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Ovarian surgery for symptom relief 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 and harms of ovarian surgery as a treatment for symptomatic relief of hirsutism, acne and menstrual disturbances in women with PCOS.

Background

Polycystic ovary syndrome is one of the most common endocrine disorders in women of childbearing age. Typically women will have menstrual disturbances, increased hair growth, acne and infrequent or absent menstrual periods. The polycystic ovary is characterised by a marked increase in preantral follicles, arranged peripherally around a dense core of stroma or scattered throughout an increased amount of stroma (Balen 2003). Polycystic ovary syndrome (PCOS) affects approximately 10% of women worldwide (Adams 1986; Homburg 2008). Other associated co‐morbidities of PCOS are obesity and metabolic disorders (Kiddy 1992; Giallauria 2008) such as type 2 diabetes and cardiovascular disease (Giallauria 2008).

The Rotterdam meeting in 2003 endorsed a consensus regarding the diagnosis of the syndrome (ESHRE/ASRM PCOS Consensus 2004a; ESHRE/ASRM PCOS Consensus 2004b) and a further meeting in Greece in 2007 proposed evidence‐based management for the treatment of PCOS related subfertility (Thessaloniki ESHRE/ASRM PCOS Consensus 2008). However, very little consensus guidance addresses the management of the non‐fertility related symptoms of this condition.

Description of the condition

The Rotterdam consensus (ESHRE/ASRM PCOS Consensus 2004b) defines PCOS, after the exclusion of related disorders, as a clinical condition exhibiting at least two of the following three features: i) oligo‐ or anovulation (infrequent or absent menstrual periods), ii) clinical or biochemical, or both, signs of hyperandrogenism (typically, hirsutism or acne), or iii) polycystic ovaries on ultrasound.

A proportion of women with PCOS suffer from non‐fertility related symptoms associated mainly with hyperandrogenism. They often present clinically with hirsutism, acne and androgen‐dependent alopecia. Hirsutism in women is defined as an increased growth of terminal hair in a male pattern. The prevalence of clinical signs of hyperandrogenism in women of reproductive age is around 5% to 25% (Azziz 2000). It is characterised biochemically by raised serum concentrations of androgens, particularly testosterone and androstenedione. These features are associated with hypersecretion of luteinising hormone (LH) but with normal or low serum concentrations of follicle stimulating hormone (FSH). In 80% of women with PCOS, the testosterone concentration will exceed the upper limit of 2.4 nmol/l (Taylor 2003). Women with PCOS also often present with menstrual disorders such as menorrhagia and oligomenorrhea. It is estimated that 30% to 70% of women with PCOS are obese (Vrbikova 2009) and many will develop glucose intolerance and type 2 diabetes. Recent studies have also shown that women with PCOS often have higher than normal anti Mullerian hormone (AMH) serum concentrations (Elmashad Al 2011). At present, controversy exists regarding whether the AMH excess in PCOS is secondary to the increase in preantral follicles or whether an intrinsic increase in AMH production by the granulosa cells is the cause of follicular arrest in PCOS. AMH may also be increased because of hyperandrogenism and altered insulin resistance. The non‐fertility clinical implications of increased AMH in women with PCOS has not been fully studied.

Conservative management with advice on lifestyle changes such as dieting and weight loss has variable effectiveness. Medical treatment with hormonal therapy or insulin sensitising agents can be associated with significant side effects and is often contraindicated in women wishing to conceive. Laparoscopic ovarian drilling (LOD) is a surgical alternative to medical treatment of anovulation in women with PCOS and subfertility. However, whilst studies have examined the effectiveness of LOD in relation to the improvement of conception, reports on the effect of LOD on non‐fertility related PCOS symptoms are contradictory.

Description of the intervention

Ovarian wedge resection was first described in 1935 by Stein and Leventhal (Homburg 2008). This surgery was primarily aimed at reducing ovarian mass by bilateral ovarian wedge resections. With the advent of laparoscopic surgery, a variant of the traditional wedge resection was developed using this technique. During LOD, uni‐ or bi‐polar electrocautery at various energy levels for a variable duration is used to puncture four to 10 holes in each ovary. These are typically 2 to 4 mm deep, penetrating into the cortex. The number of puncture holes, the type of energy source and the duration of treatment varies between practitioners. Recent advances in transvaginal hydrolaparoscopy have also allowed ovarian drilling to be performed via the transvaginal route (Gordts 2009), using a hydrolaparoscope or fertiloscope. Ovarian surgery is traditionally performed to induce ovulation in anovulatory women with PCOS. The documented advantage of LOD compared with hormone treatment is the reduction in complication rates associated with ovarian hyperstimulation syndrome (OHSS) and a decreased risk of multiple pregnancy (Farquhar 2007).

How the intervention might work

The mechanism of action of LOD is largely unexplained. Compared to medical treatment, where the treatment effect is dependent on continuous administration of the medication, many LOD induced effects appear to be long term. It is, however, not known whether LOD exerts its action through a direct effect on the ovary or through a systemic endocrine mechanism. LOD has been shown to reduce long‐term androgen serum levels through a number of mechanisms (Amer 2002). The destruction of androgen‐producing ovarian stroma and the subsequent reduction in substrate for steroid aromatisation may contribute to an overall reduction in androgen production, with improvements in acne and hirsutism. High testosterone levels increase terminal hair growth, and therefore 5a‐reductase inhibitors are implemented in the treatment of hirsutism. A more generalized increased 5a‐reductase activity may be important for increased cortisol metabolism in PCOS (Glintborg 2010). In LOD, it has been hypothesized that the drilling of punctures within the androgen‐producing stroma may depress serum androgen concentrations and offer symptomatic relief. A further possible mechanism is an impact of LOD on insulin resistance. Whilst there is currently very little evidence which documents the effect of LOD on metabolic changes and insulin levels in women with PCOS, small studies have shown that LOD (by electrocautery) can reduce insulin resistance in women with PCOS through decreased IRS‐1 Ser312 phosphorylation (Seow 2007). Other more recent studies have also suggested that LOD can decrease AMH concentrations and ovarian stroma blood flow in women with PCOS compared with controls (Elmashad Al 2011).

Why it is important to do this review

The aim of this review is to evaluate the impact of ovarian surgery on symptomatic control of PCOS. Whilst much research has focused on the effect of ovarian surgery in improving fertility in clomiphene resistant women with PCOS, the impact of LOD on symptoms of PCOS has not been reviewed.

Objectives

To assess the effectiveness and harms of ovarian surgery as a treatment for symptomatic relief of hirsutism, acne and menstrual disturbances in women with PCOS.

Methods

Criteria for considering studies for this review

Types of studies

Only randomised controlled trials (RCTs) of surgical intervention for the treatment of symptoms associated with PCOS will be eligible for inclusion. Only pre‐crossover data from cross‐over studies will be included in this study. Other data from cross‐over studies will not be included, even if there is a wash‐out period, as the effect of LOD is long term (for example some women will ovulate regularly after one year).

Types of participants

Women with PCOS (as defined by the Rotterdam Criteria) who are symptomatic with acne, hirsutism or irregular menstrual cycles (anovulation and oligomenorrhoea). Oligomennorhea is defined as a menstrual cycle of > 45 day duration, for the purposes of this review.

Types of interventions

Ovarian surgical interventions for the symptomatic treatment of women with PCOS. Types of comparisons include the following.

1. Surgical (laparotomy or laparoscopy) versus non‐surgical intervention (including placebo or non‐treatment).

2. Comparison between various surgical methods or techniques.

3. Laparotomy versus laparoscopy.

4. Comparing number of drill holes administered.

5. Comparison of various energy modalities for the ovarian drilling procedure (e.g. uni‐ versus bipolar electrocautery, or electrocautery versus laser versus harmonic scalpel).

Types of outcome measures

Primary outcomes

  1. Improvement in menstrual disturbance: number of cycles per year (or other time frame, eg six months)

  2. Androgenic symptoms of PCOS: improvements in hirsutism, acne (as defined by scoring systems such as the Ferriman Galway score (hirsutism), Global Acne Grading Score (GAGS) or the Leeds revised Acne Grading system (LRAGS))

GAGS divides the face, chest and back into six areas identified for assessment: forehead, each cheek, nose, chin, chest and back. Each area is assigned a factor of 1, 2 and 3 based on area. Acne lesions are given a value based on severity: no lesions = 0, comedones = 1, papules = 2, pustules = 3 and nodules = 4. Scores of 1 to 18 are considered mild, 19 to 30 are considered moderate, 31 to 38 as severe and > 39 very severe.

LRAGS assesses acne on the face, chest and back. A scale of 1‐10 is used. 

Secondary outcomes

  1. Harms of surgical intervention: short and long‐term surgical complications

  2. Change in body weight or body mass index

  3. Change in waist circumference

  4. Testosterone levels or free androgen index

  5. Metabolic measures: fasting glucose or insulin levels or haemoglobin A1C (Hb1AC)

  6. Changes in quality of life

Search methods for identification of studies

All published and unpublished RCTs on surgery for PCOS will be sought using the following search strategy, without language restriction and in consultation with the Menstrual Disorders and Subfertility Group (MDSG) Trials Search Co‐ordinator.

Electronic searches

The following electronic databases, trial registers and websites will be searched from inception to present: Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of controlled trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO and CINAHL. The search strategies are detailed in the Appendices: Appendix 1; Appendix 2; Appendix 3; Appendix 4; Appendix 5.

Searching other resources

The reference lists of articles retrieved by the search will be handsearched and personal contact will be made with experts in the field. Any relevant journals and conference abstracts that are not covered in the MDSG Trials Register will be handsearched in liaison with the Trials Search Co‐ordinator.

Data collection and analysis

Data collection and analysis will be conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Selection of studies

The selection of studies will be undertaken by two review authors (KS and YC). The search strategy described previously will be employed to obtain titles and, where possible, abstracts of studies that are potentially relevant to the review. We will aim to be overly inclusive rather than risk losing relevant studies. Studies from non‐English language journals will be translated if necessary. Where more than one publication of a specific trial exists, we will include only that with the most complete and up to date data. Where relevant outcomes are published only in earlier versions, we will use these data and also endeavour to highlight any discrepancies between published versions. Both review authors will independently assess whether the studies are eligible for inclusion, with disagreements being resolved in consultation with a third author (MM). Where papers contain insufficient information to enable an accurate assessment of eligibility for inclusion, we will seek further information from authors.

Data extraction and management

We will design a form to extract data. For eligible studies, at least two review authors will extract the data independently using the agreed form. We will resolve discrepancies through discussion or, if required, we will consult a third author. Data will be entered into Review Manager software (RevMan 5.1) and checked for accuracy. When information regarding any of the above is unclear, we will attempt to contact authors of the original reports for them to provide further details.

Assessment of risk of bias in included studies

We will assess the validity of each study by using the criteria available in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Two review authors will independently assess the quality of all studies deemed eligible for the review, with discrepancies resolved by discussion with MM. The quality items to be assessed will be: allocation (random sequence generation and allocation concealment); blinding of participants and personnel, blinding of outcome assessors; incomplete outcome data; selective reporting; and other bias, as follows:

(1) Random sequence generation (checking for possible selection bias)

We will assess the method as:

  • Low risk of bias (any truly random process e.g. random number table; computer random number generator), i.e. would not allow investigator or participant to know or influence the intervention group before an eligible participant entered the study.

  • Unclear risk of bias, randomisation stated but no available information on method used.

(2) Allocation concealment (checking for possible selection bias)

We will describe for each included study, in sufficient detail, the method used to conceal the allocation sequence and determine whether intervention allocation could have been foreseen in advance of or during recruitment, or changed after assignment.

(3) Blinding (checking for possible performance bias)

We will describe for each included study the methods used, if any, to blind study participants, personnel and outcome assessors from knowledge of which intervention a participant received. Studies will be judged at low risk of bias if they were blinded or if we judge that the lack of blinding could not have affected the results. Blinding will be assessed separately for different outcomes or classes of outcomes. We will assess the methods as:

  • Low, high or unclear risk of bias for participants;

  • Low, high or unclear risk of bias for personnel;

  • Low, high or unclear risk of bias for outcome assessors.

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attritions and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion, where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported, or can be supplied by the trial authors, we will re‐include missing data in the analyses which we undertake. We will assess studies as having low, high or unclear risk of bias.

(5) Selective reporting bias

We will describe for each included study how we investigated the possibility of within‐trial selective reporting bias and what was found.

We will assess the methods as:

  • Low risk of bias (where it is clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review have been reported);

  • High risk of bias (where not all the study’s prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified; outcomes of interest were reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

  • Unclear risk of bias

(6) Other sources of bias

We will describe for each included study any important concerns we have about other possible sources of bias. We will assess whether each study is at low, high or unclear risk of any such bias.

(7) Overall risk of bias

We will assess whether studies are at high risk of bias, according to criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses, see ’Sensitivity analysis’.

Measures of treatment effect

Where dichotomous data are reported then odds ratios will be reported with 95% confidence intervals. For continuous data a mean difference of the values or the change in values from baseline will be reported.

Unit of analysis issues

The primary analysis will be per woman randomised. Data reported that do not allow valid analysis (e.g. "per cycle" rather than "per woman" where women contribute more than one cycle) will be briefly summarised in an additional table and will not be meta‐analysed.

Dealing with missing data

In the event that data are missing or not available, the authors will be contacted to provide further assistance. Where no further information can be obtained this will be discussed by the review authors and stated in the review. The individual weight of missing data will be determined by the review authors. An intention‐to‐treat analysis will be undertaken as far as possible.

Assessment of heterogeneity

We will consider whether the clinical and methodological characteristics of the included studies are sufficiently similar for meta‐analysis to provide a meaningful summary (Hatala 2005). If meta‐analysis is carried out, we will apply Cochrane’s Q test and the I2 statistic to evaluate the extent of variability in results between studies (Higgins 2011).

Assessment of reporting biases

In view of the difficulty in detecting publication bias and other types of reporting bias, the authors will aim to minimise their potential impact by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. If there are 10 or more studies in an analysis, a funnel plot will be used to explore the possibility of small study effects (a tendency for estimates of the intervention effect to be more beneficial in smaller studies).

Data synthesis

We will use fixed‐effect model inverse variance meta‐analysis for combining data where trials examine the same intervention, and where the trials’ populations and methods are judged sufficiently similar. Where we suspect clinical or methodological heterogeneity between studies, sufficient to suggest that treatment effects may differ between trials, we will use a random‐effects model meta‐analysis.

1. PCOS treatment, symptomatic treatment stratified by surgical intervention:

i) low ovarian drill number;

ii) high ovarian drill number;

iii) surgical diathermy;

iv) surgical electrocautery.

2. Ovarian drilling versus alternative treatment:

i) pharmacological intervention;

ii) ovarian wedge resection.

An increase in the odds of a particular outcome, which may be beneficial (for example return of regular menses) or detrimental (for example surgical complications) will be displayed graphically in the meta‐analyses. The aim is to define analyses that are comprehensive and mutually exclusive so that all eligible study results can be fitted into only one of the strata. Comparisons should be specified so that any trials falling within each stratum can sensibly be pooled for meta‐analysis. Stratification is not a requirement but allows consideration of effects within each stratum as well as, or instead of, an overall estimate for the comparison.

Subgroup analysis and investigation of heterogeneity

Where data allow, we will carry out subgroup analyses to explore possible sources of heterogeneity (for example participants, interventions and study quality).

1. Reproductive hormone profiles (e.g. increased free androgen index).

2. Different surgical technique (i.e. laser diathermy versus electrocautery).

Sensitivity analysis

Sensitivity analysis to explore the effect of trial quality assessed by adequate methodology versus poor methodology, where adequate methodology is defined as an adequate randomisation method, adequate allocation concealment, analysis by intention to treat, and losses to follow up of less than 20%.