Gonadotrophins for ovulation induction in women with polycystic ovarian syndrome
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To compare the effectiveness and safety of all gonadotrophins (urinary and recombinant) for ovulation induction in women with PCOS.
Background
Description of the condition
Subfertility occurs in one in 10 couples world‐wide. In about one‐third of cases this is due to anovulation with polycystic ovary syndrome (PCOS). PCOS is characterised by oligo‐anovulation, clinical or biochemical hyperandrogenism and polycystic ovaries (Rotterdam consensus group 2004a; Rotterdam consensus group 2004b). The syndrome affects approximately 6% to 10% of women of childbearing age.
Infertility due to chronic anovulation is the most common reason for women to seek counselling or treatment. The first line of treatment in these women is ovulation induction with clomiphene citrate (CC), with or without metformin. However, about 20% of patients do not ovulate on CC and require alternative ovulation induction strategies. The most common treatment in women with CC‐resistant PCOS is ovulation induction with gonadotrophins (Hull 1987). A recent review showed that laparoscopic electrocautery of the ovaries is an effective alternative treatment (Farquhar 2012).
Description of the intervention
The strategy of stimulating the ovaries with exogenous gonadotrophins for ovulation induction in women with CC‐resistant PCOS is well established. Gonadotrophins were originally extracted from pituitary glands (Gemzell 1958) and later extracted from the urine of post‐menopausal women (Lunenveld 1960).
Over the last five decades, various urinary‐derived follicle stimulating hormone (FSH) products, or urofollitropins, have been developed. Menotropin (human menopausal gonadotrophin (HMG)) has been available since the early 1960s and contains FSH, luteinising hormone (LH) and large quantities of potentially allergenic urinary proteins. Purified urofollitropin (FSH‐P) has been available since the mid‐1980s. FSH‐P is devoid of LH but still contains urinary proteins. Highly purified urofollitropin (FSH‐HP) has been available since the mid‐1990s and contains very small amounts of urinary proteins. The absence of urinary proteins diminishes rare adverse reactions such as local allergy or hypersensitivity (Albano 1996; Biffoni 1994). The most recent development in urinary gonadrotrophins is highly purified menotropin (HP‐HMG), containing equal amounts of FSH and LH activity. FSH‐HP and HP‐HMG can be administered subcutaneously.
To obtain even higher purity, gonadotrophins were developed using recombinant DNA technology (recombinant FSH (rFSH)) in 1988 (Howles 1996; Keene 1989). The production of rFSH is independent of urine collection, thus guaranteeing a high availability of a biochemically pure FSH preparation that is free from LH and urinary protein contaminants. The production process also yields FSH with high specific bioactivity (roughly 100 times higher than for urine‐derived FSH products), minimal batch‐to‐batch discrepancies (Bergh 1999) and low immunogenicity, which allows subcutaneous administration.
At present two preparations of rFSH are available, follitropin alpha and follitropin beta. Both preparations are similar to pituitary and urinary FSH, although they show minor differences in the structure of the carbohydrate side chains and contain more basic and fewer acidic isohormones than the urinary‐derived gonadotrophin preparations (de Leeuw 1996; Hard 1990; Lambert 1995). In this respect the bioactivity of the various gonadotrophins may play an important role. FSH is found in the pituitary gland and in the circulation in different molecular forms. This molecular heterogeneity is due to the variation in the structures of the carbohydrate moieties, in particular of sialic acid. It is the configuration of these carbohydrate moieties that determines the FSH isoform. The configuration depends on which glycosylation enzymes are available in the cell during synthesis (Wide 1997). Each molecular glycoform has a different molecular weight, net charge, circulating half‐life and metabolic clearance (Baenziger 1988; Gray 1988; Stockell Hartree 1992; Wilson 1990).
The rFSH has a higher bioactivity. As a result less rFSH might be needed for successful ovulation induction.
How the intervention might work
In the follicular phase of a normal menstrual cycle a cohort of 10 to 20 antral follicles develops. Of this cohort only one follicle will obtain dominance over the others and will continue to grow until ovulation takes place. In women with PCOS this dominance does not occur. The aim in ovulation induction is to induce growth of up to three follicles. This is accomplished by ovarian stimulation with FSH containing gonadotrophins. A too forceful protocol will result in overstimulation and hence in ovarian hyperstimulation syndrome (OHSS); a stimulation protocol with a too low dosage of FSH will not result in a leading follicle. The dosage regimen and effectiveness of the various gonadotrophins is therefore important.
Why it is important to do this review
Gonadotrophins are frequently used for ovarian hyperstimulation in assisted reproductive cycles as well as for ovulation induction in PCOS women. A Cochrane review suggested that urinary‐derived and recombinant gonadotropins are equally effective and safe (van Wely 2011). The present review is an update and extension of two previous out‐dated Cochrane reviews (Bayram 2001; Nugent 2000). Bayram 2001 had compared rFSH with FSH‐P and FSH‐HP; Nugent 2000 had compared HMG with purified FSH. No Cochrane review has yet compared HMG with rFSH. Summarising the evidence will show what is known about the effectiveness and safety of the different gonadotrophins and hence will help fertility experts and women to make informed decisions on their use for ovulation induction.
Objectives
To compare the effectiveness and safety of all gonadotrophins (urinary and recombinant) for ovulation induction in women with PCOS.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials will be included. Quasi‐randomised controlled trials in which allocation was, for example by alternation, reference to case record numbers or to dates of birth, will be excluded. Crossover trials are not appropriate in this context (Vail 2003) and will be excluded.
Types of participants
Subfertile women with PCOS undergoing ovulation induction, not having in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI).
In old studies gonadotrophins may have been used in therapy naive women.
Nowadays, gonadotrophins are usually used in CC‐resistant PCOS or CC‐failure PCOS. If ovulation cannot be achieved with CC administration at doses of 150 mg/day, then the patient is said to be CC resistant. If pregnancy cannot be achieved after six ovulatory cycles with CC, then the patient is described as having CC failure.
Women may have been pre‐treated by metformin with or without CC or electrocautery.
Types of interventions
1. Ovulation induction with rFSH versus any other urinary gonadotrophin (HMG, FSH‐HP, FSH‐HP)
2. Ovulation induction with FSH‐HP versus FSH‐P
3. Ovulation induction with HMG or HP‐HMG versus urinary‐derived FSH (FSH‐P or FSH‐HP)
For all interventions the ovulation induction may include intrauterine insemination. Studies that used co‐treatment with for instance CC, metformin, LH or letrozole will be excluded.
Types of outcome measures
Primary outcomes
1. Live birth rate per woman
2. Incidence of ovarian hyperstimulation syndrome (OHSS) per woman (safety outcome)
Secondary outcomes
3. Clinical pregnancy rate (per woman)
4. Miscarriage rate (per woman)
5. Incidence of multiple pregnancy (per woman and per clinical pregnancy)
6. Total gonadotrophin dose per woman (IU)
7. Total duration of stimulation per woman
Search methods for identification of studies
This review will draw on the search strategy developed for the Cochrane Menstrual Disorders and Subfertility Group (MDSG) as a whole.
Electronic searches
The search strategies will be developed by Marian Showell (Trials Search Coordinator of the MDSG). See Appendix 1, Appendix 2, Appendix 3, Appendix 4, Appendix 5.
We will search the following electronic databases:
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Cochrane Central Register of Controlled Trials (CENTRAL) (current issue);
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MEDLINE (from 1966 onwards);
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EMBASE (from 1988 onwards).
The authors will do an extra search based on the following key words:
Polycystic Ovary Syndrome (PCOS)
Oligomenorrhea / oligo‐amenorrhea / amenorrhea / anovulation
ovulation induction
Follicle stimulating hormone / FSH / follitropin/recombinant FSH / follitropin alfa / follitropin beta / follitropin B / recombinant hFSH / rFSH / urinary FSH / urofollitropin/menotropin/HMG/HP‐HMG
Where other potential manuscripts are found that were not detected by the Trials Search Coordinator, we will contact her to evaluate whether the search has to be adjusted.
Searching other resources
The following conference abstracts will be searched:
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American Society for Reproductive Medicine and Canadian Fertility and Andrology Society (ASRM/CFAS) Conjoint Annual Meeting (2001 to 2012), Abstracts of the Scientific Oral and Poster Sessions, Program Supplement;
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European Society Of Human Reproduction And Embryology (ESHRE) Annual meeting (2001 to 2012), Abstracts of the Scientific Oral and Poster Sessions, Program Supplement.
We will perform handsearching of the references cited in all obtained studies.
Serono Benelux BV and Merck, Ferring and IBSA, the manufacturers of the different gonadotrophins, will be asked for ongoing studies and unpublished data.
Data collection and analysis
Selection of studies
Three review authors (MN, NW and MvW) will independently examine the electronic search results for reports of possibly relevant trials and these reports will be retrieved in full. All review authors will independently apply the selection criteria to the trial reports, rechecking trial eligibility and resolving disagreements by discussion with the other review authors.
Data extraction and management
Three review authors (MN, NW and MvW) will independently extract the outcome data and information on funding, location, clinical and design details, and participants. Any differences will be resolved by discussion among review authors. Details of the studies will be entered into the table 'Characteristics of included studies'. Studies that appeared to meet the inclusion criteria but are excluded from the review will be presented in the table 'Characteristics of excluded studies', briefly stating the reason for exclusion but giving no further information.
Assessment of risk of bias in included studies
Three review authors (MN, NW and MvW) will extract information regarding the risk of bias (threats to internal validity) under six domains (also see the Cochrane risk of bias assessment tool in Appendix 6) (Higgins 2011).
1. Sequence generation. Evidence that an unpredictable random process was used.
2. Allocation concealment. Evidence that the allocation list was not available to anyone involved in the recruitment process.
3. Blinding of participants, clinicians and outcome assessors. Evidence that knowledge of allocation was not available to those involved in subsequent treatment decisions or follow‐up efforts.
4. Completeness of outcome data. Evidence that any losses to follow‐up were low and comparable between groups.
5. Selective outcome reporting. Evidence that major outcomes had been reported in sufficient detail to allow analysis, independently of their apparent statistical significance.
6. Other potential sources. Evidence of miscellaneous errors or circumstances that might influence the internal validity of trial results.
Missing details will be sought from the authors. All details will be presented in the 'Risk of bias' table following each included study. Any differences will be resolved by discussion.
Measures of treatment effect
All binary outcomes will be summarised using the odds ratio (OR) with 95% confidence interval (CI).
Ordinal scales such as amount of gonadotrophin used and duration of ovarian stimulation will be treated as continuous outcomes. Means and standard deviations will be abstracted, calculated or requested.
Unit of analysis issues
All outcomes will be expressed per woman randomised.
The secondary outcome multiple pregnancy will also be expressed per clinical pregnancy.
Dealing with missing data
Where there is insufficient information in the published report, we will attempt to contact the authors for clarification. If missing data become available, these will be included in the analysis. It is anticipated that trials conducted over 10 years ago might not have data on live birth rates. Data extracted from the trials will be analysed on an intention‐to‐treat basis. Where randomised participants are missing from outcome assessment, we will first contact the authors for additional data. If further data are not available, we will assume that missing participants had failed to achieve pregnancy and had not suffered any of the reported adverse events.
Assessment of heterogeneity
Presence of statistical heterogeneity of treatment effect among trials will be determined using the I2 statistic. We will adopt the following broad interpretation: 0% to 40%, might not be important; 30% to 60%, may represent moderate heterogeneity; 50% to 90%, may represent substantial heterogeneity; 75% to 100%, considerable heterogeneity present (Higgins 2002; Higgins 2008).
Assessment of reporting biases
To evaluate external reporting bias, funnel plots for primary outcomes and for clinical pregnancy rate will be presented. When there is evidence of small‐study effects, publication bias will be considered as only one of a number of possible explanations. We will also informally compare the results for clinical pregnancy rates between those studies reporting ongoing pregnancy or live birth and those that did not.
Data synthesis
When multiple studies are available on a similar comparison, Review Manager software will be used to perform the meta‐analyses using a fixed‐effect model. For binary outcomes, the Peto approach will be applied. For reporting purposes, primary outcomes will be translated to absolute risks. Results for continuous outcomes will be combined using mean difference.
Subgroup analysis and investigation of heterogeneity
If excessive heterogeneity exists within strata, it will be explored informally using the clinical and design details recorded in the table 'Characteristics of included studies'. Heterogeneity between strata is anticipated, and possible reasons will be discussed.
Prospectively it is planned to undertake four different stratifications of the primary outcomes:
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single or multiple cycles performed;
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CC‐resistant women or not;
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type of dosage protocol used (low dose step‐up, step‐down, use of intrauterine insemination);
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different sponsors (commercial, non‐commercial) (Lexchin 2003).
Sensitivity analysis
We will assess the influence of risk of bias on effect size by removing trials deemed to be at high risk.
Analyses will be repeated using a random‐effects model to explore whether different conclusions would be reached.
All sensitivity analyses will be reported for live birth and clinical pregnancy only.
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 (that is 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 the reporting of results for each outcome.
