Oral anti‐oestrogens and medical adjuncts for subfertility associated with polycystic ovary syndrome
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine the relative effectiveness of anti‐oestrogen agents, with or without medical adjuncts, in women with anovulation secondary to PCOS.
Background
Polycystic ovary syndrome (PCOS) is a common condition of uncertain aetiology that occurs in 4 to 7% of women of reproductive age (Lobo 2000). The syndrome was first described in 1935 and was first known as Stein‐Leventhal syndrome. Diagnostic criteria have varied in the past. A recent consensus meeting between the European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) (ESHRE/ASRM 2003) decided on the following criteria (based upon majority opinion, not clinical trial data):
Two of the following three factors are required for diagnosis of PCOS, with exclusion of other aetiologies such as congenital adrenal hyperplasia, androgen secreting tumours, hyperprolactinaemia, and Cushing's syndrome.
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Oligo‐ or anovulation.
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Clinical and/or biochemical signs of hyperandrogenism.
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Polycystic ovaries.
Common symptoms and signs of PCOS include: hirsutism, acne, abnormal menstrual bleeding and obesity. Biochemical investigations of women with PCOS show raised luteinising hormone (LH) and testosterone levels. Ultrasound scanning (USS) will usually show enlarged ovaries (>9 ml) with peripheral cystic structures surrounded by an increased stromal mass (the supporting tissue of the ovary). Women with PCOS are at increased risk of: pregnancy loss and complications, infertility, and endometrial carcinoma. Their cardiovascular risk is also raised due to an increased risk of type 2 diabetes mellitus, hypertension and altered serum lipid profiles (Lobo 2000; ESHRE/ASRM 2003).
During normal menstruation oestrogen levels are low while follicle stimulating hormone (FSH) and LH levels begin to rise. This stimulates the development of an ovarian follicle. The mature follicle then produces androgens (male sex hormones), the majority of which are inactivated by sex hormone binding globulin (SHBG). The remaining androgens are converted, in adipose tissue, to oestrogen. This causes a rise in the levels of oestrogen which in turn causes a fall in FSH and LH levels. The oestrogen levels continue to rise, eventually causing an LH surge which triggers ovulation.
In women with PCOS the elevated levels of LH cause increased production of androgens which in turn interferes with follicular development. The normal production of oestrogen from the ovaries is disrupted and there is no LH surge. The follicles therefore do not release the egg during ovulation but instead become ovarian cysts.
Anovulatory women with PCOS who desire pregnancy seek medical intervention and advice to assist them in their reproductive intent.
Surgical ovarian wedge resection was the first effective means of inducing ovulation in women with anovulatory PCOS but fell into disrepute because of the risk of post‐surgical adhesion formation and resultant tubal subfertility (El Helw 1996). Weight reduction may result in ovulation and pregnancy and is therefore recommended for the obese woman with PCOS. Medical ovulation induction with clomiphene citrate (CC) is, at present, the first line treatment for anovulatory women with PCOS. Clomiphene is an anti‐oestrogen and competes for receptor binding sites with endogenous oestrogens. By blocking receptors in the hypothalamus and pituitary, clomiphene interferes with the feedback mechanism of endogenous oestrogen on the pituitary and hypothalamus and an increase in FSH and LH secretion by the pituitary results. The clomiphene‐induced elevation of gonadotrophins stimulates the production of ovarian follicles (folliculogenesis) and ovulation. Human chorionic gonadotrophin (hCG) injections are sometimes used to trigger ovulation when there are developed follicles, these are intramuscular injections typically given on day 16 or 17 of the cycle. Estimates for numbers of women conceiving with clomiphene therapy vary from 30 to 50% (Kousta 1997), to 15% (NICE 2004). Approximately 7% of pregnancies resulting from clomiphene induced ovulation are twin pregnancies and 0.5% are triplet pregnancies (Wolf 2000). Miscarriage rates of 13 to 25% have been reported in clomiphene induced conceptions (Kousta 1997), rates for spontaneous conceptions are reported at 10 to 15% but it is thought it may be much higher (Oates‐Whitehead 2003). Ovarian hyperstimulation syndrome (OHSS) has been reported rarely following CC use. Tamoxifen has been used to induce ovulation (Messinis 1982) but is used much less frequently than clomiphene. It's mode of action is similar as clomiphene.
Recently published United Kingdom National Institute for Clinical Excellence (NICE) guidelines state that first line treatment for anovulation due to PCOS should be clomiphene (or tamoxifen) for up to twelve months (NICE 2004). NICE recommended dosage is 50 to 100 mg with a maximum of 250 mg.
Addition of oral dexamethasone treatment to clomiphene therapy has been advocated to improve the chance of ovulation and subsequent pregnancy. The proposed mechanism of action of dexamethasone in PCOS is suppression of adrenal production of androgens particularly dehydroepiandrosterone sulphate (DHEAS). Suppression of androgens should augment clomiphene's action. Secondly it has been suggested that dexamethasone may facilitate folliculogenesis by causing an increase in FSH levels. A third mechanism of action may be to reduce the high pulsatile levels of LH seen in PCOS which contributes to anovulation (Brann 1991).
Dopamine can reduce elevated LH levels in PCOS (Leblanc 1976) and has also been reported to lead to a return in cyclical ovarian activity in normoprolactinaemic women with PCOS (Siebel 1984). Bromocriptine is a dopamine agonist. For this reason bromocriptine has been studied as an adjunctive treatment to clomiphene induced ovulation in anovulatory women with PCOS.
The available literature will be reviewed in an attempt to establish the effectiveness and complications of oral anti‐oestrogen agents alone or in combination in ovulation induction in women with PCOS.
Objectives
To determine the relative effectiveness of anti‐oestrogen agents, with or without medical adjuncts, in women with anovulation secondary to PCOS.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials (RCT) that compare oral agents for ovulation induction (alone or in conjunction with medical adjuncts) in subfertility associated with PCOS, will be considered for inclusion in the review.
Quasi randomized trials will not be included. Cross over trials will not be included unless phase one data are available, in which case only this data will be used for the purposes of the review.
Types of participants
Women of reproductive age with anovulation attributed to PCOS. Age to be determined by study author/s.
PCOS will be defined by ESHRE/ASRM criteria (ESHRE/ASRM 2003). In consideration of the wide variation of diagnostic criteria used for PCOS studies utilising different criteria will be included if the broad definition matches that of the ESHRE/ASRM criteria, to be agreed by consensus.
Women with mild hyperprolactinaemia (<3 times the upper limit of normal of the reporting laboratory's reference range) will be included or with unspecified degree of hyperprolactinaemia will be included.
Exclusion criteria:
Women with hyperprolactinaemia (greater than three times the upper limit of normal of the reporting laboratory's reference range) and Cushing's syndrome will be excluded and the studies should report that these two conditions have been excluded. Both of these conditions preclude the diagnosis of PCOS.
Types of interventions
Anti‐oestrogen vs no treatment/placebo, for example:
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clomiphene
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tamoxifen
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other
Anti‐oestrogen vs anti‐oestrogen, for example:
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clomiphene vs tamoxifen
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clomiphene vs other
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tamoxifen vs other
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other
Anti‐oestrogen plus medical adjunct vs anti‐oestrogen alone, for example:
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dopamine agonist ‐ bromocriptine
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dopamine agonist ‐ cabergoline
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corticosteroid ‐ dexamethasone
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other
Anti‐oestrogen plus medical adjunct vs Anti‐oestrogen plus medical adjunct
Trials utilizing intrauterine insemination will be excluded as they are not part of the objective of this review. Trials utilizing natural intercourse or timed intercourse will be included.
Insulin sensitizing agents such as metformin will not be included in this review as they are the subject of a separate review (Lord 2004).
Types of outcome measures
Primary Outcome
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Live birth rate (per woman)
Secondary Outcomes
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Pregnancy rate (per woman). Pregnancy will be defined as evidence of intrauterine gestation on ultrasound.
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Ovulation rate (per woman). Ovulation will be defined as evidence of serum progesterone in the luteal range for the reference laboratory or a rise of >0.4°C for 10 days or more on a basal body temperature chart.
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Miscarriage rate (per pregnancy). Miscarriage will be defined as the involuntary loss of a pregnancy before 20 weeks gestation.
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Incidence of multiple pregnancy (per pregnancy). Multiple pregnancy will be defined as greater than one intrauterine pregnancy.
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Incidence of overstimulation (per woman). This will be defined according definition adopted by the reporting author/s.
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Incidence of OHSS (per woman). This will be defined according the definition of the reporting author/s.
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Incidence of patient reported adverse effects (per woman). This will be defined according the definition of the reporting author/s.
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Definitions of the diagnosis of PCOS and the other studied outcomes (ovulation, overstimulation, OHSS) in this review will also be recorded.
Search methods for identification of studies
(1) We will search the Menstrual Disorders and Subfertility Group's trials register.
(2) We will search the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2 2004) for keywords: Polycystic Ovary Syndrome.
(3) We will search the following electronic databases for studies in all languages using the following terms:
MEDLINE (1966 to June 2004)
1) randomized controlled trial.pt
2) controlled clinical trial.pt
3) randomized controlled trials/
4) random allocation/
5) double‐blind method/
6) single‐blind method/
7) or/1‐6
8) clinical trial.pt
9) exp clinical trials/
10) (clin$ adj25 trial$).tw
11) ((singl$ or doubl$ or treb$ or tripl$) adj25 (blind$ or mask$)).tw
12) placebos/
13) placebo$.tw
14) random$.tw
15) research design/
16) or/8‐15
17) animal/ not (human/ and animal/)
18) 7 or 16
19) 18 not 17
20) polycystic adj5 ovar$.tw
21) PCOS.tw
22) PCO.tw
23) Polycystic Ovary Syndrome/
24) or/20‐23
25) anovul$.tw
26) infertil$.tw
27) subfertil$.tw
28) INFERTILITY/
29) or/25‐28
29) 24 and 29
30) 7 or 19
31) 29 and 30
EMBASE (1980 to June 2004)
1) randomized controlled trial/
2) random allocation/
3) double‐blind method/
4) single‐blind method/
5) or/1‐4
6) exp clinical trials/
7) (clin$ adj25 trial$).tw
8) ((singl$ or doubl$ or treb$ or tripl$) adj25 (blind$ or mask$)).tw
9) placebos/
10) placebo$.tw
11) random$.tw
12) research design/
13) or/6‐12
14) animal/ not (human/ and animal/)
15) 5 or 13
16) 15 not 14
17) polycystic adj5 ovar$.tw
18) PCOS.tw
19) PCO.tw
20) Polycystic Ovary Syndrome/
21) or/17‐20
22) anovul$.tw
23) infertil$.tw
24) subfertil$.tw
25) INFERTILITY/
26) or/22‐25
27) 21 and 26
28) 5 or 16
29) 27 and 28
(4) We will search the National Institute of Clinical Excellence fertility assessment and treatment guidelines (NICE 2004).
(5) We will check references of relevant systematic reviews and RCT's.
Data collection and analysis
Selection of studies
Trials to be included will be independently selected by two reviewers in accordance with mentioned criteria. Disagreements will be resolved by consensus. Studies will be excluded from the systematic review if they make comparisons other than those specified above.
Data Extraction
The following information is to be extracted from the studies included in the review and presented in a Table of Characteristics of Included Studies:
Trial Characteristics:
(a) Randomisation
(b) Allocation concealment
(c) Trial design: multicenter or single centre; single phase or crossover design
(d) Number of patients randomized, excluded and analysed
(e) Duration, timing and location of the trial
(f) Source of funding
Baseline characteristics of the studied groups:
(a) definition and duration of pre‐existing infertility
(b) age of the patients
(c) investigative work‐up
(d) other causes of infertility
(e) previous administered treatment(s)
Intervention:
(a) Type of intervention and control
(b) Dose regime
Outcomes:
(a) Outcomes reported
(b) How are outcomes defined?
(c) How are outcomes measured?
(d) Timing of outcome measurement
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.
Quality Assessment
Trials will also be screened and analysed for the following quality criteria; this information will be presented in both a quality table and the text of the review and will help provide a context for discussing the reliability of results:
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Method and timing of randomisation: randomized (e.g. by computer, or random number tables or drawing lots), quasi‐randomized (e.g. by hospital number or date of birth), not clear (e.g. stated but not further described).
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Concealment of allocation: adequate (e.g. by third party or sealed opaque envelopes), inadequate (e.g. open list of allocation codes), not clear (e.g. not stated, or 'envelopes' stated without further description).
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The use of blinding
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Whether an intention to treat analysis was performed
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The presence of a power calculation
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 graph and the overlap in their confidence intervals and, more formally, by checking the results of the chi2 tests. Where possible, the results for each comparison will be pooled statistically. A stratified meta‐analysis will be performed for each set of comparisons.
For dichotomous data (all the outcome measures in this review), results for each study will be expressed as an odds ratio (OR) with 95% confidence intervals (CI) and combined for meta‐analysis with RevMan software using a fixed effects model.
If a clinically important difference in drug regime (outside of normal clinical practice) occurs between studies an attempt to form dose sub groups for analysis will be made.
Studies performed on clomiphene‐resistant PCOS only will also be the subject of a sub group analysis.
Timeline
Completion of the review is expected within one year of publication on the Cochrane Library. It is also the intention of the reviewers that a new search for RCTs will be performed every two years and the review updated accordingly.
