Oestrogen therapy for urinary incontinence in post‐menopausal women

June D Cody; Madeleine Louisa Jacobs; Karen Richardson; Birgit Moehrer; Andrew Hextall

doi:10.1002/14651858.CD001405.pub3

. 2012 Oct 17;2012(10):CD001405. doi: 10.1002/14651858.CD001405.pub3

Oestrogen therapy for urinary incontinence in post‐menopausal women

June D Cody ^1,^✉, Madeleine Louisa Jacobs ², Karen Richardson ³, Birgit Moehrer ⁴, Andrew Hextall ⁵

Editor: Cochrane Incontinence Group

PMCID: PMC7086391 PMID: 23076892

Abstract

Background

It is possible that oestrogen deficiency may be an aetiological factor in the development of urinary incontinence in women. This is an update of a Cochrane review first published in 2003 and subsequently updated in 2009.

Objectives

To assess the effects of local and systemic oestrogens used for the treatment of urinary incontinence.

Search methods

We searched the Cochrane Incontinence Group Specialised Register of trials (searched 21 June 2012) which includes searches of MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL) and handsearching of journals and conference proceedings, and the reference lists of relevant articles.

Selection criteria

Randomised or quasi‐randomised controlled trials that included oestrogens in at least one arm in women with symptomatic or urodynamic diagnoses of stress, urgency or mixed urinary incontinence or other urinary symptoms post‐menopause.

Data collection and analysis

Trials were evaluated for risk of bias and appropriateness for inclusion by the review authors. Data were extracted by at least two authors and cross checked. Subgroup analyses were performed by grouping participants under local or systemic administration. Where appropriate, meta‐analysis was undertaken.

Main results

Thirty‐four trials were identified which included approximately 19,676 incontinent women of whom 9599 received oestrogen therapy (1464 involved in trials of local vaginal oestrogen administration). Sample sizes of the studies ranged from 16 to 16,117 women. The trials used varying combinations of type of oestrogen, dose, duration of treatment and length of follow up. Outcome data were not reported consistently and were available for only a minority of outcomes.

The combined result of six trials of systemic administration (of oral systemic oestrogens) resulted in worse incontinence than on placebo (risk ratio (RR) 1.32, 95% CI 1.17 to 1.48). This result was heavily weighted by a subgroup of women from the Hendrix trial, which had large numbers of participants and a longer follow up of one year. All of the women had had a hysterectomy and the treatment used was conjugated equine oestrogen. The result for women with an intact uterus where oestrogen and progestogen were combined also showed a statistically significant worsening of incontinence (RR 1.11, 95% CI 1.04 to 1.18).

There was some evidence that oestrogens used locally (for example vaginal creams or pessaries) may improve incontinence (RR 0.74, 95% CI 0.64 to 0.86). Overall, there were around one to two fewer voids in 24 hours amongst women treated with local oestrogen, and there was less frequency and urgency. No serious adverse events were reported although some women experienced vaginal spotting, breast tenderness or nausea.

Women who were continent and received systemic oestrogen replacement, with or without progestogens, for reasons other than urinary incontinence were more likely to report the development of new urinary incontinence in one large study.

One small trial showed that women were more likely to have an improvement in incontinence after pelvic floor muscle training (PFMT) than with local oestrogen therapy (RR 2.30, 95% CI 1.50 to 3.52).

The data were too few to address questions about oestrogens compared with or in combination with other treatments, different types of oestrogen or different modes of delivery.

Authors' conclusions

Urinary incontinence may be improved with the use of local oestrogen treatment. However, there was little evidence from the trials on the period after oestrogen treatment had finished and no information about the long‐term effects of this therapy was given. Conversely, systemic hormone replacement therapy using conjugated equine oestrogen may worsen incontinence. There were too few data to reliably address other aspects of oestrogen therapy, such as oestrogen type and dose, and no direct evidence comparing routes of administration. The risk of endometrial and breast cancer after long‐term use of systemic oestrogen suggests that treatment should be for limited periods, especially in those women with an intact uterus.

Plain language summary

Oestrogens for urinary incontinence in women

Urinary incontinence is the leakage of urine when coughing or exercising (stress urinary incontinence) or after a strong uncontrollable urge to urinate (urgency urinary incontinence). In women who have gone through the menopause, low oestrogen levels may contribute to urinary incontinence. The review found 34 trials including more than 19,000 women of whom over 9000 received oestrogen. The review found that significantly more women who received local (vaginal) oestrogen for incontinence reported that their symptoms improved compared to placebo. There was no evidence about whether the benefits of local oestrogen continue after stopping treatment but this seems unlikely as women would revert to having naturally low oestrogen levels. Trials investigating systemic (oral) administration, on the other hand, found that women reported worsening of their urinary symptoms. The evidence comes mainly from two very large trials including 17,642 incontinent women. These trials were investigating other effects of hormone replacement therapy as well as incontinence, such as prevention of heart attacks in women with coronary heart disease, bone fractures, breast and colorectal cancer. In addition, in one large trial women who did not have incontinence at first were more likely to develop incontinence. There may be risks from long‐term use of systemic oestrogen, such as heart disease, stroke and cancer of the breast and uterus.

Summary of findings

Background

There are three major naturally occurring oestrogens in women (oestradiol, oestriol, oestrone). It is possible that oestrogen deficiency, for example after the menopause, may be an aetiological factor in the development of urinary incontinence in women. However, it is not known whether oestrogen replacement will help in the treatment of this condition.

Description of the condition

Urinary incontinence is a common and embarrassing problem which may affect women of all ages. Although not life threatening, incontinence can lead to loss of confidence and in some cases social isolation. Urinary incontinence is the complaint of any involuntary leakage of urine (Haylen 2010). Although treatment may be started based on symptoms alone, investigations may be used to accurately diagnose the underlying cause of the incontinence. The value of urodynamics in the management of urinary incontinence has yet to be established (Glazener 2012).

Stress urinary incontinence (SUI), which is the symptom of involuntary loss of urine associated with coughing, sneezing or physical activity, is the most common type (Haylen 2010). Urgency urinary incontinence (UUI) is the involuntary loss of urine accompanied by or immediately preceded by urgency, which is a sudden compelling desire to pass urine that is difficult to defer. Overactive bladder (OAB) syndrome is diagnosed when women have urinary urgency, usually accompanied by frequency and nocturia, with or without UUI, and in the absence of other pathology such as urinary tract infection (UTI) (Haylen 2010). These symptoms may also occur when the bladder is overactive, known as detrusor overactivity (DO), when it is diagnosed using urodynamics. Urodynamic stress incontinence (USI) is diagnosed when stress incontinence is confirmed in the absence of DO, using urodynamic studies. However, many women have a combination of problems including urinary frequency, urgency, and urgency urinary incontinence. Mixed urinary incontinence (MUI) is diagnosed when SUI and UUI, or SUI and DO, co‐exist.

Early studies of oestrogen therapy for incontinence were performed before the widespread use of urodynamic investigation. Therefore, it is likely that those earlier studies included a heterogeneous group of women, some of whom may have had a number of different types of urinary symptoms such as overactive bladder syndrome (OAB) or voiding difficulties (VD) in addition to incontinence.

Description of the intervention

Oestrogen can be given to post‐menopausal women to prevent osteoporosis as well as treat symptoms of menopause, such as hot flushes, vaginal dryness, fatigue, irritability, sweating and incontinence. Synthetic oestrogen can be given using a variety of different doses, routes and modes of delivery or formulations (oral or vaginal tablet, cream, skin patch, subcutaneous implant). Routes include systemic, such as oral and transdermal; or local, including vaginal and into the bladder (intravesical). Duration of therapy and assessment of effect also vary widely. The situation may be confounded by the concurrent use of progestogens to prevent endometrial hyperplasia in women who have not had a hysterectomy, which may themselves exacerbate both irritative urinary symptoms and incontinence (Benness 1991).

How the intervention might work

The female genital and urinary tracts both arise from the primitive urogenital sinus and develop in close anatomical proximity. Oestrogen receptors have been identified in the tissues of the vagina, bladder, urethra and muscles of the pelvic floor (Blakeman 1996; Iosif 1981; Smith 1993). Sex hormones such as oestrogen have a substantial influence on the female bladder throughout adult life with fluctuations in their levels leading to macroscopic, histological and functional changes. Urinary symptoms may therefore develop during the menstrual cycle, in pregnancy and following the menopause (Barlow 1997; Cutner 1992; Van Geelen 1981).

As the tissues involved in the female continence mechanism are oestrogen sensitive, it is possible that oestrogen deficiency may be an aetiological factor in the development of urinary incontinence. Epidemiological surveys have shown that the peak prevalence of stress incontinence occurs around the time of the natural menopause (Jolleys 1988; Kondo 1990; Thomas 1980). In addition, 70% of incontinent post‐menopausal women have been reported to relate the onset of their incontinence to the time of their final menstrual period (Iosif 1984). On the other hand, many studies show that more pre‐menopausal women are affected by incontinence than post‐menopausal women, with the prevalence of stress incontinence actually falling following the menopause (Hannestad 2000).

Why it is important to do this review

A variety of other options are available for the treatment of incontinence, including pelvic floor muscle training (Dumoulin 2010; Boyle 2012; Herbison 2002; Kovoor 2008; Patel 2008), vaginal ring pessaries (Lipp 2011), a number of different types of medication (Alhasso 2005; Madhuvrata 2012; Nabi 2006; Roxburgh 2007) and surgery (Dean 2006; Glazener 2001; Glazener 2004; Kirchin 2012; Lapitan 2012; Liapis 2010 L; Ogah 2009; Rehman 2011). The female hormone oestrogen has been used to treat incontinence over a number of years, either alone or in combination with some of these other options. However, most trials involve only a small number of women and few have attempted long‐term follow up. Two very large trials of women receiving hormone replacement therapy have been published showing a negative effect of hormones on incontinence (Grady 2001 S; Hendrix 2005 S). This review will consider all of the evidence regarding oestrogen therapy as a treatment for incontinence.

Objectives

To assess the effects (both beneficial and harmful) of oestrogen therapy used for the treatment of urinary incontinence.

The following comparisons were made.

1. Oestrogen therapy versus placebo or no treatment for urinary incontinence.

2. Oestrogen therapy versus other forms of treatment (e.g. physical, drugs, surgery) for urinary incontinence.

3. Oestrogen combined with other therapy versus placebo or no treatment for urinary incontinence.

4. Oestrogen given in combination with another treatment versus oestrogen given alone for urinary incontinence.

5. Oestrogen given in combination with another treatment versus that other treatment given alone for urinary incontinence.

6. One type of oestrogen versus another.

7. One method of administration of oestrogen versus another.

8. A high dose of oestrogen versus a lower dose.     Subgroup analysis was performed according to the route of administration (systemic or local).

Methods

Criteria for considering studies for this review

Types of studies

All randomised or quasi‐randomised controlled trials of oestrogen therapy for the treatment of urinary stress, urgency or mixed incontinence.

Types of participants

Post‐menopausal women with urinary incontinence and diagnosed as having urinary stress, urgency or mixed incontinence either by symptom classification or by urodynamic diagnosis, as defined by the trialists.

Types of interventions

a) Oestrogen therapy, which includes different types of oestrogens, different doses and different routes of administration.

b) Comparators: no therapy, placebo, or non‐oestrogen therapies (which include physical, pessary, drugs and surgery).

Types of outcome measures

Primary outcomes

1. Women's observations

Continuing incontinence or lack of improvement in incontinence

Secondary outcomes

2. Quantification of symptoms

Pad changes over 24 hours (self‐reported number of pads used)
Incontinent episodes per 24 hours (as indicated from self‐completed bladder chart)
Frequency (micturitions per 24 hours)
Pad tests of quantified leakage (weight of urine loss)
Urgency

3. Clinician's measures (urodynamics or cystometry)

Maximum urethral closure pressure (MUCP) (cm H_²O)
Volume at first urge to void (ml)
Maximum bladder capacity (ml)

4. Quality of life

Severity of incontinence e.g. index score: slight, moderate or severe (Sandvik 1993)
Impact of incontinence on quality of life e.g. Urogenital distress Inventory (Shumaker 1994), Disease Specific Quality of Life Questionnaire (Jackson 1996; Kelleher 1997)
Psychological measures e.g. Crown‐Crisp Experimental Index (Crown 1979)
General health status e.g. Short Form‐36 (Ware 1993)

5. Socioeconomics

Costs of intervention(s)
Resource implications of differences in outcomes
Formal economic analysis (cost effectiveness, cost utility)

6. Adverse outcomes

Vaginal bleeding
Uterine cancer
Cardiovascular disease e.g. stroke, heart disease
Breast cancer

7. Other outcomes

Non‐prespecified outcomes that were judged important when performing the review

Search methods for identification of studies

Limitations such as different languages were not imposed on any of the searches described below.

Electronic searches

This review has drawn on the search strategy developed for the Cochrane Incontinence Review Group. Relevant trials were identified from the Cochrane Incontinence Group Specialised Register of controlled trials, which is described under the Incontinence Group's module in The Cochrane Library. The register contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, CINAHL and handsearching of journals and conference proceedings. The date of the most recent search of the register for this review was 21 June 2012.

The trials in the Cochrane Incontinence Group Specialised Register are also contained in CENTRAL. The terms used to search the Incontinence Group Specialised Register are given below:     ({DESIGN.CCT*} OR {DESIGN.RCT*})   AND   ({INTVENT.CHEM.HORM*} OR {INTVENT.CHEM.DRUG.ESTROGEN CREAM.} OR {INTVENT.CHEM.DRUG.MESTINON.} OR {INTVENT.CHEM.DRUG.MISOPROSTOL} OR {INTVENT.CHEM.DRUG.NORETHANDROLONE} OR {INTVENT.CHEM.DRUG.TAMOXIFEN.})   (all searches were of the keywords field of Reference Manager 12, Thomson Reuters).

Searching other resources

The review authors also searched the reference lists of relevant articles.

Data collection and analysis

Selection of studies

Trials under consideration were evaluated for risk of bias and appropriateness for inclusion by at least two review authors, without prior consideration of the results. Any disagreements were resolved by discussion or with a third party. Assessment of risk of bias was undertaken by at least two authors using the Cochrane Collaboration's assessment criteria, which include quality of random allocation concealment, description of dropouts and withdrawals, analysis on an intent to treat, and 'blinding' at treatment and outcome assessment. Again, any disagreements were resolved by discussion or with a third party.

Data extraction and management

Data extraction was undertaken independently by all three review authors. Where data may have been collected in a study but was not reported, further clarification was sought from the trialists. Trial data were analysed according to the treatment or type of intervention compared and grouped, if possible, by route of administration (systemic or local). Any differences of opinion related to the data extracted were resolved by discussion or with a third party.

Assessment of risk of bias in included studies

Studies were excluded if they were not randomised or quasi‐randomised controlled trials, or if they made comparisons other than those specified for the review. These studies are listed in the Characteristics of excluded studies table.

Measures of treatment effect

Included trial data were processed as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). When appropriate, meta‐analysis was undertaken of the parallel group studies. For categorical outcomes the numbers in each group reporting an outcome were related to the numbers at risk to derive a risk ratio (RR), where sufficient data to calculate an RR were available. The data were combined using the Mantel‐Haenszel method. For continuous variables we used means and standard deviations to derive a mean difference (MD). When summary data were not available from all trials for a particular outcome and only adjusted risk ratios were reported, the generic inverse variance method was used to combine risk ratios. A fixed‐effect model was used for calculation of pooled estimates and their 95% confidence intervals (CIs). Data from these trials were presented in 'Other data' tables only.

Assessment of heterogeneity

Trials were only combined if the interventions were similar enough based on clinical criteria (types of interventions). Differences between trials were investigated if significant heterogeneity was found at the statistical significance level of 10% or by using the I² statistic (Higgins 2003), or it appeared obvious from visual inspection of the results. If there was no obvious reason for the heterogeneity, use of a random‐effects model was considered. If a reason was found then a judgement was made as to whether it was reasonable to combine the results.

Subgroup analysis and investigation of heterogeneity

Trial data were grouped by route of administration (systemic or local), where possible. The suffix S or L was used to denote systemic or local administration, respectively. Further details on type of oestrogen, dose, length of treatment and population (type of urinary incontinence, menopausal status) are given in Table 12.

1. Summary of study characteristics: type of oestrogen, route of administration, dose, length of treatment, population.

Study ID	Type of Oestrogen	Route of administration	Dose	Length of treatment	Population
Ahlstrom 1990 S	Oestriol	Systemic (oral)	4mg	6 weeks	USI (stress), postmenopausal
Assassa 2003 L	Oestrogen	Local (vaginal ring)	?	3 months	UI, postmenopausal
Beisland 1984 L	Oestriol	Local (vaginal)	1 mg	8 weeks	UI (stress), postmenopausal
Blom 1995 S	Estradiol	Systemic (transdermal)	0.05 mg	8 weeks	UUI (OAB), elderly
Cardozo 1993 S	Oestriol	Systemic (oral)	3 mg	3 months	UUI (urge), postmenopausal
Cardozo 2001 L	Oestradiol	Vaginal (pessary, Vagifem)	25 µgm	3 months	OAB (urge), postmenopausal
Dessole 2004 L	Oestriol	Local (intravaginal ovules)	1‐2 mg	6 months	UI (stress), postmenopausal
Ek 1980 S	Oestradiol	Systemic (oral)	1 mg	6 weeks	USI (stress), postmenopausal
Enzelsberger 1990 L	Oestriol	Local (vaginal)	0.5, 1 or 2 mg	Not stated	UI (urge), OAB
Enzelsberger 1991a L; Enzelsberger 1991b L	Oestriol	Local (vaginal)	1 mg or 3 mg	3 weeks	UI (urge), OAB, postmenopausal
Fantl 1996 S	Conjugated equine oestrogens + medroxyprogesterone	Systemic (oral)	0.625 mg / 10 mg	3 months	UI (stress), postmenopausal
Grady 2001 S	Conjugated oestrogens (premarin) + medroxyprogesterone	Systemic (oral)	0.625 mg / 2.5 mg	up to 4 years	UI (unspecified), postmenopausal, heart disease, age <80 years, with uterus
Henalla 1989 L	Conjugated equine oestrogen	Local (vaginal cream)	1.25 mg	3 months	USI (stress)
Henalla 1990 L	Conjugated equine oestrogen	Local (vaginal cream)	2 gm	6 weeks	USI (stress), postmenopausal
Hendrix (hysterectomy) S	Conjugated equine oestrogen	Systemic (oral)	0.625 mg	1 year	UI (SUI, UUI, MUI), postmenopausal, prevention of heart disease and hip fracture Without uterus
Hendrix (no hysterect) S	Conjugated equine oestrogen + medroxyprogesterone	Systemic (oral)	0.625 mg / 2.5 mg	1 year	UI (SUI, UUI, MUI), postmenopausal, prevention of heart disease and hip fracture With uterus
Hilton 1990 SL	Oestrogen	Local (intravaginal) Systemic (oral)	2 gm 1.25 mg	1 month	USI (stress), postmenopausal
Ishiko 2001 S	Estriol	Systemic (oral)	1 mg	2 years	SUI (stress), postmenopausal
Jackson 1999 S	Oestradiol	Systemic (oral)	2 mg	6 months	USI (stress), postmenopausal
Judge 1969 S	Quinestradiol	Not stated	1 mg	1 month	UI (unspecified), postmenopausal, geriatric inpatients
Kinn 1988 S	Oestriol	Systemic (oral)	4 mg	1 month	USI (stress), postmenopausal
Kurz 1993 L	Oestriol	Local (intravesical)	1 mg	3 weeks	UUI, OAB (urge), postmenopausal
Liapis 2010 L	Oestradiol	Local (intravaginal tablets)	25 mcg	6 months	SUI
Lose 2000 L	Oestradiol	Local (intravaginal ring, vaginal pessaries)	ring 7.5mg, pessary 0.5 mg	6 months	UI (unspecified), LUT symptoms, postmenopausal
Melis 1997 L	Oestriol	Local (intravaginal)	0.5 mg	3 months	UI, menopausal symptoms
Ouslander 2001 S	Oestrogen + progesterone	Systemic (oral)	0.625 mg / 2.5 mg	6 months	UI (unspecified), nursing home residents
Rufford 2003 S	17‐beta oestradiol	Systemic (implant)	25 mg	6 months	UUI, OAB (urge), postmenopausal
Sacco 1990 L	Oestrogen	Local (cream)	0.5 mg	3 months	USI (stress), postmenopausal
Samsioe 1985 S	Oestriol	Systemic (oral)	3 mg	3 months	MUI (mixture), postmenopausal
Tinelli 2007 L	Oestradiol	Systemic (oral)	10 mg	12 months	SUI
Tseng 2007 L	Oestrogen	Local (vaginal)	1 gm	12 weeks	OAB
Walter 1978 S	Oestradiol + oestriol	Systemic (oral)	2 mg / 1 mg	4 months (with breaks)	SUI, MUI (stress and mixed), postmenopausal
Walter 1990 S	Oestriol	Systemic (oral)	4 mg	1‐2 months	SUI (stress), postmenopausal
Wilson 1987 S	Piperazine oestrone sulphate	Systemic (oral)	3 mg	3 months (with breaks)	USI (stress), postmenopausal
Zullo 2005 L	Estriol	Local (intravaginal ovules)	1 mg	6 months	SUI (stress), postmenopausal

Oestrogen compared to placebo or no treatment for urinary incontinence in post‐menopausal women
Patient or population: patients with urinary incontinence in post‐menopausal women   Settings:   Intervention: Oestrogen   Comparison: placebo or no treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo or no treatment	Oestrogen
Incontinence not improved (generic inverse variance) (women's observations) ‐ Systemic administration (any incontinence)	640 per 1000	845 per 1000   (749 to 948)	RR 1.32   (1.17 to 1.48)	6151   (6 studies)	⊕⊕⊝⊝   low¹
Incontinence not improved (generic inverse variance) (women's observations) ‐ Local administration (any incontinence)	888 per 1000	657 per 1000   (568 to 764)	RR 0.74   (0.64 to 0.86)	213   (4 studies)	⊕⊝⊝⊝   very low^2,3
Incontinent episodes over 24 hours ‐ Systemic administration		The mean incontinent episodes over 24 hours ‐ systemic administration in the intervention groups was   0.54 higher   (0.5 lower to 1.57 higher)		82   (2 studies)	⊕⊕⊝⊝   low
Number of women with urgency ‐ Systemic administration	Study population		RR 1.05   (0.83 to 1.33)	89   (2 studies)	⊕⊕⊕⊝   moderate⁴
	750 per 1000	788 per 1000   (622 to 998)
	Moderate
	767 per 1000	805 per 1000   (637 to 1000)
Number of women with urgency ‐ Local administration	Study population		RR 0.38   (0.15 to 0.99)	90   (2 studies)	⊕⊕⊕⊝   moderate⁵
	289 per 1000	110 per 1000   (43 to 286)
	Moderate
	290 per 1000	110 per 1000   (44 to 287)
Number with adverse effects ‐ Systemic administration	Study population		RR 13   (1.87 to 90.21)	40   (1 study)	⊕⊕⊝⊝   low⁶
	50 per 1000	650 per 1000   (94 to 1000)
	Moderate
	50 per 1000	650 per 1000   (94 to 1000)
Number with adverse effects ‐ Local administration	Study population		RR 1.33   (0.32 to 5.61)	144   (2 studies)	⊕⊕⊕⊝   moderate⁷
	42 per 1000	55 per 1000   (13 to 234)
	Moderate
	34 per 1000	45 per 1000   (11 to 191)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.

Oestrogen versus other treatments for urinary incontinence in post‐menopausal women
Patient or population: patients with urinary incontinence in post‐menopausal women   Settings:   Intervention: Oestrogen versus other treatments
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Oestrogen versus other treatments
Number with incontinence not improved (women's observations) ‐ Oestrogen vs PPA	Study population		RR 0.83   (0.63 to 1.09)	57   (2 studies)	⊕⊕⊕⊝   moderate¹
	833 per 1000	692 per 1000   (525 to 908)
	Moderate
	867 per 1000	720 per 1000   (546 to 945)
Adverse effects ‐ oestrogen vs PPA	See comment	See comment	Not estimable	30   (1 study)	⊕⊕⊝⊝   low²
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.

Oestrogen + other treatments versus placebo for urinary incontinence in post‐menopausal women
Patient or population: patients with urinary incontinence in post‐menopausal women   Settings:   Intervention: Oestrogen + other treatments versus placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Oestrogen + other treatments versus placebo
Incontinent episodes over 24 hours ‐ oestrogen + progesterone vs placebo		The mean incontinent episodes over 24 hours ‐ oestrogen + progesterone vs placebo in the intervention groups was   0.43 lower   (1.17 lower to 0.31 higher)		83   (1 study)	⊕⊕⊕⊝   moderate¹
Incontinence not improved (generic inverse variance) (women's observation) ‐ oestrogen + other treatments versus placebo	663 per 1000	736 per 1000   (689 to 782)	RR 1.11   (1.04 to 1.18)	10,635   (3 studies)	⊕⊕⊕⊝   moderate²
Number with incontinence not improved (women's observations) ‐ oestrogen + progesterone vs placebo (Copy)	Study population		RR 1.08   (1.01 to 1.16)	1514   (2 studies)	⊕⊕⊕⊕   high
	663 per 1000	716 per 1000   (669 to 769)
	Moderate
	608 per 1000	657 per 1000   (614 to 705)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.

Number with incontinence not improved (women's observations) (cross‐over trials)
Study	oestrogen + other drug	oestrogen
oestrogen + PPA vs oestrogen
Ahlstrom 1990 S	17 out of 27 women	21 out of 26 women
Kinn 1988 S	14 out of 30 women	21 out of 30 women

Volume at first urge to void (cross‐over trials)
Study	oestrogen + naproxen	oestrogen
oestrogen + PPA vs oestrogen
Blom 1995 S	172 ml (SD 12) N=16	186 ml (SD 12) N=16

Date	Event	Description
10 September 2012	New search has been performed	Added two trials (Assassa 2003 L; Liapis 2010 L). The two trials compared topical oestrogen to other interventions. Removed Chompootaweep (Chompootaweep 1998 SL) as women were not incontinent at baseline; 22 new studies have been excluded. The conclusions are unchanged since the amendment from 2009.
10 September 2012	New citation required but conclusions have not changed	Added two trials (Assassa 2003 L; Liapis 2010 L). The two trials compared topical oestrogen to other interventions. Removed Chompootaweep (Chompootaweep 1998 SL) as women were not incontinent at baseline; 22 new studies have been excluded. The conclusions are unchanged since the amendment from 2009.

Date	Event	Description
23 September 2009	Amended	changed figures for Hendrix
2 April 2009	New citation required and conclusions have changed	Substantive amendment Issue 4 2009   Substantive update of review. Six new trials have been added, and extra data were added to four existing trials. One previously included trial was excluded and 10 new studies have been excluded. The conclusions have changed as a consequence of information from two large RCTs of hormone replacement therapy, such that urinary incontinence is likely to worsen with systemic conjugated equine oestrogens. However, there may still be benefits from local administration of oestrogens.
21 May 2008	Amended	Converted to new review format.
1 February 2003	New search has been performed	First published Issue 2 2003

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number with incontinence (women's observations)	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.1 Systemic administration	4	197	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.70, 0.98]
1.2 Local administration	2	144	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.62, 0.87]
2 Number with incontinence not improved (women's observations)	9		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.1 Systemic administration	5	231	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.58, 0.93]
2.2 Local administration	4	213	Risk Ratio (M‐H, Fixed, 95% CI)	0.53 [0.43, 0.65]
3 Incontinence not improved (generic inverse variance) (women's observations)	10		Risk Ratio (Fixed, 95% CI)	Subtotals only
3.1 Systemic administration (any incontinence)	6	6151	Risk Ratio (Fixed, 95% CI)	1.32 [1.17, 1.48]
3.2 Local administration (any incontinence)	4	213	Risk Ratio (Fixed, 95% CI)	0.74 [0.64, 0.86]
4 Number with incontinence (objective observations)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.1 Local administration	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Number with incontinence not improved (objective observations)	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
5.1 Local administration	2	52	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.57, 0.95]
6 Number of pad changes over 24 hours	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
6.1 Systemic administration	3	112	Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.89, 0.66]
7 Pad test weights	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
7.1 Systemic administration	3	106	Mean Difference (IV, Fixed, 95% CI)	1.75 [‐5.67, 9.16]
8 Incontinent episodes over 24 hours	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
8.1 Systemic administration	2	82	Mean Difference (IV, Fixed, 95% CI)	0.54 [‐0.50, 1.57]
9 Number of voids over 24 hours	7		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
9.1 Systemic administration	3	125	Mean Difference (IV, Fixed, 95% CI)	‐0.25 [‐1.22, 0.73]
9.2 Local administration	4	112	Mean Difference (IV, Fixed, 95% CI)	‐1.80 [‐2.58, ‐1.03]
10 Number of nocturnal voids	5		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
10.1 Systemic administration	2	112	Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.40, 0.16]
10.2 Local administration	3	82	Mean Difference (IV, Fixed, 95% CI)	‐2.03 [‐2.82, ‐1.24]
11 Number of women with frequency	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
11.1 Systemic administration	1	46	Risk Ratio (M‐H, Fixed, 95% CI)	1.40 [0.89, 2.19]
11.2 Local administration	2	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.43 [0.19, 0.98]
12 Number of women with nocturia	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
12.1 Systemic administration	1	45	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.62, 1.62]
12.2 Local administration	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	0.5 [0.11, 2.38]
13 Number of women with urgency	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
13.1 Systemic administration	2	89	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.83, 1.33]
13.2 Local administration	2	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.15, 0.99]
14 Maximum urethral closure pressure (MUCP)	7		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
14.1 Systemic administration	2	89	Mean Difference (IV, Fixed, 95% CI)	‐1.41 [‐6.24, 3.43]
14.2 Local administration	5	202	Mean Difference (IV, Fixed, 95% CI)	4.35 [2.49, 6.22]
15 Volume at first urge to void	7		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
15.1 Systemic administration	3	153	Mean Difference (IV, Fixed, 95% CI)	9.09 [‐25.45, 43.62]
15.2 Local administration	4	116	Mean Difference (IV, Fixed, 95% CI)	19.09 [13.21, 24.96]
16 Maximum bladder capacity	7		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
16.1 Systemic administration	3	153	Mean Difference (IV, Fixed, 95% CI)	7.18 [‐33.26, 47.62]
16.2 Local administration	4	116	Mean Difference (IV, Fixed, 95% CI)	50.11 [35.81, 64.41]
17 Number with adverse effects	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
17.1 Systemic administration	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	13.0 [1.87, 90.21]
17.2 Local administration	2	144	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.32, 5.61]
18 Number with bacteriuria	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
18.1 Systemic administration	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.37, 1.42]
18.2 Local administration	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.3 [0.13, 0.68]

Number with incontinence, crossover studies (women's observations)
Study	Oestrogen	PPA
Oestrogens vs PPA
Beisland 1984 L	9 out of 10 women	10 out of10 women

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number with incontinence not improved (women's observations)	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.1 oestrogen + progesterone vs placebo	2	1514	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [1.01, 1.16]
2 Incontinence not improved (generic inverse variance) (women's observations)	3		Relative Risk (Fixed, 95% CI)	Subtotals only
2.1 Systemic administration of oestrogen + progesterone vs placebo	3	10635	Relative Risk (Fixed, 95% CI)	1.11 [1.04, 1.18]
3 Incontinent episodes over 24 hours	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.1 oestrogen + progesterone vs placebo	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Number of diurnal voids per 24 hours	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.1 oestrogen + progesterone vs placebo	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Number of nocturnal voids per 24 hours	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.1 oestrogen + progesterone vs placebo	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Pad test weights	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
6.1 oestrogen + progesterone vs placebo	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Use of drugs for incontinence	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.1 oestrogen + progesterone vs placebo	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 Number of women having incontinence surgery	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8.1 oestrogen + progesterone vs placebo	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Methods	RCT (double‐blind crossover)   ITT
Participants	29 women   Incl: USI, post‐menopausal   Excl: hypertension, significant bacteriuria, previous breast or uterine cancer, residual urine, drugs (neuroleptics, sedatives, antihistamines, ephedrine, B‐blockers, gestagens, oestrogens within previous 2 months   Mean age 63 (range 51‐73) years   Mean weight 71 (range 55‐90) kg
Interventions	Group A (n=29): 4mg oestriol + 50mg PPA twice daily for 6/52   Group B (n=29): 4mg oestriol + placebo for 6/52
Outcomes	Urodynamics, urinary diary, subjective assessment, assessment of atrophy, urethral + vaginal cytology, feeling of vaginal dryness, pad test
Notes	No useable data; adverse events: group 1: 1 sweating, 1 constipation, 1 insomnia; group 2: 1 gastritis, 1 paraesthesia, 1 tachycardic attack, 1 dizziness, 2 nausea, 1 vomiting, 1 constipation; losses to follow up: group 1:1
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomization was made in groups of 4"
Allocation concealment (selection bias)	Unclear risk	no description
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias)   All outcomes	Low risk	"all 29 completed, one woman withdrawn from analyses of second treatment period due to failure in medication"

Methods	RCT (double‐blind placebo)
Participants	220 post‐menopausal women Inclusion: Urinary incontinence and storage symptoms
Interventions	Topical oestrogen (Estring) versus placebo for 3 months Assessment was undertaken using urinary diaries, pad tests and physical examination
Outcomes	Primary: Symptom severity including urinary incontinence, frequency, urgency and nocturia. Impact on activities, cost effectiveness and patient satisfaction. Secondary: Clinical improvement in incontinence and voiding function. Changes in atrophic vaginitis and sexual function.
Notes	All women received standard non‐pharmacological therapies by fully trained nurses for storage symptoms.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No expansion on "randomisation"
Allocation concealment (selection bias)	Unclear risk	no description
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	no description

Methods	Randomised open comparative crossover trial; duration of study: 12/52; assessment after each 4/52 period of treatment
Participants	20 post‐menopausal women   Inclusion criteria: incontinence   Exclusion criteria: neurological and gynaecological disorders, urinary tract infections or tumours, general conditions contraindicating oestrogen and phenylpropanolamine therapy
Interventions	Group A (n=20): 1mg oestriol vaginally daily for 4/52, then 50mg phenylpropanolamine (PPA) orally twice daily for 4/52, then combined for 4/52   Group B (n=20): 50 mg phenylpropanolamine twice daily for 4/52, then 1mg oestriol vaginally daily for 4/52, then combined for 4/52
Outcomes	Subjective assessment of treatment result, urodynamics, atrophy evaluation by clinical picture, cytological investigation by urethral smear   Definition of cure: patient described improvement as good, definition of improvement: patient‐reported improved, definition of failure: patient‐reported unchanged or worse
Notes	adverse events: 1 genital bleeding in period of combined treatment, 1 complete insomnia after 3 days with PPA   losses to follow up: 2 (same patients as for adverse events)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	no description
Allocation concealment (selection bias)	Unclear risk	Unclear
Blinding (performance bias and detection bias)   All outcomes	High risk	"randomised open comparative cross‐over trial"
Incomplete outcome data (attrition bias)   All outcomes	Low risk	18 out of 20 completed the study

Methods	Placebo controlled, single‐blind randomised crossover study   Duration of study: 28/52
Participants	16 women,   Inclusion criteria: ambulant elderly women with established detrusor instability; 13 out of 16 had hysterectomy   Exclusion criteria: breast or endometria carcinoma, thromboembolic disorders, severe hypertension, cardiac failure, diabetes mellitus, peptic ulceration   Drugs that could interact with effects of study medication were discontinued
Interventions	Crossover study   Group A(n=16): oestradiol TTS transdermal system 0.05 mg/day, patch twice weekly for 8/52   Group B (n=16): oestradiol TTS transdermal system 0.05 mg/day, patch twice weekly + naproxen tablets 250 mg bd for 8/52   Group C (n=16): placebo TTS transdermal system, patch twice weekly for 8/52   Washout period of 2/52 followed each medication regimen
Outcomes	Urinary diary, cystometry
Notes	No useable data; adverse events: skin reactions to transdermal system: mild erythema and itching, 2 patients had more severe cutaneous reactions, but continued with treatment, systemic adverse effects: mild breast tenderness, 1 patient with uterus experienced spotting   Losses to follow‐up: 3, for reasons not related to study medication
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	no description
Allocation concealment (selection bias)	Unclear risk	Unclear
Blinding (performance bias and detection bias)   All outcomes	High risk	Open‐label single blind (patients blinded?)
Incomplete outcome data (attrition bias)   All outcomes	Low risk	16 out of 19 completed. "Drop out not related to study medication"

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Number of pad changes over 24 hours	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.1 oestrogen cream vs oestrogen orally	1	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Number of voids over 24 hours	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.1 oestrogen cream vs oestrogen orally	1	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Pad test weights	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.1 oestrogen cream vs oestrogen orally	1	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of voids over 24 hours	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.1 high dose vs low dose	2	65	Mean Difference (IV, Fixed, 95% CI)	‐1.02 [‐1.87, ‐0.16]
2 Number of nocturnal voids	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
2.1 high dose vs low dose	2	65	Mean Difference (IV, Fixed, 95% CI)	‐1.80 [‐2.36, ‐1.24]
3 Maximum urethral closure pressure (MUCP)	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
3.1 high dose vs low dose	2	65	Mean Difference (IV, Fixed, 95% CI)	3.84 [‐5.77, 13.46]
4 Volume at first urge to void	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
4.1 high dose vs low dose	2	65	Mean Difference (IV, Fixed, 95% CI)	‐1.56 [‐12.20, 9.08]
5 Maximum bladder capacity	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
5.1 high dose vs low dose	2	65	Mean Difference (IV, Fixed, 95% CI)	34.90 [8.35, 61.45]

Methods	Multicentre study, 6 centres (10 participated, but 4 did not recruit any patients), countries: UK, NL, D, DK (London, Bristol, Maastricht, Munich, Aalborg, Cheltenham)   Double‐blind placebo controlled RCT, randomisation code held centrally   Duration of study 3/12, assessments at 1/12 with 3‐day urinary diary and 4‐point severity score + at 3/12 with subjective and objective investigations   Definition of cure: absence of a specific symptom at 3/12 that was present at entry obtained from direct symptom questions
Participants	64 post‐menopausal women with urodynamically confirmed urgency urinary incontinence   Baseline characteristics comparable   Inclusion criteria: ambulant, postmenopausal >1 year, FSH > 40 IU/l, oestradiol < 220 pmol/l, urgency urinary incontinence   Exclusion criteria: symptoms present for > 3 years before menopause, voiding difficulty, pelvic anatomic defect requiring surgery, neurological disease, recent oestrogen usage (< 6/12), concomitant medication that could affect bladder or urethral function, standard contraindications to oestrogen therapy
Interventions	Group A (n=34): oestriol orally 3 mg for 3/12   Group B (n=30): placebo orally for 3/12
Outcomes	Subjective assessment with doctor‐administered questionnaire concerning presence or absence of specific urinary symptoms (24 questions) and 4‐point severity score scale (9 questions), objective assessment with 3‐day urinary diary, filling and voiding cystometry, urethral pressure profile where available, vaginal smear for maturation index calculated by single pathologist;   Definition of cure: absence of a specific symptom at 3/12 that was present at entry obtained from direct symptom questions Number not cured: urgency urinary incontinence: A, 14/25; B, 16/23; stress incontinence: A, 5/11; B, 4/10
Notes	Urgency incontinence stratified into motor and sensory urgency incontinence, motor urgency incontinence defined as uninhibited detrusor contractions exceeding 15 cm of water, sensory urgency incontinence defined as first desire to void during filling cystometry at less than 150 ml and a cystometric capacity of 400 ml in absence of detrusor activity   Losses to follow‐up: group A : 3, group B: 5   No adverse outcomes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	no description
Allocation concealment (selection bias)	Low risk	"Randomisation code was held centrally"
Blinding (performance bias and detection bias)   All outcomes	Low risk	"double blind"
Incomplete outcome data (attrition bias)   All outcomes	Low risk	8 out of 64 women did not complete study (3 reason unknown,1 loss of motivation, 1 lack of efficacy, 1 UTI, 1 exclusion criteria, 1 did not start. Equal dropouts between groups

Methods	Double‐blind placebo controlled RCT   Duration of study: 12/52, assessments at 4/52 and 12/52
Participants	105 post‐menopausal women,   Inclusion criteria: at least 1 year since last menstrual period, FSH > 40 U/l, estradiol < 220 pmol/l, complaining of lower urinary tract   symptoms of urgency, frequency and/or urgency urinary incontinence with onset not earlier than 3 years prior to menopause;   Exclusion criteria: currently or recently (within the last 6/12) on oestrogen therapy, present or past history of oestrogen dependent neoplasia, abnormal genital bleeding of unknown origin, present or past history of thromboembolic disorders, urinary or vaginal infection, recent commencement or change in diuretic treatment
Interventions	Group A: 17B‐oestradiol vaginal pellet (Vagifem) 25 µgm at night for 12/52   Group B: placebo pellet at night for 12/52
Outcomes	Questionnaire and frequency/volume chart, urethral brushing for cytology, compliance check regarding tablet usage, urodynamics, MSU, FSH, LH, oestradiol, endometrial biopsy, visual analogue score, symptom assessment sheet, cystometry data sheet   Key endpoints of interest: symptoms of frequency, urgency, nocturia at final visit
Notes	No useable data; no numbers of women in groups; no adverse events   Losses to follow up: 9, of which 2 due to medical reasons (1 intercurrent medical disease, 1 died of myocardial infarction)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	no description
Allocation concealment (selection bias)	Unclear risk	no description
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias)   All outcomes	High risk	In both groups three women failed to commence treatment. Outcome data on 106 out of 110 randomised

Methods	RCT: placebo controlled, sealed opaque envelopes   Duration of study: 6 months   Follow up: none after end of treatment
Participants	88 post‐menopausal women   Groups comparable at baseline on age, menopause duration, duration of UI, bacteriuria   Inclusion: urodynamic stress incontinence (moderate to severe), urogenital atrophy, recurrent UTI   Exclusion: detrusor overactivity, abnormal maximal cystometric capacity, prolapse Grade II or III; systemic disorders, systemic disease, thromboembolic disease, biliary lithiasis, breast or uterine cancer, abnormal uterine bleeding, BMI>25
Interventions	Group A (44): intravaginal oestriol ovules, 1 mg daily for 2 weeks, 2 mg weekly for 6 months   Group B (44): matching placebo   Dropout: A: 4/44, B: 3/44 (discomfort, local adverse effects), + B: 4/44 (no benefit)
Outcomes	Incontinent at 6 months: group A: 37/44, group B; 44/44   Not improved at 6 months:group A: 14/44, group B: 37/44   Adverse effects: group A: 4/44,group B: 3/44 (caused dropout)   Significant bacteriuria, group A: 6/44, group B: 20/44
Notes	Participants and outcome assessors blinded to treatment
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	no description
Allocation concealment (selection bias)	Low risk	"sequenced, sealed, opaque envelopes"
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind "participants and investigators were blinded to the drug being dispensed and to the assigned treatment group"
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No dropouts

Methods	RCT (double‐blind crossover in 5th and 6th weeks of the study); duration of study: 8/52, F/U at 8/52
Participants	16 post‐menopausal women with urodynamically proven GSI
Interventions	All women (n=16): oestradiol valerate 2mg daily for 3/52, then 1mg for 1/52   group A (n=13): oestradiol 1mg + norephedrine 200mg daily for 2/52 after first 4/52   group B (n=13): oestradiol 1mg + placebo daily for 2/52 after first 4/52   after 2 weeks, groups 1 and 2 crossed over to the opposite arm
Outcomes	Residual urine, MSU, urodynamics, clinical stress test, periurethral vaginal biopsies, subjective symptoms
Notes	No useable data; adverse events: "few and acceptable", very small changes in BP, no uterine bleeding   Losses to follow up: group 2: 2, group 3: 1
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	no description
Allocation concealment (selection bias)	Unclear risk	no description
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	no description
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	no description

Methods	RCT, duration of study 4/52
Participants	35 women   Inclusion criteria: urgency symptoms, urgency urinary incontinence, frequency, nocturia   Exclusion criteria: renal disease, infections in the urogenital area, anticholinergic or hormone therapy
Interventions	Group A (n=15): 0.5 or 1 mg oestriol vaginally   Group B (n=20): 2 mg oestriol vaginally
Outcomes	Urinary diary, cystoscopy, urodynamics, urethral and vaginal smear
Notes	No endometrial stimulation or breast tenderness noted
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	no description
Allocation concealment (selection bias)	Unclear risk	no description
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	no description
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	no description

Methods	Placebo controlled RCT, randomisation following randomisation scheme, duration of study: 4/52
Participants	40 post‐menopausal women   Inclusion criteria: urgency symptoms, urgency urinary incontinence, frequency ( 6 or more micturitions/day), nocturia (3 or more micturitions/ night)   Exclusion criteria: neurological bladder problems, renal disease, diabetes, infections in the urogenital area, anticholinergic or hormone‐therapy, malignancy
Interventions	Group A (n=15): 1 mg oestriol vaginally for 3/52   Group B (n=15): 3 mg oestriol vaginally for 3/52   Group C (n=10): placebo vaginally for 3/52
Outcomes	Cystometry, urethral pressure profile, cystoscopy, urethral smear, urinary diary, MSU, FSH levels, E2 levels
Notes	Adverse outcomes: breast tenderness in 2 patients in group 2   Losses to follow up: group B: 2, group C: 1
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	no description
Allocation concealment (selection bias)	Unclear risk	no description
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	no description
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	no description

Methods	as Enzelsberger A
Participants
Interventions
Outcomes
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	no description
Allocation concealment (selection bias)	Unclear risk	no description
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	no description
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	no description

Methods	Multicentre trial, 2 centres, double‐blind placebo controlled RCT, patients stratified by baseline severity of symptoms, urodynamics and treatment site; blocked randomisation within each stratum at each site; sequenced sealed opaque envelopes   Women and investigators were blinded to treatment allocated   Duration of study 3/12
Participants	83 post‐menopausal women with UI Inclusion criteria: all patients ambulatory, community‐dwelling residents, age 45 or older, involuntary loss of urine at least once a week, GSI was diagnosed when urine was objectively seen to be lost during exertion in absence of DI; DI defined as involuntary detrusor contractions during retrograde subtracted provocative cystometry; hypooestrogenism = plasma E2 levels 30 pg/ml or less Exclusion criteria: institutionalisation, permanent catheterisation, impaired mental status, functional disability limiting use of toilet, neuropathic or uncontrolled metabolic conditions (e.g. diabetes mellitus), chronic UTI, reversible causes of urinary incontinence (e.g. faecal impaction), major contraindications for use of oestrogens (e.g. breast cancer)
Interventions	Group A (n=39): conjugated equine oestrogens 0.625 mg for 30 days + medroxyprogesterone 10 mg for 10 days of each cycle   Group B (n=44): placebo similar cyclic regimen   Women, clinicians and pharmacists were blinded to actual treatment
Outcomes	Data recorded in standardised urinary diaries Primary outcome: number of incontinent episode per week, N, mean (SD): A 39, 10 (10), B 44 13 (14) cure (definition not given), results provided as patient's perception of somewhat or much better: A 54% (21/39), B 45% (20/44), P= 0.435 Secondary outcomes:   pad test (volume of urine loss): A 101 (150), B 50 (68)   number of voluntary diurnal micturitions per week: A 50 (14), B 49 (15)   number of voluntary nocturnal micturitions per week: A 9 (6), B 8 (5)   quality of life measurements generic: SF‐36 Health survey + Centre of epidemiological studies depression scale,   condition specific QoL:   Incontinence Impact Questionnaire‐revised (IIQ‐R): A 97 (87), B 100 (82)   Urogenital Distress Inventory (UDI): A 101 (58), B 102 (55)   E2 level: A 61 (42), B 10 (16) (placebo unchanged from baseline)   vaginal parabasal cell count: A 3±17%, B 49±43%
Notes	Loss to follow up: 2, and 8 only had diary or QoL data. Groups not given, unclear if these are extra to the 83 with outcome data reported   Patients also taking progesterone which may have altered results   Power calculation: study had 80% power to detect a difference of 4.5 episodes per week
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Blocked randomisation
Allocation concealment (selection bias)	Low risk	Sequenced, sealed, opaque envelopes, each containing the bottle number to be given to an individual patient
Blinding (performance bias and detection bias)   All outcomes	Low risk	Participants, clinicians and pharmacists blind to drug being dispensed
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No dropouts

PERMALINK

Oestrogen therapy for urinary incontinence in post‐menopausal women

June D Cody

Madeleine Louisa Jacobs

Karen Richardson

Birgit Moehrer

Andrew Hextall

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

1. Women's observations

Secondary outcomes

2. Quantification of symptoms

3. Clinician's measures (urodynamics or cystometry)

4. Quality of life

5. Socioeconomics

6. Adverse outcomes

7. Other outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Assessment of heterogeneity

Subgroup analysis and investigation of heterogeneity

1. Summary of study characteristics: type of oestrogen, route of administration, dose, length of treatment, population.

Results

Description of studies

Results of the search

1.

Included studies

Sample characteristics

Type of incontinence

Menopausal status

Route of administration

Systemic (18 trials)

Local (17 trials)

Type of oestrogen

1. Oestrogen versus placebo

Systemic

Local

2. Oestrogen versus other treatments

Systemic

Local

3. Oestrogen plus other treatment versus placebo

Systemic

4. Oestrogen plus other treatment versus oestrogen

Systemic

Local

5. Oestrogen plus other treatment versus other treatment

6. Different types of oestrogen

7. Different routes of administration

8. High‐dose versus low‐dose oestrogen

Outcome measures

Duration of follow up

Excluded studies

Risk of bias in included studies

Methods	RCT, randomisation stratified by clinical centre, within‐strata treatment randomised in fixed size blocks Follow up at 4 months then annually for 4 years
Participants	1525 participants age less than 80, post‐menopausal, with intact uterus, and at least 1 episode of UI per week   all patients had coronary heart disease   Baseline characteristics in both groups similar for age, race, education, menopause age, parity, chronic medical conditions, smoking and alcohol consumption and BMI
Interventions	Group A (n=768) conjugated oestrogen (Premarin) 0.625mg + medroxyprogesterone acetate (Cycrin) 2.5mg   Group B (n=757) identical placebo   Oral tablets
Outcomes	Worse or unchanged at 1 year: A 525/716, B 479/715   Worse or unchanged at 2 years: A 499/680, B 464/686   Worse or unchanged at 3 years: A 478/640, B 436/639   Worse or unchanged at 4 years: A 541/756, B 506/747 Number of incontinent episodes: A 5.5 per week (increase of 0.7), B 5.6 per week (decrease of 0.1)   Using drugs for incontinence by 4 years: A 49/756, B 31/747   Incontinence surgery by 4 years: A 10/756, B 7/747   No change in either group in frequency of stress or urgency urinary incontinence, or in diurnal or nocturnal frequency
Notes	Compliance at 1st year: A 82%, B 88% still taking the treatment
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation codes prepared prepared with computer generated random numbers. Stratified by site and performed using randomly permuted blocks of 4
Allocation concealment (selection bias)	Low risk	Eligible participants assigned with equal probability to the two groups by tamper proof randomisation
Blinding (performance bias and detection bias)   All outcomes	Low risk	Participants and investigators blind to treatment
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	no description

Methods	RCT, duration of study: 3/12, follow up at 3/12 and 9/12
Participants	100 women;   Inclusion criteria: urodynamically proven GSI   Exclusion criteria: complicated history of incontinence such as fistula or more than one previous incontinence surgery, major prolapse, absolute contraindication to oestrogen treatment
Interventions	Group A (n=24): conjugated equine oestrogen vaginal cream (Premarin) 1.25 mg at night for 12/52   Group B (n=25): no treatment
Outcomes	Pad test, urethral pressure studies at 3/12, symptom questionnaire at 9/12   Definition of cure: negative pad test after previous positive; improvement: more than 50% reduction in pad weights
Notes	Numbers given as "cured or improved" and "unchanged"; recurrences of symptoms at 9/12 in women who had initially improved: group A: 3, group B: 1, group C: 3 (recurrence of symptoms immediately after discontinuing oestrogen treatment)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"allocated at random"
Allocation concealment (selection bias)	Unclear risk	no description
Blinding (performance bias and detection bias)   All outcomes	High risk	Not possible, drug compared to PFMT
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	100 out of 104 evaluated no info on dropouts

Methods	RCT, duration of study: 6/52
Participants	26 post‐menopausal women; inclusion criteria: GSI
Interventions	Group A (n=11): conjugated equine oestrogen vaginal cream (Premarin) 2 g at night for 6/52   Group B (n=7): control   All failures had surgical repair
Outcomes	Vaginal pH, vaginal cell count from smear, pad test, electromyographic traces to assess urethral sphincter activity;   Definition of failure: < 50% reduction from original pad test loss; numbers given as "cured or improved" and "unchanged"
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	no description
Allocation concealment (selection bias)	Unclear risk	no description
Blinding (performance bias and detection bias)   All outcomes	High risk	Not possible
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	no description

Methods	RCT   As Hendrix 2005
Participants	Wet at baseline   Population 1: (hysterectomy) N=6528 at baseline, outcome data at one year N=5920
Interventions	Population 1 (wet at baseline, without uterus):   Group A (2950): conjugated equine oestrogen alone   Group B (2970): matching placebo
Outcomes	Population 1 (wet at baseline, without uterus)   Likelihood of worsening amount of UI: A versus B: RR = 1.59 (95% CI 1.39 to 1.82)   Likelihood of worsening frequency of UI: A versus B: RR = 1.47 (1.35 to 1.61)   Likelihood of limitation of activities related to UI: A versus B: RR = 1.29 (1.15 to 1.45) Worsening was not related to one type of urinary incontinence alone
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The study pill bottles had unique bar codes and computer based selection to enable double blinded dispensing"
Allocation concealment (selection bias)	Low risk	"Randomization was performed using a study database distributed by the WHI Clinical Coordinating Center to the local centres"
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind ‐ clinic staff and participants
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	At 1 year vital status was known for 99.9% of participants in the oestrogen + progesterone trial and 100% for those in oestrogen only trial?? At 1 year 9.7% of women taking oestrogen + progesterone and 6.6% taking placebo stopped taking the pills Oestrogen alone 8.4% and placebo 8% stopped taking the pills

Methods	RCT, 25,597 women   Central randomisation, computer‐based selection, double‐blind dispensing   Follow up at one year and then a subsample after 3 years   Baseline QOL, questionnaire, interview, examination and bloods
Participants	RCT of hormone replacement for prevention of coronary heart disease and hip fracture, with and without symptoms of stress, urgency urinary or mixed incontinence at baseline   Women all aged between 50‐79 years, post‐menopausal Incontinent (wet) women (Populations 1 and 2)   Population 1: (hysterectomy) N=6528 at baseline, outcome data at one year N=5920   Population 2: (with uterus) N=9889 at baseline, outcome data at one year N=9121 Continent (dry) women (Populations 3 and 4)   Population 3: (hysterectomy) N=3473 at baseline, outcome data at one year N=3073   Population 4: (with uterus) N=5707 at baseline, outcome data at one year N=5182 All women on HRT treatment at baseline had to have 3 month washout   Whole sample comparable at baseline on age, education, illness, menopause, parity, breastfeeding history, hormone use, hysterectomy status, physical activity and smoking   Exclusion criteria: breast CA, other invasive carcinoma in the last ten years, venous thromboembolism, hypertriglyceridaemia, medical condition which may result in death in the next three years, unwilling or unable to be randomised to placebo, severe menopausal symptoms at washout   All women had a four week trial with placebo to which they had to show 80% adherence
Interventions	Population 1 (wet at baseline, without uterus):   group A (2950): conjugated equine oestrogen alone   group B (2970): matching placebo   Population 2 (wet at baseline, with uterus):   group C (n=4572): conjugated equine oestrogen + medroxyprogesterone acetate   group D (n=4549): matching placebo   Population 3 (continent at baseline, without uterus):   group E (1526): conjugated equine oestrogen alone   group F (1547): matching placebo   Population 4 (continent at baseline, with uterus):   group G (2675): conjugated equine oestrogen alone   group H (2507): matching placebo
Outcomes	Population 1 (wet at baseline, without uterus)   Likelihood of worsening amount of UI: A versus B: RR = 1.59 (95% CI 1.39 to 1.82)   Likelihood of worsening frequency of UI: A versus B: RR = 1.47 (1.35 to 1.61)   Likelihood of limitation of activities related to UI: A versus B: RR = 1.29 (1.15 to 1.45) Population 2 (wet at baseline, with uterus)   Likelihood of worsening amount of UI: C versus D: RR = 1.20 (95% CI 1.06 to 1.36)   Likelihood of worsening frequency of UI: C versus D: RR = 1.38 (1.28 to 1.49)   Likelihood of limitation of activities related to UI: C versus D: RR = 1.18 (1.06 to 1.32) Worsening was not related to one type of urinary incontinence alone Population 3 (dry at baseline)   Any UI at 1 year: E, 557/1526, F, 368/1547 RR=1.53 (1.37 to 1.71)   Stress UI at 1 year: E, 266/1526, F, 131/1547 RR=2.15 (1.77 to 2.62)   Urgency UI at 1 year: E, 210/1526, F, 184/1547 RR=1.32 (1.10 to 1.58)   Mixed UI at 1 year: E, 76/1526, F, 50/1547 RR=1.79 (1.26 to 2.53) Population 4 (dry at baseline)   Any UI at 1 year: G, 834/2675; H, 563/2507 RR=1.39 (1.27 to 1.52)   Stress UI at 1 year: G, 429/2675; H, 218/2507 RR=1.87 (1.61 to 2.18)   Urgency UI at 1 year: G, 304/2675, H, 272/2507 RR=1.15 (0.99 to 1.34)   Mixed UI at 1 year: G, 99/2675, H, 69/2507 RR=1.49 (1.10 to 2.01)
Notes	No data suitable for meta‐analysis were provided in the original report but these have been requested   Data used in generic inverse variance analysis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The study pill bottles had unique bar codes and computer based selection to enable double blinded dispensing"
Allocation concealment (selection bias)	Low risk	"Randomization was performed using a study database distributed by the WHI Clinical Coordinating Center to the local centres"
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind, clinic staff and participants
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	At 1 year vital status was known for 99.9% of participants in the oestrogen + progesterone trial and 100% for those in oestrogen only trial?? At 1 year 9.7% of women taking oestrogen + progesterone and 6.6% taking placebo stopped taking the pills Oestrogen alone 8.4% and placebo 8% stopped taking the pills

Methods	Double‐blind RCT, patients were randomised into 6 groups; duration of study 4/52, evaluation on day 28 of study
Participants	n= 60 women   Inclusion: USI, post‐menopausal   Exclusion: Undiagnosed vaginal bleeding, oestrogen therapy within preceding 6 months, malignancy of oestrogen‐dependent tissue, BP >160 mmHg systolic, >100 mmHg diastolic, previous thromboembolic disease, liver disease, patients withholding informed consent   Age range 45‐70 years
Interventions	A (10): Intravaginal oestrogen (2 gr nocturnal) + PPA (50 mg twice daily)   B(10): Intravaginal oestrogen (2 gr nocturnal) + placebo (twice daily)   C (10): Oral oestrogen (1.25 mg daily) + PPA (50 mg twice daily)   D (10): Oral oestrogen (1.25 mg daily) + placebo (twice daily)   E (10): PPA (50 mg twice daily)   F (10): Intravaginal placebo (nocturnal) + placebo (twice daily)   Duration of treatment: 4 weeks
Outcomes	Subjective improvement: A: 9/10, B: 1/9, C: 4/10 D: 2/10, E: 0/9, F: 2/11   Mean number of pads/day: A: 0.9, B: 0.3, C: 0.9, D: 1.3, E: 2, F: 1.1   Mean pad weights: A: 8, B: 4, C: 4, D: 4, E: 4, F: 12   Adverse events: A: 3/10, B: 3/10, C: 5/10, D: 5/10, E: 4/10, F: 3/10 (headache, nausea, flushing, sweating, tingling, breast tenderness, ecchymoses)   Side effects causing discontinuation: C: 1/10, E: 1/10
Notes	Data estimated from graphs   No SDs   Comparisons: alpha adrenergic drug + oestrogen (I and III) versus oestrogen alone (II and IV) versus alpha‐adrenergic drug alone (V) versus placebo (VI)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	no description
Allocation concealment (selection bias)	Unclear risk	no description
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	no description

Methods	Randomised controlled trial Duration of study 2 years Monthly uterine ultrasound examination and 6‐monthly endometrial PAP smears Setting: Japan
Participants	66 post‐menopausal women with stress urinary incontinence, age 54 to 75 years, groups comparable at baseline Dropouts: a further 6 by choice, 1 for adverse drug reaction hepatopathy): A, 4; B, 3 Inclusion criteria: stress urinary incontinence alone (based on questionnaires) Exclusion criteria: urgency or mixed urinary incontinence 10% of women had a previous hysterectomy
Interventions	A (32): PFMT + oestriol tablet (1 mg/day) B (34): PFMT alone PFMT was taught by a gynaecology specialist, supplemented by videotape. The aim was 15 minutes of exercise a day
Outcomes	Persisting incontinence: A: 7/32; B, 11/34 (Mild UI: A, 0/12; B, 2/11: Moderate UI: A, 3/14; B, 5/18: Severe UI: A, 4/6; B, 4/5) Adverse effects: A: 1/36; B, 0/37 No report of effect on uterus
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	no description
Allocation concealment (selection bias)	Unclear risk	Randomly assigned
Blinding (performance bias and detection bias)   All outcomes	High risk
Incomplete outcome data (attrition bias)   All outcomes	Low risk	4 out of 36 withdrew from exercise and oestrogen group 3 out of 37 from exercise only group

Methods	Double‐blind placebo controlled RCT, duration of study 6/12; no definition of cure given, but results of no demonstrable stress incontinence on repeat cystometry (urodynamically 'cured')
Participants	67 post‐menopausal women with urodynamically proven GSI; inclusion criteria: >12/12 post‐menopausal, not taken HRT in previous 12/12 Exclusion criteria: cancer of endometrium, liver, breast; endometrial thickness > 4mm Included women who had had hysterectomy
Interventions	Group A (n=33): oestradiol 2 mg orally for 6/12   Group B (n=34): placebo orally similar regime
Outcomes	Urinary diary for 1 week, SF‐36 + B‐FLUTS questionnaires, 1 hour perineal pad test, urodynamics, repeat trans‐vaginal sampling + Pipelle biopsy if endometrial thickness>6mm, compliance, serum oestradiol levels
Notes	Losses to follow up: 3 in group A, 2 in group B; 1 patient in each group left at 3/12 for surgery, both were reassessed and data are included   Adverse outcomes: 6 women taking oestradiol had breakthrough bleeding, they started taking cyclical progestogen, repeat investigations in progestogen‐free part of their cycle, no case of endometrial atypia
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation sequence generated by computer in block sizes of 10 (5 oestradiol, 5 placebo)
Allocation concealment (selection bias)	Low risk	Randomised by hospital pharmacy
Blinding (performance bias and detection bias)   All outcomes	Low risk	Women participants and care providers
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Three out of 33 on oestradiol failed to complete the trial, two out of 34 on placebo. One woman in each arm left trial at three months opting for surgery (included in the analysis)

Methods	Multicentre trial, 2 hospitals; placebo‐controlled double‐blind crossover RCT, duration of study 5 weeks
Participants	20 post‐menopausal women, patients in two hospitals in geriatric long‐stay beds for at least 1 month, 10 patients confused, 1 demented, 8 mentally normal; 14 had neurological disease   Types of incontinence divided into: incontinent and unaware of it; incontinent, aware but not distressed by it; incontinent, aware and distressed   Patients divided naturally into two groups (two hospitals), one group mildly incontinent, one group severely incontinent   No change of diuretic during trial   Excluded if faecally impacted
Interventions	Group A (n=18): quinestradol 0.25 mg qds for 1/12   Group B (n=18) placebo similar regime   All 18 patients had quinestradol and placebo, but not stated how many had quinestradol first and then placebo or placebo first and then quinestradol
Outcomes	Observed numbers of incontinent episodes requiring bed change per week
Notes	No useable data; unclear if groups were treated identically as patients had neurological disease or confusion and lived in different geriatric hospitals; losses to follow up: 2 (from initial 20); patients too confused for subjective assessment
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	A set of random numbers was used
Allocation concealment (selection bias)	Low risk	Hospital pharmacist provided with active ingredient labelled capsule X and capsule Y along with an emergency sealed key for emergency use
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	no description

Methods	RCT (randomised double‐blind crossover)
Participants	36 post‐menopausal women   Inclusion criteria: GSI   Exclusion criteria: not mentioned   Mean age 66 (49‐82)   Urgency urinary incontinence n = 7, previous anti‐incontinence operation n = 8, previous gynaecological operations n = 5
Interventions	Group A (n=36): oestriol 2mg orally + placebo twice daily   Group B (n=36): oestriol 2 mg orally + PPA 50 mg twice daily   for 4/52
Outcomes	Subjective improvement: A: 9/30, B: 16/30   Leakage episode/day: A: 2.4, B: 2.4   Mean number of voids/day: A: 7.2, B: 6.9   Mean pad weight/day:A: 34.9, B: 24.9
Notes	No useable data; adverse events: dryness of the mouth + ? arrhythmia, itch, depression; but not clear on which treatment losses to Follow up: 6 (3 intercurrent diseases, 3 possible drug effects: arrhythmia, itch, depression)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	no description
Allocation concealment (selection bias)	Low risk
Blinding (performance bias and detection bias)   All outcomes	High risk	Crossover design
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	no descriptioin