Non-contraceptive oestrogen-containing preparations for controlling symptoms of premenstrual syndrome

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To evaluate the effectiveness and safety of non-contraceptive oestrogen-containing preparations in controlling PMS symptoms.

Background

Description of the condition

Premenstrual syndrome (PMS) is a disorder affecting large numbers of women, characterised by a set of symptoms that occur during the luteal phase of the menstrual cycle. Symptoms disappear by the end of menstruation and do not recur before ovulation, giving a symptom-free interval of at least one week. PMS is cyclical and occurs in most menstrual cycles (O'Brien 2011). PMS is marked by a variety of emotional, physical, and behavioural symptoms. The symptoms typically include irritability, depression, mood swings, bloating, breast tenderness and sleep disturbances (Gianetto-Berruti 2002; Johnson 2004; O'Brien 2003; Panay 2005). A severe form of PMS is known as premenstrual dysphoria or premenstrual dysphoric disorder and was previously known as late luteal phase dysphoric disorder (O'Brien 2011) that causes significant distress and interferes with normal functioning. Studies have reported that as many as 85% of menstruating women would have experienced at least one or more symptoms of PMS (Gianetto-Berruti 2002; Johnson 2004). In about 3 to 10% of women, the symptoms have adverse effects on activities of their daily living and may affect their interpersonal relationships (Gianetto-Berruti 2002; Halbreich 2003; Johnson 2004; O'Brien 2003; Panay 2005; Smith 1995). About 1.5 million women in the United Kingdom experience such severe PMS that greatly reduces their quality of life. Studies have demonstrated deterioration in work effectiveness and cognitive function in women with PMS compared to women without PMS (Johnson 2004; Panay 2005).The precise causation or aetiology of PMS remains unclear. No significant racial or ethnic differences have been shown to exist (Gianetto-Berruti 2002). PMS tends to be more severe among women aged 25 to 35 years old (Johnson 2004). There appears to be a genetic link with PMS risk; monozygotic twins are twice as likely to suffer from PMS as dizygotic twins (Gianetto-Berruti 2002). Similarly, daughters of affected mothers have a 70% greater chance of experiencing PMS than those with unaffected mothers (Gianetto-Berruti 2002). Past history of depressive illness is another significant reported risk factor for PMS (Johnson 2004;Kaur 2004). Previous publications have variably hypothesised that PMS may be associated with excess oestrogen, a deficiency of progesterone or changes in the ratio of oestrogen and progesterone (Gianetto-Berruti 2002). It is now thought that the condition is due to complex interactions between ovarian steroids and neurotransmitters (Rapkin 2007). Although much has been written on diagnostic criteria over the past 30 years, there is no true consensus on which technique is acceptable. A clinical diagnosis requires symptoms to be confirmed by prospective recording for at least two menstrual cycles and that they cause substantial distress or impairment to daily life (e.g. work, school, social activities, hobbies, interpersonal relationships (ACOG 2001; O'Brien 2011). Individual studies have used idiosyncratic techniques, this being true particularly true for older studies. Typically these methods have included visual analogue scales, categorical scales such as Moos' Menstrual Distress questionnaire, Calendar of Premenstrual Experiences and the Daily Record of Severity of Problems. There remains no established consensus but the Daily Record of Severity of Problems has been used in most recent publications.

 

Description of the intervention

Oestrogen therapy has been proposed as a method for management in PMS through its ability to suppress ovulation and the subsequent endocrine changes of the cycle. Oestrogen can be delivered as oral tablets, transdermal patches, implants, vaginal pessaries, gels and creams. The oestrogens which have been used and studied in the management of PMS include  mainly oestradiol in the form of transdermal patches or subcutaneous implants to suppress ovulation in controlled studies (Magos 1986; Smith 1995; Watson 1990). Both routes of administering oestradiol appear to show positive effects for treating mental and physical symptoms .To prevent endometrial hyperplasia, cyclical progestogens are given to ensure a regular withdrawal bleed. The potential oestrogens which may suppress ovulation include natural and synthetic oestrogens including steroids and non steroidal preparations.

How the intervention might work

Though many theories have been proposed, the exact pathway and definitive aetiology of PMS is unknown (O'Brien 2003; Smith 1995; Watson 1990). PMS is probably related to ovulation as symptoms do not occur before the onset of puberty, during pregnancy or after menopause. Menstruation per se  is not be necessary for PMS and it can occur after hysterectomy and endometrial ablation as ovarian function is unaffected (Magos 1986). This knowledge has led to use of several ovulation-suppressing drugs. The nature of some of these drugs limits their long-term use because of associated safety issues, thereby also limiting their success. For example, gonadotrophin releasing hormone agonists (GnRH agonist) and danazol have both demonstrated efficacy in alleviating several premenstrual symptoms. Though effective, the use of danazol is limited because of its androgenic side effects and so it cannot be used on a long term basis. GnRH is very effective but long term use is limited by the resulting oestrogen deficient state.  

Controlled trials have demonstrated that 17 ß-oestradiol combined with cyclical progestogen (for regular withdrawal periods and to prevent endometrial hyperplasia) administered as an implant or patch is highly effective in controlling PMS symptoms for long term use (Magos 1986; Smith 1995; Watson 1990). Though oestrogen is an effective agent for treating PMS, its use may be limited in individual patients by the need for a progestogen in women with a uterus and because of the subsequent progestogenic/PMS-like side effects. As oestrogen-only treatment has been found to be associated with endometrial hyperplasia/cancer, progestogen therapy is recommended for endometrial protection. The use of local progesterone (Mirena IUS) has now enabled oestrogen to be one of the most effective treatment options for PMS. It is widely used in UK but there are no fully published randomised controlled trials (RCTs). We specifically exclude studies on oral contraceptives (OCs) especially those containing drospirenone as this has been considered as a side issue in another Cochrane review (Lopez 2012).

Why it is important to do this review

Whilst there are several published trials of oestrogen treatment of PMS, there is no existing systematic review evaluating the therapeutic effectiveness of non-contraceptive oestrogen-containing preparations in the management of PMS. Oral contraceptives are not included in this systematic review. A Cochrane review of oral contraceptives has been published but, surprisingly, this focused only on those containing drospirenone and ethinyl oestradiol (Lopez 2012). There is a need for a separate review of all OCs but that is not within the context of the present review.

Objectives

To evaluate the effectiveness and safety of non-contraceptive oestrogen-containing preparations in controlling PMS symptoms.

Methods

Criteria for considering studies for this review

Types of studies

Published and unpublished truly RCTs. Quasi RCTs will not be included.

Types of participants

Inclusion

Women in the studies will almost by definition be of reproductive age and individual studies will each define the age range of participants; the review will accept all ages published assuming they fulfil criteria for diagnosis of PMS. Diagnosis of PMS must be confirmed by prospective recording of symptoms for at least two menstrual cycles; they must demonstrate substantial distress, or impairment to daily life. Diagnosis of premenstrual dysphoric disorder must meet established psychiatric diagnostic criteria (DSM-IV-TR).

Exclusion
  • Studies which include women on other medication which result in ovulation suppression

  • Studies which include women with primary psychiatric diagnosis (other than premenstrual dysphoric disorder)

  • Studies where women are taking any other hormone therapy (i.e. other than oestrogen and progestogens) will not be included though women already receiving psychotropic medication (e.g. selective serotonin re-uptake inhibitors) will not be excluded

  • Studies of women with only a self-diagnosis of PMS will be excluded

Types of interventions

Only non-contraceptive oestrogen-containing preparations (with or without progestogen) will be included regardless of route of administration (eg. oral, vaginal, transdermal patch, cream, gels, intrauterine route) or dosage.

All combined oral contraceptive preparations (oestrogen/progesterone) will be excluded. All studies of progesterone alone are excluded.

Types of outcome measures

Primary outcomes
  • Effectiveness (significant reduction/improvement in global symptoms scores will be assessed using a validated prospective screening tool or by pre-defined medical diagnostic criteria)

  • Adverse events (specific adverse effects including withdrawals for adverse effects and abnormal uterine bleeding)

Secondary outcomes
  • Specific symptoms of PMS: psychological, physical and functional symptoms

  • Quality of life measures

  • Patient satisfaction

Search methods for identification of studies

All published and unpublished RCTs of non-contraceptive oestrogens versus placebo will be sought using the following search strategy; if they exist, publications which compare one oestrogen preparation with another will be sought. All will be conducted without language restriction and in consultation with the Cochrane Menstrual Disorders and Subfertility Group Trials Search Coordinator.

Electronic searches

We will use the following computerised bibliographic databases to identify all potentially relevant published clinical trials of non-contraceptive oestrogen in the management of premenstrual syndrome:

  • the Cochrane Central Register of Controlled Trials (CENTRAL)

  • EMBASE

  • MEDLINE

  • PsycINFO

We will use specific MeSH headings and additional keywords to identify all relevant studies. The complete search strategies for the database searches are provided in Appendix 1, Appendix 2, Appendix 3 and Appendix 4. There will be no restriction on language.

Searching other resources

Ongoing and unpublished trials

We will search for ongoing and unpublished studies in trial registers, such as ClinicalTrials.gov (http://clinicaltrials.gov/), metaRegister of Controlled trials (mRCT) (http://www.controlled-trials.com/mrct/) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) Search Portal (http://apps.who.int/trialsearch/).

Conference proceedings

We will search for relevant conference abstracts on the ISI Web of Knowledge; proceedings from the following main conferences will be handsearched:

  • International Federation of Fertility Societies

  • American Society for Reproductive Medicine

  • British Fertility Society

  • European Society for Human Reproduction and Embryology

Researchers and organizations

We will contact individual researchers working in the field, to identify trials either completed or ongoing.

Reference lists

We will also check the reference lists of all studies identified by the above methods and examine any systematic reviews or meta-analyses found.

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

Two authors (BN (Bushra Naheed)) and OU (Olalekan A Uthman)) will review the titles and potential relevant abstracts retrieved by the search strategy. We will obtain full articles of potentially relevant trials that meet the inclusion criteria, using an eligibility form based on pre-specified inclusion criteria. All disagreements will be resolved by a third author (PMSO (Patrick Michael Shaughn O'Brien)). We will give reasons for excluding potentially relevant trials in the 'Characteristics of excluded studies' table. We will contact primary study authors for clarification when necessary. The selection process will be illustrated in a flow diagram according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Moher 2009).

Data extraction and management

Two authors (BN and OU) will independently extract the data using pre-designed data collection forms. For each of the studies, the extracted data will include the following; citation, study design, methodological criteria, inclusion and exclusion criteria, comparison group intervention, participant characteristics, trial setting, elements of intervention, all relevant outcome measures, and results. Where reports are uncertain or include summary measures, authors will be contacted for clarification.

We aim to extract data to allow an intention-to-treat analysis (all randomised participants should be analysed in the groups to which they were originally randomised). We will calculate the percentage lost to follow-up and report this information. For dichotomous outcome measures, we will record the number of participants experiencing the event and the number analysed in each group. For continuous outcome measures, we will extract the mean change from baseline, the standard deviation of the mean change, and the number of participants for each treatment group at each assessment. Where changes from baseline are not reported, the mean, standard deviation, and the number of participants for each intervention group at each point in time will be extracted if available. If the data have been reported using geometric means, we will record this information and extract a standard deviation on a log scale.

In studies with a crossover design we will use only data from the first intervention phase after randomisation. If needed, study authors will be contacted for clarification and missing or insufficient data.

Assessment of risk of bias in included studies

The included studies will be assessed for risk of bias using the Cochrane Collaboration's tool for assessing risk of bias (Appendix 5):

  • sequence generation;

  • allocation concealment;

  • blinding of participants, providers and outcome assessors;

  • completeness of outcome data;

  • selective outcome reporting; and

  • other potential sources of bias.

We will present results in both a risk of bias graph and a risk of bias summary. We will interpret the results of meta-analyses in the light of the findings with respect to risk of bias. We will conduct sensitivity analysis based on risk of bias. Any disagreements will be resolved by consensus or by discussion with a third author.

Measures of treatment effect

For dichotomous data (e.g. adverse events), we will use the numbers of events in the control and intervention groups of each study to calculate Mantel-Haenszel odds ratios (ORs). For continuous data (e.g. mood score), if all studies report exactly the same outcomes on the same scale we will calculate mean differences (MDs) between treatment groups. If similar outcomes are reported on different scales (e.g. change in weight) we will calculate the standardised mean difference (SMD). We will reverse the direction of effect of individual studies, if required, to ensure consistency across trials. We will present 95% confidence intervals (CIs) for all outcomes. Where data to calculate ORs or MDs are not available, we will utilise the most detailed numerical data available that may facilitate similar analyses of included studies (e.g. test statistics, P values). We will compare the magnitude and direction of effect reported by studies with how they are presented in the review, taking account of legitimate differences.

Unit of analysis issues

The unit of analysis in meta-analysis will be women with diagnoses of PMS. If the woman is not the unit of randomisation, such as is the case in cluster randomised trials (i.e. general practitioners), adjustments for clustering will be made following the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Dealing with missing data

The data will be analysed on an intention-to-treat basis as far as possible and attempts will be made to obtain missing data from the original investigators.

Assessment of heterogeneity

The authors will consider whether the clinical and methodological characteristics of the included studies are sufficiently similar for meta-analysis to provide a meaningful summary. Statistical heterogeneity will be assessed by measurement of the I2 statistic. An I2 greater than 50% will be taken to indicate substantial heterogeneity (Higgins 2003). If substantial heterogeneity is detected, possible explanations will be explored in sensitivity analyses

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. If there are 10 or more studies in an analysis, we will use a funnel plot 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

All eligible studies will be analysed in the Cochrane Collaboration's statistical software, Review Manager 2013. Of the two authors who will extract the data; the first author will enter all data into Review Manager 2013, and the second will recheck all entries. Disagreements will be resolved by discussion. A narrative synthesis will be provided for all results, along with a statistical meta-analysis if possible. An increase in the odds of a particular outcome, which may be beneficial (e.g. improvement in global symptoms scores) or detrimental (e.g. adverse effects), will be displayed graphically in the meta-analyses to the right of the centre-line and a decrease in the odds of an outcome to the left of the centre-line.

If the studies are sufficiently similar, we will combine the data using a fixed-effect model in the following comparisons:

1. Oestrogen versus placebo

2. Oestrogen in combination with progestogen (sequential or continuous) versus placebo.

Subgroup analysis and investigation of heterogeneity

Where data are available, we will conduct subgroup analyses to determine the separate evidence within the following subgroups:

  • subgroups by route of administration of oestrogens;

  • subgroups by route of administration of co-administered progestogens required for protection of endometrium (not for therapeutic effects as indeed they may re-introduce PMS-like symptoms).

If we detect substantial heterogeneity, we will explore possible explanations in sensitivity analyses. We will take any statistical heterogeneity into account when interpreting the results, especially if there is any variation in the direction of effect.

Sensitivity analysis

We will conduct sensitivity analyses for the primary outcomes to determine whether the conclusions are robust to arbitrary decisions made regarding the eligibility and analysis. These analyses will include consideration of whether the review conclusions would have differed if:

  1. eligibility were restricted to studies without high risk of bias;

  2. a random-effects model had been adopted;

  3. the summary effect measure was relative risk (RR) rather than OR.

Overall quality of the body of evidence: 'Summary of Findings' table

A 'Summary of Findings' table will be used to evaluate the overall quality of the body of evidence for the main review outcomes, using the Grading of Recommendations Assessment, Development and Evaluation (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.

Acknowledgements

We are grateful for the support given by the staff of the Cochrane Menstrual Disorders and Subfertility Group, especially the Trials Search Co-ordinator.

Appendices

Appendix 1. Search strategy for CENTRAL (EBM Reviews)

1 Premenstrual Syndrome/
2 Premenstrual Syndrome.tw.
3 PMS.tw.
4 PMD.tw.
5 PMDD.tw.
6 LLPDD.tw.
7 Premenstrual Tension.tw.
8 (Dysphor$ adj2 disorder$).tw.
9 (luteal adj2 dysphori$).tw.
10 mastalgi$.tw.
11 (Premenstrual adj2 depressi$).tw.
12 PMT.tw.
13 (Premenstrual adj2 dysphor$).tw.
14 (luteal adj2 symptom$).tw.
15 or/1-14
16 exp estrogens/ or exp estradiol/ or exp "estrogens, conjugated (usp)"/ or exp ethinyl estradiol/
17 (estrogen$ or estradiol).tw.
18 (oestrogen$ or oestradiol).tw.
19 vivelle.tw.
20 Oestrone$.tw.
21 Oestridae.tw.
22 Estraderm.tw.
23 or/16-22
24 15 and 23

Appendix 2. Search strategy for EMBASE

1 exp premenstrual syndrome/
2 Premenstrual Syndrome.tw.
3 PMS.tw.
4 PMD.tw.
5 PMDD.tw.
6 LLPDD.tw.
7 Premenstrual Tension.tw.
8 (Dysphor$ adj2 disorder$).tw.
9 (luteal adj2 dysphori$).tw.
10 mastalgi$.tw.
11 (Premenstrual adj2 depressi$).tw.
12 PMT.tw.
13 (Premenstrual adj2 dysphor$).tw.
14 (luteal adj2 symptom$).tw.
15 or/1-14
16 conjugated estrogen/ or estrogen/ or conjugated estrogen plus medroxyprogesterone acetate/ or estrogen therapy/
17 (estrogen$ or estradiol).tw.
18 (oestrogen$ or oestradiol).tw.
19 vivelle.tw.
20 Oestrone$.tw.
21 Oestridae.tw.
22 Estraderm.tw.
23 or/16-22
24 Clinical Trial/
25 Randomized Controlled Trial/
26 exp randomization/
27 Single Blind Procedure/
28 Double Blind Procedure/
29 Crossover Procedure/
30 Placebo/
31 Randomi?ed controlled trial$.tw.
32 Rct.tw.

33 random allocation.tw.
34 randomly allocated.tw.
35 allocated randomly.tw.
36 (allocated adj2 random).tw.
37 Single blind$.tw.
38 Double blind$.tw.
39 ((treble or triple) adj blind$).tw.
40 placebo$.tw.
41 prospective study/
42 or/24-41
43 case study/
44 case report.tw.
45 abstract report/ or letter/
46 or/43-45
47 42 not 46
48 15 and 23 and 47

Appendix 3. Search strategy for MEDLINE (Ovid)

1 Premenstrual Syndrome/
2 Premenstrual Syndrome.tw.
3 PMS.tw.
4 PMD.tw.
5 PMDD.tw.
6 LLPDD.tw.
7 Premenstrual Tension.tw.
8 (Dysphor$ adj2 disorder$).tw.
9 (luteal adj2 dysphori$).tw.
10 mastalgi$.tw.
11 (Premenstrual adj2 depressi$).tw.
12 PMT.tw.
13 (Premenstrual adj2 dysphor$).tw.
14 (luteal adj2 symptom$).tw.
15 or/1-14
16 exp estrogens/ or exp estradiol/ or exp "estrogens, conjugated (usp)"/ or exp ethinyl estradiol/
17 (estrogen$ or estradiol).tw.
18 (oestrogen$ or oestradiol).tw.
19 vivelle.tw.
20 Oestrone$.tw.
21 Oestridae.tw.
22 Estraderm.tw.
23 or/16-22
24 15 and 23
25 randomized controlled trial.pt.
26 controlled clinical trial.pt.
27 randomized.ab.
28 placebo.tw.
29 clinical trials as topic.sh.
30 randomly.ab.
31 trial.ti.
32 (crossover or cross-over or cross over).tw.
33 or/25-32
34 exp animals/ not humans.sh.
35 33 not 34
36 24 and 35

Appendix 4. Search strategy for PsycINFO

1 exp Premenstrual Syndrome/
2 Premenstrual Syndrome.tw.
3 PMS.tw.
4 PMD.tw.
5 PMDD.tw.
6 LLPDD.tw.
7 Premenstrual Tension.tw.
8 (Dysphor$ adj2 disorder$).tw.
9 (luteal adj2 dysphori$).tw.
10 mastalgi$.tw.
11 (Premenstrual adj2 depressi$).tw.
12 PMT.tw.
13 (Premenstrual adj2 dysphor$).tw.
14 (luteal adj2 symptom$).tw.
15 or/1-14
16 exp Estrogens/
17 (estrogen$ or estradiol).tw.
18 (oestrogen$ or oestradiol).tw.
19 vivelle.tw.
20 Oestrone$.tw.
21 Oestridae.tw.
22 Estraderm.tw.
23 or/16-22
24 15 and 23
25 random.tw.
26 control.tw.
27 double-blind.tw.
28 clinical trials/
29 placebo/
30 exp Treatment/
31 or/25-30
32 24 and 31

Appendix 5. The Cochrane Collaboration's tool for assessing risk of bias

DomainSupport for judgementReview authors' judgement
Selection bias
Random sequence generationDescribe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence.
Allocation concealmentDescribe the method used to conceal the allocation sequence in sufficient detail to determine whether intervention allocations could have been foreseen in advance of, or during, enrolment.Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment.
Performance bias
Blinding of participants and personnel Assessments should be made for each main outcome (or class of outcomes)Describe all measures used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. Provide any information relating to whether the intended blinding was effective.Performance bias due to knowledge of the allocated interventions by participants and personnel during the study.
Detection bias
Blinding of outcome assessment Assessments should be made for each main outcome (or class of outcomes)Describe all measures used, if any, to blind outcome assessors from knowledge of which intervention a participant received. Provide any information relating to whether the intended blinding was effective.Detection bias due to knowledge of the allocated interventions by outcome assessors.
Attrition bias
Incomplete outcome data Assessments should be made for each main outcome (or class of outcomes)Describe the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis. State whether attrition and exclusions were reported, the numbers in each intervention group (compared with total randomised participants), reasons for attrition/exclusions where reported, and any re-inclusions in analyses performed by the review authors.Attrition bias due to amount, nature or handling of incomplete outcome data.
Reporting bias
Selective reportingState how the possibility of selective outcome reporting was examined by the review authors, and what was found.Reporting bias due to selective outcome reporting.
Other bias
Other sources of bias

State any important concerns about bias not addressed in the other domains in the tool.

If particular questions/entries were pre-specified in the review’s protocol, responses should be provided for each question/entry.

Bias due to problems not covered elsewhere in the table.

Contributions of authors

BN developed the protocol. PMSO, OAU and FO reviewed and provided comments on the protocol.

Declarations of interest

None.

Sources of support

Internal sources

  • None, Not specified.

External sources

  • None, Not specified.

Ancillary