "PCOS" or "polycystic ovary syndrome" or "Polycystic Ovary Syndrome"  or Title CONTAINS "PCOS" or "polycystic ovary syndrome" or "Polycystic Ovary Syndrome" or Title CONTAINS "PCOS" or "polycystic ovary syndrome" or "Polycystic Ovary Syndrome"  AND Keywords CONTAINS "*Lifestyle" or "lifestyle change" or "lifestyle modification" or "lifestyle program" or "Weight Loss" or "diet therapy" or "diet" or "dietary intervention" or "dietary counselling" or "dietary" or "exercise" or "Exercise Therapy" or "physical performance" or "physical well being" or "behavioral effects" or "behavioral therapy" or Keywords CONTAINS "*Lifestyle" or "lifestyle change" or "lifestyle modification" or "lifestyle program" or "Weight Loss" or "diet therapy" or "diet" or "dietary intervention" or "dietary counselling" or "dietary" or "exercise" or "Exercise Therapy" or "physical performance" or "physical well being" or "behavioral effects" or "behavioral therapy"

(2) We will search the listed electronic databases for studies in all languages using the following terms.

The Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE , CINAHL, EMBASE, PSYCHINFO.

(3) We will handsearch references of relevant reviews, systematic reviews and included studies to locate other potentially eligible studies.

(4) We will search the meta Register of Controlled Trials (http://controlled‐trials.com/mrct/) and the National Institute of Health Clinical Trials register (http://clinicaltrials.gov) for the keywords polycystic ovary syndrome (PCOS).

Data collection and analysis

Statistical analysis will be performed in accordance with the guidelines for statistical analysis developed by the Cochrane Collaboration. Heterogeneity (variations) between the results of different studies will be examined by inspecting the scatter in the data points on the graphs and the overlap in their confidence intervals and, more formally, by checking the results of the chi‐squared tests. Where possible, the outcomes will be pooled statistically. A sensitivity analysis will be performed whereby only studies with a low risk of bias (assessed by allocation concealment) will be assessed in a separate analysis. For dichotomous data, results for each study will be expressed as an odds ratios with 95% confidence intervals and combined for meta‐analysis with RevMan software using the Peto method and a fixed effects model.

For continuous data, results from each study will be expressed as a weighted mean difference (WMD) with 95% confidence intervals and combined for meta‐analysis. Meta‐analytic methods for continuous data assume that the underlying distribution of the measurements is normal. Where data are clearly skewed and results reported in the publication as median and range with non parametric tests of significance, the results will also be reported in the Other Data section of the review.

Selection of studies

The study selection will be undertaken by two reviewers (LJM and SKH), both of who work in the field of lifestyle management of PCOS. The titles and abstracts of articles found in the search will be screened by LJM, who will discard studies that are clearly ineligible but will aim to be overly inclusive rather than risk losing relevant studies. LJM will obtain copies of the full text articles and will make copies for SKH. Both reviewers will independently assess whether the studies meet the inclusion criteria, with disagreements to be resolved by discussion. Further information will be sought from the authors where papers contain insufficient information to make a decision about eligibility.

Data extraction and management

The following information is to be extracted from the studies included in the review and presented in a Table of Characteristics of Included Studies. All data will be extracted independently by two of the authors using forms designed to Cochrane guidelines. Additional information will be sought on trial methodology and/or actual trial data from the authors of trials which appear to meet the eligibility criteria but have aspects of methodology that are unclear or data in an unsuitable form for meta‐analysis. Differences of opinion are to be registered and resolved by consensus.

LJM will then provide SKH with the results sections of the included studies and both reviewers will independently extract information using the proformas designed by the Review Group.  Discrepancies will be resolved by discussion. For each included trial, information will be collected regarding the location of the study, methods of the study (as per quality assessment checklist), the participants (age range, eligibility criteria), the nature of the interventions, and data relating to the outcomes specified above. Where possible, missing data will be sought from the authors.

Assessment of risk of bias in included studies

The quality of all studies that are deemed eligible for the review will then be assessed independently by the two reviewers (LJM and SKH), with discrepancies to be resolved by discussion. The risk of bias in studies will be assessed in the domains of sequence generation, allocation concealment, blinding, incomplete outcome data and selective outcome reporting and will be graded as adequate (A), unclear (B, seek details from author), or inadequate (C), following the detailed descriptions of these categories provided by the Menstrual Disorders and Subfertility Review Group. It is intended to use this grading in investigation of any heterogeneity and in sensitivity analyses. This information will be presented in a table describing the included studies and will provide a context for discussing the reliability of the results. Specifically we will assess:

  • Methods

  • Sequence generation

  • Allocation concealment

  • Blinding

  • Incomplete outcome data

  • Selective outcome reporting

Other study characteristics to be assessed include:

Methods

  • Design

  • Location and setting

  • Losses to follow‐up

  • Non‐compliance

  • Source of funding

Participants

  • Definition of PCOS (used in inclusion criteria and exclusion criteria)

  • Were the inclusion and exclusion criteria for entry clearly defined?

  • Comparable at baseline (age, weight, body mass index (BMI), fasting insulin, fasting glucose, testosterone)

  • Concurrent treatments

  • Number of patients randomised, excluded and analysed

Interventions

  • Type of intervention and control

  • Duration

  • Were the care programs, other than the trial options, identical?

Outcomes

  • Outcomes reported

  • Timing of outcome measurement

Subgroup analysis and investigation of heterogeneity

We plan to perform subgroup analyses for:

1. Duration of intervention (short (2 ‐ 4 weeks), medium (4 weeks ‐ 6 months), long (greater than 6 months)

2. Component of intervention (dietary alone versus exercise alone versus behavioural intervention alone versus combined intervention).

3. Primary fertility outcomes (pregnancy,  live birth and miscarriage) will only be measured in a subgroup of eligible participants actively seeking pregnancy as part of the inclusion criteria. Where individual level data is required for this subgroup analysis, the authors will be contacted.