Aromatase inhibitors for subfertile women with polycystic ovary syndrome
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objectives of this systematic review are to evaluate the effectiveness and safety of use of aromatase inhibitors for subfertile women with PCOS.
Background
Description of the condition
Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea), affecting about 4‐8% of women worldwide in their fertile years Abu 2012.
The diagnosis can be made based on the “Rotterdam criteria 2003”, jointly proposed by European Society for Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine Rotterdam 2003. The woman must have two of the following three criteria to be diagnosed with PCOS.
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Oligoovulation (infrequent ovulation) and/or anovulation (absence of ovulation).
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High male hormone levels (hyperandrogenism) diagnosed either clinically (excessive hair growth, hirsutism) or biochemically (raised serum testosterone levels).
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Ovaries which appear to be polycystic on vaginal sonogram defined by the presence of 12 or more antral follicles in an ovary or an ovarian volume of >10mL. Antral follicles are defined as measuring between 2 and 9 mm in diameter.
However, the exact mechanisms causing polycystic ovary syndrome remain unknown.
Description of the intervention
There are many possible options for treatment. Clomiphene citrate (a selective oestrogen receptor modulator or SERM) is the most common medication used for treating this condition. Clomiphene citrate (CC) is a selective oestrogen receptor modulator that was firstly introduced in 1960 for treatment of World Health Organisation (WHO) type II anovulation (a type of subfertility where hormone levels remain to be normal) in subfertile women and it has been first line treatment since that date. CC is given orally and it is relatively safe and inexpensive, but there are also adverse effects found with CC. In particular, negative changes in endometrium and cervical mucus due to down‐regulation of oestrogen receptors can be found, which might impair implantation after successful induction of ovulation Casper 2006.
Aromatase inhibitors (AIs) are a novel class of drugs that were introduced for ovulation induction in 2001 by Mitwally and Casper Mitwally 2001. Over the last ten years data from many clinical trials have been collected and there is evidence that the aromatase inhibitor letrozole might be as effective as clomiphene citrate, but the outcome data vary. Aromatase Inhibitors, like clomiphene citrate, are administered orally, but due to their short half‐life elimination time of 48 hours there are fewer adverse effects on oestrogen target tissues such as endometrium and cervix compared to clomiphene citrate Baruah 2009; Jirge 2010; Samani 2009. In 2005 a study published by Biljan et al. including 150 babies raised some concerns about teratogenicity of letrozole, but there were major methodological flaws in this study as the intervention group was not well controlled Biljan 2005. Furthermore, two other large studies including 911 and 470 infants compared use of letrozole to CC and spontaneously conceiving women. Both reported no higher levels of minor or major congenital malformations or cardiac abnormalities in newborns after usage of letrozole for ovulation induction Forman 2007; Tulandi 2006. Additionally, due to the short half‐life elimination time of letrozole it should be completely cleared out of the system before implantation takes place. Some authors recommend to test the blood levels of ß‐hCG prior to treatment with letrozole to exclude pregnancy Casper 2011.CC and AIs are usually both given for five days starting on day 3 of the cycle. The doses for CC and letrozole range from 50mg to 150mg per day and 2.5mg to 7.5 mg per day, respectively Lee 2011.
Since many women with PCOS experience insulin resistance or impaired glucose tolerance, metformin and other insulin‐sensitising agents were thought to be a superior drug for treatment of ovulation induction Velázquez 1997. However, the latest version of the Cochrane Review on oral agents for ovulation induction concluded that the use of metformin and other insulin‐sensitising agents as an adjunct is limited and might be favourable only in patients who are resistant to CC alone Brown 2009.
Human menopausal gonadotrophins (hMG) for ovulation induction were introduced into clinical practice in 1961. They have a central role in ovulation induction in subfertile women with normal hormone levels (normogonadotropic anovulatory women) who were clomiphene citrate resistant Lunenfeld 2004. However, women with PCOS are at particular risk for complications and a low‐dose step‐up protocol was introduced to reach the FSH (follicle stimulating hormone) threshold gradually in order to minimize the risk of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies White 1996.
Another possible option for ovulation induction in case of clomiphene resistance is laparoscopic ovarian diathermy (or drilling). These techniques damage localized areas in the ovarian cortex and stroma and seem to have similar success rates as gonadotropin therapy Farquhar 2002. However, it is unknown how partial destruction of the ovary results in follicle development and ovulation induction.
How the intervention might work
Aromatase inhibitors down‐regulate the production of oestrogen by inhibiting the cytochrome P450 isoenzymes 2A6 and 2C19 of the aromatase enzyme complex Cole 1990. They inhibit the negative feedback loop of oestrogen in the hypothalamus and result in stronger gonadotropin releasing hormone (GnRH) pulses. The elevated levels of GnRH stimulate the pituitary gland to produce more follicle stimulating hormone (FSH), which induces development of follicles in the ovaries. Because AIs do not deplete oestrogen receptors, in contrast to CC, the central feedback mechanism remains intact and as the dominant follicle grows and oestrogen levels rise, normal negative feedback occurs centrally. This results in suppression of FSH and the smaller growing follicles will undergo atresia, leading to a single dominant follicle and monoovulation (ovulation of a single egg) in most cases Casper 2006; Lee 2011. Therefore, by leaving the central mechanism intact, AIs might lower the risk of high multiple ovulation and OHSS compared to CC.
Why it is important to do this review
Because evidence for and against the effectiveness and safety of these agents has fluctuated over the last decade and new data based on recent randomised controlled trials have become available, a systematic Cochrane Review is necessary to provide up to date information for daily practice. Therefore, this review aims to evaluate the effectiveness and safety of aromatase inhibitors compared to other agents for ovulation induction or laparoscopic ovarian drilling, to provide evidence as to whether or not AIs should be used as first‐line treatment.
Objectives
The objectives of this systematic review are to evaluate the effectiveness and safety of use of aromatase inhibitors for subfertile women with PCOS.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCT) will be considered for inclusion in the review. Quasi‐randomised trials will be excluded. Cross‐over trials will be excluded unless phase one data are available separately, because treatment success in pregnancy and live birth precludes a "cross over".
Types of participants
Women of reproductive age with WHO type II anovulation (women with normogonadotropic normoestrogenic anovulation) due to polycystic ovary syndrome (PCOS), diagnosed according to the Rotterdam Criteria 2003, the NIH consensus criteria or the AES criteria.
Exclusion criteria
Women with hyperprolactinaemia or Cushing’s syndrome, or both, will be excluded and trials which report on women with these two conditions will be excluded from the review. Trials containing women with WHO type I anovulation will also be excluded (hypogonadotropic hypogonadal anovulation: women in this group have amenorrhea, low or low‐normal serum follicle‐stimulating hormone (FSH) concentrations and low serum estradiol concentrations due to decreased hypothalamic secretion of gonadotropin‐releasing hormone (GnRH) or pituitary unresponsiveness to GnRH). Studies using methods other than ovulation induction will also be excluded, for example IUI or IVF.
Types of interventions
Aromatase inhibitors (AIs) for ovulation induction (alone or in conjunction with medical adjuncts, e.g. metformin, FSH) in anovulatory infertility will be considered for inclusion in the review. AIs will be compared to each other and to other choices of treatment, including CC, tamoxifen, recombinant and urinary gonadotropin (FSH), insulin‐sensitizing agents such as metformin and laparoscopic ovarian drilling.
Types of outcome measures
Primary outcomes
Effectiveness:
1. Live birth rate per woman randomised.
Adverse effects:
2. Ovarian hyperstimulation syndrome (OHSS) rate per woman randomised, defined according the definition adopted by the reporting authors.
Secondary outcomes
3. Clinical pregnancy rate per woman randomised, where clinical pregnancy will be defined as the presence of a gestational sac on ultrasound.
4. Miscarriage rate per woman randomised, where miscarriage will be defined as the involuntary loss of a pregnancy before 20 weeks gestation.
5. Miscarriage rate per pregnancy, where miscarriage will be defined as the involuntary loss of a pregnancy before 20 weeks gestation.
6. Multiple pregnancy rate per woman randomised, where multiple pregnancy will be defined as more than one intrauterine pregnancy.
Search methods for identification of studies
We will search for all published and unpublished RCTs studying use of AIs in anovulatory women with PCOS. The following search
strategy will be used, without language restriction. The Cochrane Menstrual Disorders and Subfertility Group (MDSG) Trials Search Co‐ordinator will be consulted.
Electronic searches
1. Menstrual Disorders and Subfertility Group Specialised Register (MDSG) (inception to present) (Appendix 1)
2. The Cochrane Central Register of Controlled Trials (CENTRAL) (inception to present, Appendix 2)
3. MEDLINE(R) In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) (inception to present, Appendix 3)
4. EMBASE (inception to present, Appendix 4)
5. PsycINFO (inception to present, Appendix 5)
The MEDLINE search will be combined with the Cochrane highly sensitive search strategy for identifying randomised trials which appears in The Cochrane Handbook of Systematic Reviews of Interventions (Version 5.1.0 chapter 6, 6.4.11) The EMBASE search is combined with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) http://www.sign.ac.uk/mehodology/filters.html#random There is no language restriction in these searches.
Searching other resources
The references of relevant systematic reviews and RCTs obtained by the search will be looked through manually and experts in the field and manufacturers of aromatase inhibitors will be contacted personally to pick up any additional, relevant data. Additionally, the databases of the WHO, clinicaltrials.gov, web of knowledge, PubMed and LILACS will also be searched.
Data collection and analysis
Data collection and analysis will be conducted in accordance with The Cochrane Handbook for Systematic Reviews of InterventionsHiggins 2011.
Selection of studies
The trials to be included will be independently selected by two review authors (SF, WN or CF) in accordance with the aforementioned criteria. Trials will be excluded from the systematic review if they made comparisons other than those specified above. Studies from non‐English language journals will be translated if necessary. If a specific trial was published more than once we will only include the most complete and up to date data. Authors of primary studies will be contacted if papers contained insufficient information to enable an accurate assessment of eligibility for inclusion. We will also provide a list of excluded studies and the reasons for exclusion will be shown in the ’Characteristics of excluded studies’ table.
Data extraction and management
The data obtained will be extracted by two review authors independently and any disagreement between these review authors will be resolved by a third review author. Extraction of the data from eligible studies will be done by using a data extraction form designed and pilot‐tested by the authors. If studies have multiple publications, only the main trial report will be included. The review authors will contact study investigators to resolve any data queries, as required.
Assessment of risk of bias in included studies
Included studies will be assessed for risk of bias, using the Cochrane risk of bias tool. Seven domains of possible biases will be assessed, including:
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Random sequence generation
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Allocation concealment
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Blinding of participants and personnel
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Blinding of outcome assessment
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Incomplete outcome data
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Selective reporting
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Other bias
The different types of biases will be judged using the criteria from the Cochrane Handbook Table 8.5.d: Criteria for judging risk of bias in the ‘Risk of bias’ assessment tool Higgins 2011. The seven domains of biases will be evaluated by two authors independently as "high risk of bias", "low risk of bias" or "unclear risk of bias". The assessments made by the two review authors will be compared and any disagreements resolved by consensus or by discussion with a third review author. The conclusions will be presented in the ’Risk of bias’ table and will be incorporated into the interpretation of review findings by means of sensitivity analyses.
Measures of treatment effect
Where dichotomous data measures are used we will express the results in the control and intervention groups of each study as Peto odds ratios (OR) with 95% confidence intervals (CI). Based on the specified outcomes there will be no continuous data measures.
Unit of analysis issues
The primary analysis will be per woman randomised.
Dealing with missing data
If data are missing from included studies, the original investigators will be contacted to request the relevant missing data. In case this will not be possible, we will impute individual values for the primary outcomes only. In participants without a reported outcome we are will assume that live births have not occurred. For other outcomes only the available data will be analysed. Any imputation undertaken will be subjected to sensitivity analysis. The data will be analysed on an intention‐to‐treat (ITT) basis, as far as possible.
Assessment of heterogeneity
The results of the different trials will be tested for heterogeneity by measuring the scatter in the data points on the graph and the overlap in their confidence intervals. This will be done by using I2 statistics which describe the percentage of total variation across the trials that is due to heterogeneity rather than chance Higgins 2011. The values of the I2 statistics will lie between 0% (no heterogeneity) and 100% (heterogeneity). Values above 50% will be taken to indicate substantial heterogeneity. Any data with substantial heterogeneity will be explored in sensitivity analyses to detect possible explanations for the heterogeneity.
Assessment of reporting biases
In view of the difficulty of detecting and correcting for publication bias and other reporting biases, 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. We will compare all outcome measures stated in the methods section to the outcomes reported in the results section to ensure comparability.
If there are at least 10 trials included in the study a funnel plot will be produced.
Data synthesis
If the studies are sufficiently similar we will use a fixed‐effect model to combine the data from the primary studies. Statistical analysis will be performed with Review Manager 5 in accordance with the guidelines for statistical analysis developed by The Cochrane Collaboration Higgins 2011.
Our comparisons will be:
1. Aromatase inhibitors compared to placebo;
2. Aromatase inhibitors compared to other ovulation induction agents;
3. Aromatase inhibitors with adjuncts compared to other ovulation induction agents;
4. Aromatase inhibitors compared to laparoscopic ovarian drilling;
5. Letrozole compared to anastrozole;
6. Five days administration compared to 10 days administration protocol of letrozole; and
7. Dosage studies of aromatase inhibitors
Beneficial increases in the odds of an outcome (e.g. live birth) will be shown in the forest plots of the meta‐analysis on the right of the centre‐line. Detrimental increases in the odds of an outcome (e.g. ovarian hyperstimulation syndrome) will be shown in the forest plots of the meta‐analysis on the left of the centre‐line.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis will be done to evaluate the evidence within the following subgroups, if enough data are available for subgrouping:
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mean BMI (study groups with a mean BMI ≤ 25kg/m² compared to study groups with a mean BMI > 25kg/m²)
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mean age (study groups with a mean age of 33 years or younger compared to study groups with a mean age older than 33)
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clomiphene resistant patients (defined as non‐responders to clomiphene citrate within three cycles, including one cycle at a dose of 150 mg/day for 5 days) compared to primary drugs‐based infertility treatment
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primary compared to secondary infertile patients (if separated in the study population)
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doses of aromatase inhibitors given
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2.5 mg (low dose)
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5 mg (medium dose)
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7.5 mg (high dose)
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duration of treatment (5 or 10 days)
Sensitivity analysis
A sensitivity analysis will be done for all our outcomes to determine if the conclusions are stable to arbitrary decisions made regarding the eligibility and analysis. Specifically, we will do sensitivity analyses to see if the conclusions of our review would have differed if eligibility were restricted to studies without high risk of bias, a random effects model had been used, alternative imputation strategies had been used or if the summary effect measure was relative risk rather than odds ratio.
Overall quality of the body of evidence: Summary of Findings Table
A Summary of findings table will be generated using GRADEPRO software. This table will evaluate the overall quality of the body of evidence for main review outcomes, using GRADE criteria (study limitations (i.e. risk of bias), consistency of effect, imprecision, indirectness and publication bias). Judgements about evidence quality (high, moderate or low) will be justified, documented, and incorporated into reporting of results for each outcome.
