Objectives
This is a protocol for a Cochrane Review (intervention). The objectives are as follows:
To assess the effects of oestrogen therapy for treating pelvic organ prolapse in postmenopausal women; and summarise the principal findings of relevant economic evaluations.
Background
For a glossary of terms, see Appendix 1.
Description of the condition
Pelvic organ prolapse (POP) is common, affecting 50% of women over 50 years old who have given birth to at least one child (DeLancey 1993). POP is defined by the International Continence Society (ICS) as the "descent of one or more of the anterior vaginal wall, posterior vaginal wall, the uterus (cervix) or the apex of the vagina ... [correlated with] relevant POP symptoms" (Haylen 2016). Symptoms can include a bothersome vaginal lump or bulge, and an impact on urinary, bowel and sexual health. The condition has been shown to adversely impact women's quality of life and body image (Jelovsek 2006). There are a number of recognised risk factors for POP, including older age, increasing number of births (parity), higher body mass index (BMI) and vaginal delivery (Vergeldt 2015). Age is a particular risk factor for POP; both the incidence and prevalence of the condition increase with age (Salvatore 2016). Additionally, 6% to 12% of women who have undergone a hysterectomy will develop prolapse (Maher 2016). Nonetheless, the aetiology is often multifactorial (Dietz 2008).
In addition to the effect that POP has on the quality of life of women, there are considerable resource implications which impact the health care system. Subramanian 2009 estimated that the annual cost of managing POP, in 2005 euros (EUR), was over EUR 144.2 million in Germany; more than EUR 83 million in France and just over EUR 81 million in England.
Description of the intervention
There are various conservative and surgical management options for treating POP (Maher 2013). When deciding on the most appropriate option, factors to consider include the woman's preference, age, comorbidities, lifestyle factors, the type of prolapse and previous pelvic floor surgery (NICE 2019). Conservative management includes lifestyle modifications (such as weight loss, minimising heavy lifting and preventing or treating constipation) (NICE 2019), pelvic floor muscle training (PFMT) (Hagen 2011), and vaginal pessaries (small mechanical devices placed in the vagina to provide support) (Bugge 2020).
Oestrogen‐only hormone replacement therapy (or oestrogen therapy) is often used as a treatment for POP. Both natural and synthetic oestrogens can be used and they can be administered either systemically (using either oral, transdermal skin patches or subcutaneous implants) or locally (using vaginal cream, tablets, rings or pessaries impregnated with oestrogen) (Stevenson 2009). Locally‐applied oestrogens result in less systemic absorption and hence a lower incidence of systemic side effects. When administered for the treatment of vaginal atrophy, there is no evidence of a difference between the various topical preparations with regards to efficacy or side effect profile (Lethaby 2016).
Oestrogen therapy can be used either as a standalone option or in conjunction with other treatments. It can be used alongside pelvic floor muscle training (PFMT) to improve the vaginal wall, improve sensation and possibly improve pelvic floor muscle function. Oestrogen therapy can also be used alongside vaginal pessaries to help prevent or treat vaginal atrophy (a thinning, drying and inflammation of the vaginal walls that can occur if a woman's body has less oestrogen) before insertion (NICE 2019).
If conservative treatments for POP fail, or if a woman declines these treatments, they may be offered surgery (NICE 2019). Surgical methods include anterior and posterior vaginal wall repair, hysterectomy or hysteropexy for uterine prolapse, and sacrospinous fixation or sacrocolpopexy for apical prolapse (Maher 2013). Surgery has a 30% POP recurrence rate (Olsen 1997), with the incidence of repeat surgery for POP estimated to be 11.5% within 15 to 20 years (Løwenstein 2018). Like any operation, there is a risk of anaesthetic, thrombotic, cardiovascular and surgical complications, as well as failure and recurrence (NICE 2019). One of the main intended benefits of preoperative use of local oestrogen is to improve local tissues for surgery to avoid tearing or reduce infection. A recent feasibility study has shown that the necessary randomised controlled trial to address this question would be feasible, with high fidelity (Verghese 2020).
How the intervention might work
The female genital tract is sensitive to oestrogen. After the menopause, there is a reduction in circulating oestrogen leading to atrophy with loss of vaginal folds (rugae) (Whiteside 2005), vaginal dryness, weakening and thinning of vaginal epithelium and pelvic supporting fascia and ligaments, as well as changes in vaginal pH (DeLancey 2002; Naumova 2018). Many of these issues can be improved with oestrogen therapy (Naumova 2018). The exact mechanism of how oestrogen therapy helps to treat POP has been debated, but it is thought that collagen degradation in the pelvic floor connective tissue is decreased in the presence of oestrogen (Bodner‐Adler 2020).
If used with other therapies, oestrogen could improve their efficacy to reduce POP symptoms. Using oestrogen in conjunction with these other treatments may also minimise the associated side effects of treatments by optimising the strength of pelvic organ supporting ligaments, muscles and vaginal mucosa. For example, the thinner vaginal tissues after menopause make them more susceptible to trauma from the friction of a pessary. Locally‐applied oestrogen could improve the elasticity, strength and moistness of the vaginal wall and reduce pessary‐related complications (Lindahl 2014).
Why it is important to do this review
As one of the greatest risk factors, our ageing population is likely to lead to an increase in the incidence of POP (Vergeldt 2015). Therefore, evidence is necessary to guide clinicians in optimising the management of postmenopausal women with POP. Oestrogens are currently being used by many clinicians in daily clinical practice in the treatment of POP in women, sometimes in conjunction with other therapies, such as pessaries or surgery, without clear supporting evidence. This review would allow the synthesis of information from randomised controlled trials to confirm the appropriateness of current practice, ensure that the management of POP using oestrogens is evidence‐based and highlight the potential need for future research.
Objectives
To assess the effects of oestrogen therapy for treating pelvic organ prolapse in postmenopausal women; and summarise the principal findings of relevant economic evaluations.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs) and quasi‐randomised controlled trials (studies where allocation to groups is not strictly random, e.g. by day of the week), including multi‐arm and cross‐over trials.
Types of participants
We will include studies where the participants are either symptomatic or asymptomatic postmenopausal women (one year since last menses) with any grade or type of POP of any compartment. We will consider trials with a mix of postmenopausal and premenopausal women if they present data for postmenopausal women separately.
Types of interventions
We will include studies that use any compound containing natural or synthetic oestrogen in any form or dose, for any length of time. We will analyse systemic and local routes of administration via subgroup analyses.
We will prepare 'Summary of findings' tables for the following comparisons.
Oestrogen therapy alone versus no treatment or placebo
Oestrogen therapy alone versus PFMT
Oestrogen therapy alone versus devices such as vaginal pessaries
Oestrogen therapy alone versus surgery
Other specific comparisons in the review will be as follows.
Oestrogen therapy in conjunction with PFMT versus PFMT alone
Oestrogen therapy in conjunction with vaginal pessaries versus vaginal pessaries alone
Oestrogen therapy in conjunction with surgery versus surgery alone
Types of outcome measures
Abbreviations of outcome measurement tools can be found in Appendix 2.
Primary outcomes
Patient‐reported subjective improvement or cure of pelvic organ prolapse symptoms, measured by tools such as VAS (Ulrich 2014) or PGI‐I (Srikrishna 2010)
Secondary outcomes
Improvement or cure of associated urinary symptoms (measured by validated questionnaires such as KHQ (Kelleher 1997); ICIQ‐UI‐SF (Avery 2004); ICIQ‐FLUTS (Brookes 2004))
Improvement or cure of associated bowel symptoms (measured by validated questionnaires such as KHQ (Kelleher 1997))
Improvement or cure of associated sexual symptoms (measured by validated questionnaires such as PISQ‐IR (Constantine 2017))
Patient satisfaction with treatment for prolapse (measured by patient self‐report such as PGI‐I (Srikrishna 2010))
Objective improvement or cure of pelvic organ prolapse (measured objectively by POP‐SS (Hagen 2009); ICIQ‐VS (Price 2006); POP‐Q (Bump 1996); APFQ (Baessler 2009))
Condition‐specific quality of life (measured by prolapse‐specific quality of life questionnaires such as PFDI (Barber 2001); PFIQ (Barber 2001); P‐QOL (Digesu 2005); ePAQ‐PF (Radley 2006))
Generic quality of life or health status (measured by generic quality of life questionnaires such as QOLI (Frisch 2003); GQOL (Hyland 1996); AQoL (Hawthorne 1999))
Psychological or emotional well‐being outcome measures, ability to cope with daily activities (measured by generic quality of life questionnaires such as QLQ (Evans 1985))
Minor adverse effects or treatment burden of oestrogen therapy (e.g. vaginal discomfort, discharge, infection or ulceration, urinary tract infection, intolerance) or poor compliance
Major adverse events or medical complications of oestrogen therapy (e.g. endometrial hyperplasia, stroke, heart disease, venous thromboembolism or effect on other pre‐existing medical conditions)
Pessary management outcomes (e.g. discontinuation of pessary use or conversion from pessary use to surgery)
Surgical outcomes (e.g. prolapse recurrence or development of de novo prolapse in another compartment, surgical trauma to surrounding tissues or organs intraoperatively)
Timing of outcome assessment
We will assess all outcomes at six months, 12 months, five years, and 10 years.
Minimum important difference for outcomes
We will look for the reported minimum important difference (MID) using specific symptom and quality of life questionnaires. It is noted that some reported MIDs relate to surgical and non‐surgical management of prolapse. We will look for reported MIDs for using oestrogen(s), either alone or alongside another treatment, or other treatment for POP. For example, a relevant MID would be the change to be expected as a result of using local oestrogen cream either before and after pessary or surgery for POP, or before and after pessary or surgery for POP.
ICIQ‐UI‐SF: clinical MID is shown to be a reduction of four following non‐surgical intervention (Lim 2009).
KHQ: a change from baseline of five points on KHQ has been shown to be the clinical MID following an intervention (Kelleher 2004).
POP‐SS: MID is seen with a reduction of 1.5 points or more (Hagen 2010).
PFDI: an 8‐point improvement in the stress subscale of the PFDI for non‐surgical treatments is considered to be the MID (Barber 2009).
PFIQ: a 16‐point improvement in the urinary impact questionnaire of the PFIQ is considered to be the MID for non‐surgical treatment (Barber 2009).
AQOL: MID is suggested to be 0.06 utility points over time (Hawthorne 2005).
APFQ: MID is suggested to be one point after POP surgery (Baessler 2019).
There are no MID for PGI‐I, ICIQ‐FLUTS, PISQ‐IR, ICIQ‐VS, P‐QOL, QOLI/GQOL or QLQ. MID data for ePAQ‐PF are only available following surgical treatment for urinary incontinence.
Main outcomes for 'Summary of findings' tables for outcomes at 12 months
Subjective improvement or cure of pelvic organ prolapse symptoms
Objective improvement or cure of pelvic organ prolapse symptoms
Improvement or cure of associated urinary symptoms
Improvement or cure of associated bowel symptoms
Improvement or cure of associated sexual symptoms
Minor adverse effects
Major adverse events or medical complications
Search methods for identification of studies
We will not impose any restrictions, for example language or publication status, on the searches described below.
Electronic searches
Search for clinical effectiveness studies
We will identify relevant trials from the Cochrane Incontinence Specialised Register. For more details of the search methods used to build the Specialised Register, please see the Group's webpages where details of the Register's development (from inception) and the most recent searches performed to populate the Register can be found. To summarise, the Register contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In‐Process, MEDLINE Epub Ahead of Print, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and handsearching of journals and conference proceedings. Many of the trials in the Cochrane Incontinence Specialised Register are also contained in CENTRAL.
The terms that we will use to search the Cochrane Incontinence Specialised Register are given in Appendix 3.
Search for economic evaluations
We will perform additional searches for the brief economic commentary (BEC). We will search:
The NHS Economic Evaluation Database (NHS EED) on the Centre for Reviews and Dissemination (CRD) website (covering from the earliest record in NHS EED, dating from 1968, up to and including 31 December 2014, when their coverage ended).
As NHS EED is no longer actively updated, we will perform additional searches of the following databases to identify eligible studies added to these databases from 1 January 2015 onwards:
MEDLINE on OvidSP (covering 1 January 1946 to the most recent available version); and
Embase (on OvidSP) (covering 1 January 1974 to the most recent available version).
Details of the searches that will be performed can be found in Appendix 4.
Searching other resources
We will search the reference lists of all relevant reviews and trial reports to identify further relevant studies.
Data collection and analysis
We will conduct data collection and analysis in accordance with methods specified in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021).
Selection of studies
Two review authors (AT and EJ) will independently screen titles and abstracts of all results returned by the search, as well as assessing the eligibility of full‐text articles identified by the initial stage. We will resolve any disagreements by discussion or arbitration by a third review author.
Data extraction and management
Two review authors (AT and EJ) will independently perform data extraction for included studies using a piloted data extraction form. We will compare completed data extraction forms for disagreements, which we will resolve by consensus. We will input all outcome data into Review Manager 5 (Review Manager 2020).
Assessment of risk of bias in included studies
Two review authors (AT and one other) will independently assess the risk of bias for each included study using Cochrane's 'Risk of bias' tool (Higgins 2011). The tool covers the following domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other bias. We will assess each source of bias as either high, low, or unclear and provide a justification for our judgement in the 'Risk of bias’ tables. We will resolve any disagreements by discussion.
Measures of treatment effect
We will base our analyses on available data from all included trials relevant to the comparisons and outcomes of interest. We will summarise effect estimates for dichotomous outcomes using risk ratios (RRs) and corresponding 95% confidence intervals (CIs). For continuous outcomes, we will use the mean difference (MD) or standardised mean difference (SMD) and corresponding 95% CI. For continuous outcome data, we will use the MD of post‐treatment scores unless change from baseline data are available.
Unit of analysis issues
Where appropriate, we will analyse cross‐over trial data using paired sample means and SE tests. We will analyse multi‐arm studies that compare two interventions arms with one control group using the methods described by Higgins 2021. We will prevent double‐counting of individuals by analysing each treatment arm separately against the common control group and dividing the sample size of the common comparator group proportionately across each intervention comparison.
Dealing with missing data
We will contact study authors in order to obtain missing data where possible. If numerical data such as standard deviations or correlation coefficients are missing, we will use the methods described in the Cochrane Handbook for Systematic Reviews of Interventions to attempt to calculate them from other available statistics, such as P values (Higgins 2021). If we have not received any response after two attempts to contact study authors, we will list the study as 'awaiting classification'.
Assessment of heterogeneity
We will assess clinical heterogeneity (i.e. differences in study populations, interventions, and outcomes) of studies qualitatively. For studies that have sufficient homogeneity to be included in a meta‐analysis, we will assess heterogeneity by visual examination of the forest plots, the Chi2 test (P ≤ 0.10) for heterogeneity and the I2 statistic. We will interpret I2 as follows:
0% to 40%: represents low heterogeneity;
30% to 60%: may represent moderate heterogeneity;
50% to 90%: may represent substantial heterogeneity;
75% to 100%: represents considerable heterogeneity.
We will discuss possible explanations for observed statistical heterogeneity. We will investigate the causes of heterogeneity between trials, qualitatively assessing any differences between individual trials in the populations and interventions. We plan to explore heterogeneity through the use of subgroup and sensitivity analyses.
Assessment of reporting biases
We will search study registries of prospectively registered trials to identify trials that have been completed but not published. We will investigate potential reporting bias in meta‐analyses with 10 or more studies by generating funnel plots (Egger 1997; Sterne 2011).
Data synthesis
Where appropriate, we plan to combine the outcome data from the individual trials in a meta‐analysis using Review Manager 5 (Review Manager 2020). Where outcome data from individual trials are not sufficiently similar to be combined quantitatively, we will narratively describe results from clinically comparable trials.
Where appropriate, we will pool effects across similar studies using fixed‐effect or random‐effects meta‐analysis techniques with 95% CIs. We will use the random‐effects model if the studies show heterogeneity, defined by an I2 statistic over 50%. Otherwise, we will use a fixed‐effect model to pool the data, using the Mantel‐Haenszel method for dichotomous data and the inverse variance method for continuous data (Mantel 1959). If available, we will use change from baseline data for continuous outcome data; otherwise, we will use raw outcome data.
Subgroup analysis and investigation of heterogeneity
Where data allow, we plan to perform the following subgroup analyses:
systemic or topical oestrogen;
parous or nulliparous women; and
women with or without a uterus.
Sensitivity analysis
If sufficient data are available, we will exclude studies with a high risk of bias from our meta‐analyses for the primary outcomes to assess the robustness of our conclusions.
Incorporating economics evidence
Following the search outlined in the Search methods for identification of studies, we will develop a BEC to summarise the availability and principal findings of the full economic evaluations that assess oestrogen therapy for treating pelvic organ prolapse in postmenopausal women (Aluko 2021). This BEC will encompass full economic evaluations (i.e. cost‐effectiveness analyses, cost‐utility analyses and cost‐benefit analyses) conducted as part of a single empirical study, such as an RCT, a model based on a single such study or a model based on several such studies.
Summary of findings and assessment of the certainty of the evidence
If there is sufficient evidence, we will prepare 'Summary of findings' tables using the GRADEpro GDT software for the main comparisons listed in the Types of interventions. To ensure clarity, we will create individual 'Summary of findings' tables for specific clinically important outcomes within the main comparisons.
We will use the GRADE approach to assess the certainty of evidence related to the primary and secondary outcomes, as stated in the Types of outcome measures (Schünemann 2021). We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the certainty of the body of evidence for the prespecified outcomes. We will justify all decisions to downgrade the certainty of studies using footnotes.
History
Protocol first published: Issue 5, 2021
Notes
To aid clarity, the previous Cochrane Review on this topic has been split into prevention and treatment (this review) of this condition (Ismail 2010).
Acknowledgements
We are grateful to Rohna Kearney, Luke Vale and Durhane Wong‐Rieger for valuable comments on drafts of this protocol.
Appendices
Appendix 1. Glossary of terms
| Term | Definition |
| Anterior vaginal wall | The front wall of the vagina (anterior compartment) |
| Cuff scar | The apex of the vagina which has formed a scar following a hysterectomy |
| Hysterectomy | Surgical removal of the uterus |
| Hysteropexy (sacrohysteropexy) | A surgical procedure for correcting prolapse of the uterus in women who wish to preserve their uterus |
| Nulliparous | Having never given birth |
| Parous | Having given birth one or more times |
| Pelvic floor muscle training (PFMT) | Intensive and regular pelvic floor exercises so that they become firm and supportive |
| Pelvic organ prolapse | Bulging or herniation of one or more pelvic organs (uterus, vagina, bowel or bladder) into or out of the vagina. |
| Posterior vaginal wall | The back wall of the vagina (posterior compartment). |
| Sacrocolpopexy | A surgical procedure for correcting prolapse of the vaginal vault in women who have had a hysterectomy. The vaginal vault is supported by using mesh attached to the sacrum (lower part of the spine) |
| Sarospinous fixation | A surgical procedure to restore support to the uterus or vaginal vault, where sutures are placed to attached the vaginal vault or cervix to the sacrospinous ligament in the pelvis |
| Topical oestrogens | Oestrogen applied directly to the vagina, either in the form of a vaginal tablet, cream, gel or ring pessary |
| Vaginal epithelium | The inner lining of the vagina. |
| Vaginal pessaries | Vaginal devices that come in various shapes and sizes to provide mechanical support to the prolapsed organs |
| Vaginal vault | The apex or top of the vagina. |
Appendix 2. Abbreviations: outcome measurement tools
| APFQ | Australian Pelvic Floor Questionnaire |
| AQoL | Assessment of Quality of Life |
| ePAQ‐PF | electronic Personal Assessment Questionnaire Pelvic Floor |
| GQOL | Global Quality of Life Scale |
| ICIQ‐FLUTS | International Consultation on Incontinence Questionnaire Female Lower Urinary Tract Symptoms Modules |
| ICIQ‐UI‐SF | International Consultation on Incontinence Questionnaire‐Urinary Incontinence Short Form |
| ICIQ‐VS | International Consultation on Incontinence Questionnaire Vaginal Symptoms |
| KHQ | King's Health Questionnaire |
| P‐QOL | Prolapse Quality of Life Questionnaire |
| PFDI | Pelvic Floor Distress Inventory |
| PFIQ | Pelvic Floor Impact Questionnaire |
| PGI‐I | Patient Global Impression of Improvement |
| PISQ‐IR | Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire, International Urogynecological Association‐Revised |
| POP‐Q | Pelvic Organ Prolapse Quantification system |
| POP‐SS | The Pelvic Organ Prolapse Symptom Score |
| QLQ | The Quality of Life Questionnaire |
| QOLI | Quality of Life Inventory |
| VAS | Visual analogue scale |
Appendix 3. Search of the Cochrane Incontinence Specialised Register ‐ for clinical effectiveness studies
The search terms that will be used to search the Cochrane Incontinence Specialised Register are given below:
((design.cct*) OR (design.rct*)) AND topic.prolapse* AND intvent.chem.horm*
All searches will be of the 'keywords' field of EndNote 2018.
Appendix 4. Search methods for the brief economic commentary (BEC)
We will perform electronic searches designed to identify published reports of relevant economic evaluations to inform the BEC (see 'Incorporating economic evidence' in the Methods). We will search:
The NHS Economic Evaluation Database (NHS EED) on the UK Centre for Reviews and Dissemination (CRD) website (covering from the earliest record in NHS EED, dating from 1968, up to and including 31 December 2014 when their coverage ended).
As NHS EED is no longer actively updated, we will perform additional searches of the following databases to identify eligible studies added to these databases from 1 January 2015 onwards:
MEDLINE on OvidSP (covering 1 January 1946 to the most recent available version); and
Embase (on OvidSP) (covering 1 January 1974 to the most recent available version).
The economic evaluation search filters which we will apply to our MEDLINE and Embase search strategies will be those formerly used by the CRD to identify published reports of full economic evaluations for indexing on NHS EED. These economic evaluation search filters remain freely available on the CRD Database website (CRD 2015). The other search lines in the MEDLINE and Embase search strategies will be adapted from the electronic search strategies run for our Cochrane Incontinence Specialised Register, along with additional terms for this population developed specifically for this review. Similarly, our NHS EED search strategy will be adapted from search strategies run for our Specialised Register and based on text word and MeSH terms (capturing relevant P‐I‐C concepts) used to identify eligible studies of intervention effects. We will follow the current economic methods guidance (Aluko 2021).
Contributions of authors
AT: drafting the Background, drafting the PICO, commenting on other aspects of the protocol, approval of the protocol SII: drafting the PICO, commenting on other aspects of the protocol, approval of the protocol EJ: drafting the Methods, commenting on other aspects of the protocol, approval of the protocol EBM: drafting the Methods, commenting on other aspects of the protocol, approval of the protocol AK: drafting the aspects of the text relating to the economics component, approval of the protocol RT: drafting of the PICO, commenting on clinical aspects of the protocol, approval of the protocol
Sources of support
Internal sources
No sources of support provided
External sources
-
National Institute for Health Research (NIHR), UK
This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to Cochrane Incontinence. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Evidence Synthesis Programme, the NIHR, NHS or the Department of Health and Social Care.
Declarations of interest
In accordance with Cochrane's Commercial Sponsorship Policy, the following declarations are applicable for the three years prior to the publication date of this protocol.
AT: none known SII: none known EJ: is Assistant Managing Editor for Cochrane Incontinence. She did not take part in the editorial process for this protocol. EBM: none known RT: unrelated educational lectures for Astellas and Pfizer
New
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