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. 2011 Jun 15;2011:0804.

Menopausal symptoms

Nikolaos Burbos 1,#, Edward P Morris 2,#
PMCID: PMC3275139  PMID: 21696644

Abstract

Introduction

Menopause is a physiological event. In the UK, the median age for onset of menopausal symptoms is 45.5 to 47.5 years. Although endocrine changes are permanent, menopausal symptoms such as hot flushes, which are experienced by about 70% of women, usually resolve with time, although they can persist for decades in some women.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of medical treatments for menopausal symptoms? What are the effects of non-prescribed treatments for menopausal symptoms? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 79 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: agnus castus, antidepressants, black cohosh, clonidine, oestrogens, phyto-oestrogens, progestogens, testosterone, and tibolone.

Key Points

In the UK, the median age for onset of menopausal symptoms is 45.5 to 47.5 years.

  • Symptoms associated with the menopause include vasomotor symptoms, sleeplessness, mood changes, reduced energy levels, loss of libido, vaginal dryness, and urinary symptoms.

  • Many symptoms, such as hot flushes, are temporary, but those resulting from reduced hormone levels, such as genital atrophy, may be permanent.

Progestogens reduce menopausal vasomotor symptoms compared with placebo. However, the clinical usefulness of progestogens given alone for menopausal symptoms is limited by the unwanted adverse effects of the relatively high doses needed to achieve relief of menopausal symptoms.

Oestrogens reduce vasomotor and sexual symptoms but, like progestogens, they increase the risk of serious adverse effects.

  • Oestrogens, used alone or with progestogens, reduce vasomotor and urogenital symptoms, and improve quality of life compared with placebo over 3 to 6 months.

  • However, oestrogens increase the risk of breast cancer, endometrial cancer, stroke, and venous thromboembolism.

  • We don't know whether phyto-oestrogens, such as those in soy flour, reduce menopausal symptoms. Phyto-oestrogens have not been shown consistently to improve symptoms, and they may increase the risk of endometrial hyperplasia in perimenopausal women.

CAUTION: Women with an intact uterus who are prescribed oestrogen replacement therapy should also take continuous or cyclical progestogens.

Tibolone reduces vasomotor symptoms in postmenopausal women compared with placebo.

  • Tibolone may improve sexual function compared with placebo or compared with combined oestrogens plus progestogens.

  • We don't know if tibolone is more effective than oestrogen and progestogen combined treatment in reducing vasomotor symptoms.

  • Tibolone may be associated with an increased risk of breast cancer recurrence in women previously treated surgically for breast cancer.

We don't know whether testosterone alone reduces menopausal symptoms, as we found no RCTs. Testosterone plus oestrogen-based HRT reduces sexual symptoms in postmenopausal women but does not seem to reduce vasomotor symptoms, compared with oestrogen HRT alone.

Antidepressants may be more effective than placebo at relieving vasomotor symptoms in postmenopausal women in the short term. However, we don't know whether they are effective in the long term.

We don't know whether clonidine, black cohosh, or agnus castus reduce menopausal symptoms.

Clinical context

About this condition

Definition

Menopause is defined as the end of the last menstrual period. A woman is deemed to be postmenopausal 1 year after her last period. For practical purposes, most women are diagnosed as menopausal after 1 year of amenorrhoea. Menopausal symptoms often begin in the perimenopausal years. The complex of menopausal symptomatology includes vasomotor symptoms (hot flushes), sleeplessness, mood changes, reduction in energy levels, loss of libido, vaginal dryness, and urinary symptoms.

Incidence/ Prevalence

In the UK, the mean age for the start of the menopause is 50 years and 9 months. The median onset of the perimenopause is 45.5 to 47.5 years. One Scottish survey (6096 women aged 45–54 years) found that 84% of the women had experienced at least one of the classic menopausal symptoms, with 45% finding one or more symptoms to be a problem.[1]

Aetiology/ Risk factors

Urogenital symptoms of menopause are caused by decreased oestrogen concentrations, but the cause of vasomotor symptoms and psychological effects is complex and remains unclear.

Prognosis

Menopause is a physiological event. Timing of the natural menopause in healthy women may be determined genetically. Although endocrine changes are permanent, menopausal symptoms such as hot flushes, which are experienced by about 70% of women, usually resolve with time, although in some women they can persist for decades.[2] However, some symptoms, such as genital atrophy, may remain the same or worsen.

Aims of intervention

To reduce or prevent menopausal symptoms; and to improve quality of life, with minimum adverse effects of treatment.

Outcomes

Frequency and severity of vasomotor, urogenital, and psychological (includes psychological, cognitive, and sleep) symptoms; quality of life; and adverse effects (notably breast cancer recurrence and endometrial hyperplasia).

Methods

Clinical Evidence search and appraisal June 2010. The following databases were used to identify studies for this systematic review: Medline 1966 to June 2010, Embase 1980 to June 2010, and The Cochrane Database of Systematic Reviews, Issue 2, 2010 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least single-blinded, and containing >20 individuals of whom >80% were followed up. There was no minimum length of follow-up required to include studies apart from the HRT options, where the minimum length of follow-up was at least 3 months. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied, applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. Many of the RCTs identified were crossover trials, which may have important limitations because treatment effects may persist after crossover, confounding the results for each treatment. Where results are reported for comparisons with only pretreatment values, they have been omitted because these comparisons may be influenced in many (often unquantifiable) ways by factors other than treatment effect. Many RCTs assessing alleviation of symptoms with HRT are too small or do not have long enough follow-up to give useful information on adverse effects. Therefore, where we have found RCTs and systematic reviews specifically evaluating adverse effects, we have reported these in preference to any information from trials primarily examining benefits. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Menopausal symptoms.

Important outcomes Adverse effects, Breast cancer recurrence, Endometrial hyperplasia, Psychological symptoms, Quality of life, Urogenital symptoms, Vasomotor symptoms
Studies (Participants) Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of medical treatments for menopausal symptoms?
3 (1253) Vasomotor symptoms Tibolone versus placebo 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
1 (38) Urogenital symptoms Tibolone versus placebo 4 –3 0 0 0 Very low Quality points deducted for sparse data, no reporting of pre-crossover results, and lack of washout period
1 (3148) Breast cancer recurrence Tibolone versus placebo 4 0 0 0 0 High
2 (672) Vasomotor symptoms Tibolone versus oestrogen plus progestogen 4 –1 –1 0 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results
2 (487) Urogenital symptoms Tibolone versus oestrogen plus progestogen 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
11 (at least 3649) Vasomotor symptoms Oestrogens alone versus placebo 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
at least 12 (at least 3344) Urogenital symptoms Oestrogens alone versus placebo 4 0 0 0 0 High
5 (at least 3430) Psychological symptoms Oestrogens alone versus placebo 4 –3 0 0 0 Very low Quality points deducted for incomplete reporting of results, inclusion of cohort studies, and weak methods
3 (489) Quality of life Oestrogens alone versus placebo 4 0 –1 0 0 Moderate Consistency point deducted for conflicting results between studies
at least 52 (at least 41,113) Adverse effects Oestrogens alone versus placebo 4 0 0 –1 0 Moderate Directness point deducted for inclusion of combined HRT preparations in the analysis
4 (615) Urogenital symptoms Different oestrogen preparations versus each other 4 0 –1 –1 0 Low Consistency point deducted for conflicting results. Directness point deducted for small number of events in some analyses
1 (132) Vasomotor symptoms Different oestrogen preparations versus each other 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for restricted population (surgical menopause)
1 (100) Psychological symptoms Different oestrogen preparations versus each other 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for restricted population (surgical menopause)
1 (43) Vasomotor symptoms Oestrogens alone versus progestogens 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
at least 4 (20,328) Vasomotor symptoms Oestrogens plus progestogens versus placebo 4 –1 0 0 +1 High Quality point deducted for incomplete reporting of results. Effect-size point added for OR >2
3 (16,834) Urogenital symptoms Oestrogens plus progestogens versus placebo 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
2 (20,952) Psychological symptoms Oestrogens plus progestogens versus placebo 4 –1 0 –1 0 Low Consistency point deducted for inconsistent results depending on outcome measure used. Directness point deducted for large RCT in atypical age group
2 (16,882) Quality of life Oestrogens plus progestogens versus placebo 4 0 –1 –1 0 Low Consistency point deducted for inconsistent results depending on outcome measure used. Directness point deducted for RCT in atypical age group
at least 28 (at least 39,508) Adverse effects Oestrogens plus progestogens versus placebo 4 0 0 –1 0 Moderate Directness point deducted for single agents included in analysis
2 (533) Quality of life Different preparations of oestrogens plus progestogens versus each other 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for no statistical analysis between groups in 1 RCT
1 (459) Vasomotor symptoms Different preparations of oestrogens plus progestogens versus each other 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for small number of comparators
6 (550) Vasomotor symptoms Progestogens versus placebo 4 –2 0 0 0 Moderate Quality points deducted for post-crossover analysis in 1 RCT and no ITT analysis in 1 RCT
2 (303) Psychological symptoms Progestogens versus placebo 4 –2 0 0 0 Low Quality points deducted incomplete reporting of results and no ITT analysis in 1 RCT
1 (80) Quality of life Progestogens versus placebo 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
11 (1456) Vasomotor symptoms Antidepressants versus placebo 4 –1 –1 –1 0 Very low Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results. Directness point deducted for inclusion of a co-intervention
4 (446) Vasomotor symptoms Clonidine versus placebo 4 –1 0 –2 0 Very low Quality point deducted for short follow-up. Directness points deducted for co-intervention, and results sensitive to analysis undertaken
9 (2215) Urogenital symptoms Testosterone plus oestrogen-containing HRT versus oestrogen-containing HRT alone 4 –2 0 0 0 Low Quality point deducted for incomplete reporting of results and weak methods
1 (26) Psychological symptoms Testosterone plus oestrogen-containing HRT versus oestrogen-containing HRT alone 4 –3 0 0 0 Very low Quality points deducted for sparse data, incomplete reporting of results, and weak methods
2 (166) Vasomotor symptoms Testosterone plus oestrogen-containing HRT versus oestrogen-containing HRT alone 4 –3 0 0 0 Very low Quality points deducted for sparse data, incomplete reporting of results, and weak methods
What are the effects of non-prescribed treatments for menopausal symptoms?
2 (273) Vasomotor symptoms Black cohosh 4 –1 0 –2 0 Very low Quality point deducted for incomplete reporting of results. Directness points deducted for clinical heterogeneity (lack of standardised dose) and for use of a composite outcome
40 (2730) Vasomotor symptoms Phyto-oestrogens versus placebo 4 –3 –1 –1 0 Very low Quality points deducted for weak methods, incomplete reporting of results, unclear comparisons, and lack of standardisation of interventions. Consistency point deducted for conflicting results. Directness point deducted for lack of standard dosing
2 (154) Urogenital symptoms Phyto-oestrogens versus placebo 4 –2 0 –2 0 Very low Quality points deducted for sparse data and crossover design. Directness points deducted for use of non-clinical assessment and lack of standardised dosing
2 (172) Psychological symptoms Phyto-oestrogens versus placebo 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for lack of standardised dosing
4 (754) Endometrial hyperplasia Phyto-oestrogens versus placebo 4 0 0 –2 0 Low Directness points deducted for non-standard dose and small number of events
1 (79) Vasomotor symptoms Phyto-oestrogens versus oestrogen alone 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for lack of standard preparations and dosing
1 (136) Vasomotor symptoms Phyto-oestrogens versus oestrogens plus progestogens 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for lack of standard preparations and dosing
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We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Beck Depression Inventory

Standardised scale to assess depression. This instrument consists of 21 items to assess the intensity of depression. Each item is a list of 4 statements (rated 0, 1, 2, or 3), arranged in increasing severity, about a particular symptom of depression. The range of scores possible are 0 = least severe depression to 63 = most severe depression. It is recommended for people aged 13 to 80 years. Scores of more than 12 or 13 indicate the presence of depression.

Greene Climacteric Scale

A numerical index that scores 21 menopausal symptoms in three domains: psychological, somatic, and vasomotor. Each symptom is rated from 0 to 3 where 0 = no symptoms and 3 = extreme symptoms.

Hamilton Anxiety Rating Scale

A 14-item observer-rated scale for measuring the severity of anxiety. It has been investigated for validity and reliability. Each item is rated on a 5-point scale from 0 (no symptoms) to 4 (severe or grossly disabling symptoms). Total score ranges from 0 to 56, with 14 or higher indicating clinically significant anxiety.

Hamilton Depression Rating Scale

A 21-item observer-rated scale for measuring the severity of depression. Hamilton recommended that the first 17 items only be used for this purpose, as the last 4 items do not measure the severity of depression. It has been investigated for validity and reliability. Items are measured on a scale of 0–4 or 0–2 (with a higher score indicating more severe symptoms). Total score ranges from 0 to 50, with a score of 8 or above indicating clinically significant depression.

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect.

Kupperman Index

A numerical index that scores 11 menopausal symptoms: hot flushes, paraesthesia, insomnia, nervousness, melancholia, vertigo, weakness, arthralgia or myalgia, headache, palpitations, and formication. Each symptom is rated from 0 to 3 according to severity and symptoms (where 0 = no symptoms and 3 = most severe), weighted and the total sum calculated. The maximum score is 51 points.

Low-quality evidence

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.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Very low-quality evidence

Any estimate of effect is very uncertain.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Nikolaos Burbos, Norfolk and Norwich University Hospital, Norwich, UK.

Edward P Morris, Norfolk and Norwich University Hospital, Norwich, UK.

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BMJ Clin Evid. 2011 Jun 15;2011:0804.

Tibolone

Summary

Tibolone reduces vasomotor symptoms in postmenopausal women compared with placebo.

Tibolone may improve sexual function compared with placebo or compared with combined oestrogens plus progestogens.

We don't know whether tibolone is more effective than oestrogen and progestogen combined treatment in reducing vasomotor symptoms.

Tibolone may be associated with an increased risk of breast cancer recurrence in women previously treated surgically for breast cancer compared with placebo.

We found no direct information from RCTs about the effects of tibolone on psychological, cognitive, and sleep symptoms, or on quality of life.

Benefits and harms

Tibolone versus placebo:

We found 4 RCTs comparing tibolone versus placebo.[3] [4] [5] [6]

Vasomotor symptoms

Compared with placebo Tibolone seems more effective at reducing the frequency and severity of hot flushes at 12 weeks (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom improvement
[3]
RCT
Crossover design 		82 women with menopausal symptoms Vasomotor symptom severity score 16 weeks (before crossover point)
with tibolone
with placebo
Absolute results reported graphically
Significance not assessed
[4]
RCT
5-armed trial 		775 women Frequency of hot flushes and sweating episodes (assessed using symptom diaries) 12 weeks
with tibolone 0.625 mg
with placebo
Absolute results reported graphically
Reported as not significant
P value not reported 		Not significant
[4]
RCT
5-armed trial 		775 women Frequency of hot flushes and sweating episodes (assessed using symptom diaries) 12 weeks
with tibolone 1.25 mg
with placebo
Absolute results reported graphically
P <0.0001 		Effect size not calculated tibolone 1.25 mg
[4]
RCT
5-armed trial 		775 women Frequency of hot flushes and sweating episodes (assessed using symptom diaries) 12 weeks
with tibolone 2.5 mg
with placebo
Absolute results reported graphically
P <0.0001 		Effect size not calculated tibolone 2.5 mg
[4]
RCT
5-armed trial 		775 women Frequency of hot flushes and sweating episodes (assessed using symptom diaries) 12 weeks
with tibolone 5 mg
with placebo
Absolute results reported graphically
P <0.0001 		Effect size not calculated tibolone 5 mg
[5]
RCT
3-armed trial 		396 symptomatic postmenopausal women Mean change in flushes/day 12 weeks
–8.3 with tibolone 1.25 mg
–5.5 with placebo
P = 0.003 or less 		Effect size not calculated tibolone 1.25 mg
[5]
RCT
3-armed trial 		396 symptomatic postmenopausal women Mean change in flushes/day 12 weeks
–9.7 with tibolone 2.5 mg
–5.5 with placebo
P <0.001 		Effect size not calculated tibolone 2.5 mg
[5]
RCT
3-armed trial 		396 symptomatic postmenopausal women Mean change in severity scores of flushes 12 weeks
–0.9 with tibolone 1.25 mg
–0.3 with placebo
P <0.001 		Effect size not calculated tibolone 1.25 mg
[5]
RCT
3-armed trial 		396 symptomatic postmenopausal women Mean change in severity scores of flushes 12 weeks
–1.7 with tibolone 2.5 mg
–0.3 with placebo
P <0.001 		Effect size not calculated tibolone 2.5 mg
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Urogenital symptoms

Compared with placebo Tibolone may be more effective at increasing sexual fantasies and arousability at 3 months, but we don't know about other urogenital symptoms (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Libido
[6]
RCT
Crossover design 		38 women Sexual fantasy frequency from diary (post-crossover) 3 months
2.78 episodes/week with tibolone
1.68 episodes/week with placebo
P <0.03 		Effect size not calculated tibolone
[6]
RCT
Crossover design 		38 women Arousal frequency from diary (post-crossover) 3 months
12.08 episodes/week with tibolone
9.05 episodes/week with placebo
P <0.01 		Effect size not calculated tibolone
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Psychological symptoms

No data from the following reference on this outcome.[3] [4] [5] [6]

Quality of life

No data from the following reference on this outcome.[3] [4] [5] [6]

Breast cancer recurrence

Compared with placebo Tibolone is associated with an increased risk of breast cancer recurrence in women previously treated surgically for breast cancer at a median of 3.1 years (high-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Breast cancer recurrence
[7]
RCT		 3148 women who had previously been treated surgically for breast cancer Rate of breast cancer recurrence median 3.1 years
237/1556 (15%) with tibolone
165/1542 (11%) with placebo
P = 0.001
HR 1.40
95% CI 1.14 to 1.70 		Small effect size placebo
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Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Cardiovascular adverse effects
[8] [9]
RCT		 Population details not reported Adverse effects
with tibolone
Vaginal bleeding
[4]
RCT
5-armed trial 		775 women Adverse effects
with tibolone
with placebo
[10]
Cohort study		 Population details not reported Adverse effects
with tibolone
Androgenic adverse effects
Population details not reported Adverse effects
with tibolone
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Tibolone versus oestrogen plus progestogen:

We found three RCTs comparing tibolone versus combined oestrogen and progestogen.[11] [12] [13]

Vasomotor symptoms

Compared with oestrogen plus progestogen We don't know how tibolone and oestrogen plus progestogen compare at reducing hot flushes; results varied among RCTs (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom improvement
[11]
RCT		 437 women with menopausal symptoms Hot flushes (assessed using a 5-point scoring system, where 1 = none and 5  = very severe [mean score 3.1 at baseline in both groups]) 48 weeks
1.56 with tibolone
1.25 with combined oestrogen/progestogen (oestradiol plus norethisterone)
P <0.001 		Effect size not calculated combined oestrogen/progestogen
[12]
RCT		 235 postmenopausal women Vasomotor symptoms 52 weeks
with tibolone
with combined oestrogen/progestogen
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
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No data from the following reference on this outcome.[13]

Urogenital symptoms

Compared with oestrogen plus progestogen Tibolone seems more effective at reducing vaginal dryness, but it may be no more effective at improving sexual satisfaction (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Vaginal dryness
[11]
RCT		 437 women Vaginal dryness (assessed using a 5-point scoring system, where 1 = none and 5  = very severe [mean score 2.1 at baseline in both groups]) 48 weeks
1.33 with tibolone
1.27 with combined oestrogen/progestogen (oestradiol plus norethisterone)
Significance not assessed
Sexual satisfaction
[14]
RCT		 437 women
Further report of reference [11] 		Sexual satisfaction (change in McCoy's Sex Scale Questionnaire from baseline) 48 weeks
3.85 with tibolone
2.20 with combined oestrogen/progestogen (oestradiol plus norethisterone)
Reported as not significant
P value not reported 		Not significant
Libido
[13]
RCT		 50 women attending a university gynaecology clinic Proportion of women with improvement in sexual desire scores from baseline (measured using a questionnaire) 12 months
12/23 (23%) with tibolone
3/21 (14%) with combined oestrogen/progestogen (conjugated oestrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg)
P <0.05 		Effect size not calculated tibolone
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No data from the following reference on this outcome.[12]

Psychological symptoms

No data from the following reference on this outcome.[11] [12] [13]

Quality of life

No data from the following reference on this outcome.[11] [12] [13]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[11]
RCT		 437 women Adverse effects
74% with tibolone
87% with combined oestrogen/progestogen (oestradiol plus norethisterone)
Absolute numbers not reported
Significance not reported
[13]
RCT		 50 women attending a university gynaecology clinic Adverse effects
with tibolone
with combined oestrogen/progestogen (conjugated oestrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg)
Open in a new tab

No data from the following reference on this outcome.[12]

Further information on studies

The RCT also evaluated coital and orgasm frequency, and dyspareunia, but did not summarise the results (proportion of people with each total score reported only; significance of differences unclear).

Comment

Data on the risk associated with the long-term use of tibolone, and on the effects on the endometrium, will be appraised in future updates.

Clinical guide:

Based on the evidence presented above, clinicians should avoid prescribing tibolone for women with known or suspected breast cancer, and those with a history of previous breast cancer. It remains reasonable to prescribe tibolone for women with no history of breast cancer, although we found no data from RCTs on the effects of tibolone on breast cancer risk in this group.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jun 15;2011:0804.

Oestrogens alone

Summary

Oestrogens reduce vasomotor and sexual symptoms but, like progestogens, increase the risk of serious adverse effects.

Oestrogens, used alone or with progestogens, reduce vasomotor and urogenital symptoms, and improve quality of life compared with placebo over 3 to 6 months.

However, oestrogens increase the risk of breast cancer, endometrial cancer, stroke, and venous thromboembolism.

CAUTION: Women with an intact uterus who are prescribed oestrogen replacement therapy should also take continuous or cyclical progestogens.

Benefits and harms

Oestrogens alone versus placebo:

We found one systematic review (search date 2002, 24 RCTs, 3329 women)[15] and 8 subsequent RCTs comparing the effectiveness of oestrogens alone versus placebo on vasomotor symptoms.[16] [17] [18] [19] [20] [21] [22] [23] Five RCTs assessed newly developed delivery systems and lower doses of oestrogen preparations versus placebo: these preparations are not widely available and further data are required.[19] [20] [21] [22] [23] We found two systematic reviews (search date 1998, 5 RCTs, 334 people;[24] search date 2006, 19 RCTs, 4162 women)[25] and 5 subsequent RCTs[17] [26] [27] [23] [28] assessing the effects of various preparations of oestrogen on urogenital symptoms. For psychological, cognitive, and sleep symptoms, we found three systematic reviews.[29] [30] [31] The first systematic review compared the effects of HRT versus placebo on menopausal depressed mood (search date 1995, 14 RCTs including several crossover RCTs, 12 cohort studies; duration of treatment ranged from 1 month to 2 years).[29] We found no RCTs of oestrogen treatment in women with clinically diagnosed depression. The second (search date 1996, 6 RCTs, 4 non-RCTs, 9 observational studies)[30] and third (search date 2006, 16 RCTs including 4 RCTs also in the second review, 10,114 postmenopausal women)[31] reviews compared the effects of oestrogen versus placebo on cognitive function in postmenopausal women. The second review found that studies were too weak to allow reliable conclusions to be drawn, and is not reported further.[30] We found three RCTs assessing the effects of oestrogen on quality of life: one RCT compared transdermal oestradiol versus placebo,[32] one RCT compared oral oestradiol versus placebo,[33] and the third RCT compared micro-dose transdermal oestradiol versus placebo.[23] We found two systematic reviews (search date 2008, 45 RCTs, 38,702 women;[34] search date not reported, 51 RCTs, >160,000 women),[35] one non-systematic review (4 RCTs, >20,000 women),[36] and 6 subsequent RCTs[37] [38] [27] [22] [23] [28] assessing adverse effects of oestrogens. We found three systematic reviews (search date 2004, 28 RCTs, 39,769 people, 3 RCTs included men;[39] search date 2008, 31 RCTs, 41,113 women;[40] search date 2007, 9 RCTs, 7 case control studies, and 1 prospective cohort study)[41] evaluating cardiovascular complications of HRT. All the reviews compared either oestrogen alone, or oestrogen plus progestogen, versus placebo or no treatment.[39] [40] [41] The reviews did not report results for oestrogen alone. The systematic reviews identified many RCTs in common; together, they identified 44 different RCTs. We found one systematic review reporting on weight gain with HRT (search date 1998, 9 RCTs, 10,194 women).[42]

Vasomotor symptoms

Compared with placebo Oestrogen (oral, intranasal, topical, or via vaginal ring) seems more effective at reducing the frequency of hot flushes and improving symptom scores (Kupperman Index; Greene Climacteric Scale) (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Vasomotor symptoms (all)
[15]
Systematic review		 959 women
3 RCTs in this analysis		 Proportion of women with hot flushes 6 months to 3 years
115/738 (16%) with oestrogen-only HRT
81/221 (37%) with placebo
OR 0.35
95% CI 0.22 to 0.55 		Moderate effect size oestrogen-only HRT
[15]
Systematic review		 365 women
3 RCTs in this analysis		 Frequency of hot flushes 6 months to 3 years
with oestrogen-only HRT
with placebo
Absolute results not reported
WMD –14.8 flushes/week
95% CI –20.9 flushes/week to –8.7 flushes/week 		Effect size not calculated oestrogen-only HRT
[16]
RCT
9-armed trial 		2673 women entered, 2152 analysed Vasomotor symptoms (assessed using diary cards to record number and severity of hot flushes) 3 to 12 weeks
with oral conjugated equine oestrogens (0.3, 0.45, or 0.625 mg) alone
with placebo
Absolute results reported graphically
P <0.05 		Effect size not calculated oral conjugated equine oestrogens
[17]
RCT
3-armed trial 		165 women Mean reduction from baseline in number of moderate to severe vasomotor symptoms/day (assessed with diaries and the Kupperman Index) 12 weeks
9.39 with high-dose intranasal oestradiol (300 micrograms)
5.22 with placebo
P = 0.002 for intranasal oestradiol 300 micrograms v placebo 		Effect size not calculated high-dose intranasal oestradiol
[17]
RCT
3-armed trial 		165 women Mean reduction from baseline in number of moderate to severe vasomotor symptoms/day (assessed with diaries and the Kupperman Index) 12 weeks
7.86 with low-dose intranasal oestradiol (150 micrograms)
5.22 with placebo
P <0.001 for intranasal oestradiol 150 micrograms v placebo 		Effect size not calculated low-dose intranasal oestradiol
[18]
RCT
3-armed trial 		333 women Hot flushes/week measured using 4-point scale in daily diary 12 weeks
15.5 with vaginal ring releasing oestradiol 50 micrograms
42.2 with placebo
P <0.05 for vaginal ring releasing oestradiol 50 micrograms v placebo 		Effect size not calculated oestradiol
[18]
RCT
3-armed trial 		333 women Hot flushes/week measured using 4-point scale in daily diary 12 weeks
8.3 with vaginal ring releasing oestradiol 100 micrograms
42.2 with placebo
P <0.05 for vaginal ring releasing oestradiol 100 micrograms v placebo 		Effect size not calculated oestradiol
[18]
RCT
3-armed trial 		333 women Reduction in Greene Climacteric Scale scores (score range 0–63) 12 weeks
10.52 with vaginal ring releasing oestradiol 50 micrograms
5.95 with placebo
P <0.002 for vaginal ring releasing oestradiol 50 micrograms v placebo 		Effect size not calculated oestradiol
[18]
RCT
3-armed trial 		333 women Reduction in Greene Climacteric Scale scores (score range 0–63) 12 weeks
10.72 with vaginal ring releasing oestradiol 100 micrograms
5.95 with placebo
P <0.002 for vaginal ring releasing oestradiol 100 micrograms v placebo 		Effect size not calculated oestradiol
[19]
RCT
6-armed trial 		454 postmenopausal women, mean age 53 years Reduction from baseline in flushes/day 12 weeks
–8.44 with transdermal oestradiol spray (3-spray dose)
–5.32 with placebo
P <0.001 for transdermal oestradiol spray (3-spray dose) v placebo 		Effect size not calculated transdermal oestradiol spray (3-spray dose)
[19]
RCT
6-armed trial 		454 postmenopausal women, mean age 53 years Reduction from baseline in flushes/day 12 weeks
–8.66 with transdermal oestradiol spray (two-spray dose)
–6.19 with placebo
P = 0.010 for transdermal oestradiol spray (two-spray dose) v placebo 		Effect size not calculated transdermal oestradiol spray (two-spray dose)
[19]
RCT
6-armed trial 		454 postmenopausal women, mean age 53 years Reduction from baseline in flushes/day 12 weeks
–8.10 with transdermal oestradiol spray (one-spray dose)
–4.76 with placebo
P <0.001 for transdermal oestradiol spray (one-spray dose) v placebo 		Effect size not calculated transdermal oestradiol spray (one-spray dose)
[19]
RCT
6-armed trial 		454 postmenopausal women, mean age 53 years Reduction in flush severity scores 12 weeks
from 2.58 to 1.50 with transdermal oestradiol spray (3-spray dose)
from 2.54 to 2.23 with placebo
P <0.001 for transdermal oestradiol spray (3-spray dose) v placebo 		Effect size not calculated transdermal oestradiol spray (3-spray dose)
[19]
RCT
6-armed trial 		454 postmenopausal women, mean age 53 years Reduction in flush severity scores 12 weeks
from 2.54 to 1.63 with transdermal oestradiol spray (two-spray dose)
from 2.29 to 2.00 with placebo
P = 0.041 for transdermal oestradiol spray (two-spray dose) v placebo 		Effect size not calculated transdermal oestradiol spray (two-spray dose)
[19]
RCT
6-armed trial 		454 postmenopausal women, mean age 53 years Reduction in flush severity scores 12 weeks
–1.04 with transdermal oestradiol spray (one-spray dose)
–0.26 with placebo
P <0.001 for transdermal oestradiol spray (one-spray dose) v placebo 		Effect size not calculated transdermal oestradiol spray (one-spray dose)
[21]
RCT
4-armed trial 		484 postmenopausal women, typical time of 8 to 9 years since last period Mean change in moderate to severe hot flushes/day 3 weeks
–9.5 with oestradiol gel 2.6 g
–5.4 with placebo
P <0.001 for oestradiol gel 2.6 g v placebo 		Effect size not calculated oestradiol gel 2.6 g
[21]
RCT
4-armed trial 		484 postmenopausal women, typical time of 8 to 9 years since last period Mean change in moderate to severe hot flushes/day 3 weeks
–8.2 with oestradiol gel 1.7 g
–5.4 with placebo
P = 0.007 for oestradiol gel 1.7 g v placebo 		Effect size not calculated oestradiol gel 1.7 g
[21]
RCT
4-armed trial 		484 postmenopausal women, typical time of 8 to 9 years since last period Mean change in moderate to severe hot flushes/day 5 weeks
–7.7 with oestradiol gel 0.87 g
–5.5 with placebo
P <0.001 for oestradiol gel 0.87 g v placebo 		Effect size not calculated oestradiol gel 0.87 g
[21]
RCT
4-armed trial 		484 postmenopausal women, typical time of 8 to 9 years since last period Mean change in moderate to severe hot flushes/day 4 to 12 weeks
with oestradiol gel 2.6 g
with placebo
Absolute results reported graphically
Reported as significant
P value not reported 		Effect size not calculated oestradiol gel 2.6 g
[21]
RCT
4-armed trial 		484 postmenopausal women, typical time of 8 to 9 years since last period Mean change in moderate to severe hot flushes/day 4 to 12 weeks
with oestradiol gel 1.7 g
with placebo
Absolute results reported graphically
Reported as significant
P value not reported 		Effect size not calculated oestradiol gel 1.7 g
[21]
RCT
4-armed trial 		484 postmenopausal women, typical time of 8 to 9 years since last period Mean change in moderate to severe hot flushes/day 6 to 12 weeks
with oestradiol gel 0.87 g
with placebo
Absolute results reported graphically
Reported as significant
P value not reported 		Effect size not calculated oestradiol gel 0.87 g
[20]
RCT		 200 postmenopausal women Change from baseline in number of flushes/day 12 weeks
–11.1 with oestradiol topical emulsion
–7.2 with placebo emulsion
P = 0.001 		Effect size not calculated oestradiol topical emulsion
[20]
RCT		 200 postmenopausal women Change in severity of flushing 12 weeks
with oestradiol topical emulsion
with placebo emulsion
Absolute results reported graphically
P <0.001 		Effect size not calculated oestradiol topical emulsion
[22]
RCT
4-armed trial 		495 postmenopausal women Change from baseline in median daily frequency of moderate to severe vasomotor symptoms (MSVMS) 12 weeks
with 1 g transdermal oestradiol gel 0.1%
with placebo
Absolute results reported graphically
P less than or equal to 0.001 		Effect size not calculated 1 g transdermal oestradiol gel 0.1%
[22]
RCT
4-armed trial 		495 postmenopausal women Change from baseline in median daily frequency of MSVMS 12 weeks
with 0.5 g transdermal oestradiol gel 0.1%
with placebo
Absolute results reported graphically
P less than or equal to 0.001 		Effect size not calculated 0.5 g transdermal oestradiol gel 0.1%
[22]
RCT
4-armed trial 		495 postmenopausal women Change from baseline in median daily frequency of MSVMS 12 weeks
with 0.25 g transdermal oestradiol gel 0.1%
with placebo
Absolute results reported graphically
P less than or equal to 0.001 		Effect size not calculated 0.25 g transdermal oestradiol gel 0.1%
[22]
RCT
4-armed trial 		495 postmenopausal women Reduction from baseline in daily severity of MSVMS 12 weeks
with 1 g transdermal oestradiol gel 0.1%
with placebo
Absolute results reported graphically
P less than or equal to 0.001 		Effect size not calculated 1 g transdermal oestradiol gel 0.1%
[22]
RCT
4-armed trial 		495 postmenopausal women Reduction from baseline in daily severity of MSVMS 12 weeks
with 0.5 g transdermal oestradiol gel 0.1%
with placebo
Absolute results reported graphically
P less than or equal to 0.01 		Effect size not calculated 0.5 g transdermal oestradiol gel 0.1%
[22]
RCT
4-armed trial 		495 postmenopausal women Reduction from baseline in daily severity of MSVMS 12 weeks
with 0.25 g transdermal oestradiol gel 0.1%
with placebo
Absolute results reported graphically
P less than or equal to 0.001 		Effect size not calculated 0.25 g transdermal oestradiol gel 0.1%
[23]
RCT		 165 menopausal women Reduction in mean weekly number of hot flushes 12 weeks
55% with transdermal micro-dose oestradiol 0.014 mg daily
40% with placebo
Absolute results reported graphically
P <0.01 		Effect size not calculated transdermal micro-dose oestradiol 0.014 mg daily
[23]
RCT		 165 menopausal women Reduction in moderate and severe hot flushes 12 weeks
58% with transdermal micro-dose oestradiol 0.014 mg daily
39% with placebo
Absolute results reported graphically
P <0.05 		Effect size not calculated transdermal micro-dose oestradiol 0.014 mg daily
Open in a new tab

No data from the following reference on this outcome.[24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [37] [38] [39] [40] [41]

Urogenital symptoms

Compared with placebo Oestrogen is more effective at reducing urinary tract infections, vaginal dryness, vaginal atrophy, and dyspareunia (high-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Dyspareunia
[25]
Systematic review		 67 women
Data from 1 RCT		 Proportion of women with improvement in dyspareunia (patient-assessed) 12 weeks
30/33 (91%) with oestrogen ring
15/34 (44%) with placebo
OR 12.67
95% CI 3.23 to 49.67 		Large effect size oestrogen ring
[25]
Systematic review		 716 women
2 RCTs in this analysis		 Proportion of women with dyspareunia
105/358 (29%) with oestrogen tablet
256/358 (72%) with placebo
OR 0.17
95% CI 0.12 to 0.23 		Large effect size oestrogen tablet
[17]
RCT
3-armed trial 		165 women Dyspareunia and "urinary troubles" (measured on a visual analogue scale) 12 weeks
with intranasal oestradiol 150 micrograms/day
with placebo
Absolute results not reported
P <0.001 for intranasal oestradiol 150 micrograms/day v placebo 		Effect size not calculated intranasal oestradiol 150 micrograms/day
[17]
RCT
3-armed trial 		165 women Dyspareunia and "urinary troubles" (measured on a visual analogue scale) 4 weeks
with intranasal oestradiol 300 micrograms/day
with placebo
Absolute results not reported
P = 0.014 for intranasal oestradiol 300 micrograms/day v placebo 		Effect size not calculated intranasal oestradiol 300 micrograms/day
[27]
RCT
4-armed trial 		622 postmenopausal women Reduction in severity of dyspareunia 12 weeks
1.76 with synthetic conjugated oestrogens (SCE) 1 g cream
0.94 with placebo
Absolute results reported graphically
P <0.0001 		Effect size not calculated synthetic conjugated oestrogens 1 g cream
[28]
RCT
4-armed trial 		423 postmenopausal women Reduction in dyspareunia severity score 12 weeks
–1.4 points with conjugated oestrogen cream 0.3 mg once daily, 21 days on/7 days off
–0.4 points with placebo
P <0.001 		Effect size not calculated conjugated oestrogen cream 0.3 mg
[28]
RCT
4-armed trial 		423 postmenopausal women Reduction in dyspareunia severity score 12 weeks
–1.4 points with conjugated oestrogen cream 0.3 mg twice weekly
–0.7 points with placebo
P less than or equal to 0.01 		Effect size not calculated conjugated oestrogen cream 0.3 mg
Burning and itching
[25]
Systematic review		 774 women
2 RCTs in this analysis		 Proportion of women with burning and itching
89/385 (23%) with oestrogen tablet
249/389 (64%) with placebo
OR 0.15
95% CI 0.10 to 0.20 		Large effect size oestrogen tablet
Vaginal dryness
[25]
Systematic review		 1140 women
3 RCTs in this analysis		 Proportion of women with vaginal dryness
108/568 (19%) with oestrogen tablet
423/572 (74%) with placebo
OR 0.08
95% CI 0.06 to 0.10 		Large effect size oestrogen tablet
[26]
RCT
3-armed trial 		145 women Days free from vaginal dryness 9 to 12 weeks
86% with oestradiol 1 mg
76% with oestradiol 0.5 mg
74% with placebo
Absolute numbers not reported
Significance of the difference between oestradiol groups and placebo not assessed
[27]
RCT
4-armed trial 		622 postmenopausal women Severity of vaginal dryness 12 weeks
1.65 with synthetic conjugated oestrogens (SCE) 1 g cream
1.17 with placebo
Absolute results reported graphically
P <0.0012 		Effect size not calculated synthetic conjugated oestrogens 1 g cream
[28]
RCT
4-armed trial 		423 postmenopausal women Reduction in vaginal dryness severity score 12 weeks
–1.1 points with conjugated oestrogen cream 0.3 mg once daily, 21 days on/7 days off
–0.7 points with placebo
P <0.05 		Effect size not calculated conjugated oestrogen cream 0.3 mg
Vaginal atrophy
[25]
Systematic review		 1256 women
2 RCTs in this analysis		 Proportion of women with vaginal atrophy
129/626 (21%) with oestrogen tablet
454/630 (72%) with placebo
OR 0.09
95% CI 0.07 to 0.12 		Large effect size oestrogen tablet
Urinary tract infection
[24]
Systematic review		 334 people
5 RCTs in this analysis		 Incidence of urinary tract infection
with oral or vaginal oestrogen HRT
with placebo or no treatment
Absolute results not reported
OR 2.51
95% CI 1.48 to 4.25 		Moderate effect size oral or vaginal oestrogen HRT
Pallor
[25]
Systematic review		 52 women
Data from 1 RCT		 Proportion of women with absence of pallor (physician-assessed)
21/25 (84%) with oestrogen ring
14/27 (52%) with placebo
OR 4.88
95% CI 1.32 to 18.05 		Moderate effect size oestrogen ring
Friability
[25]
Systematic review		 52 women
Data from 1 RCT		 Proportion of women with absence of friability (physician-assessed)
18/21 (86%) with oestrogen ring
9/20 (45%) with placebo
OR 7.33
95% CI 1.63 to 33.08 		Large effect size oestrogen ring
Treatment satisfaction
[25]
Systematic review		 159 women
Data from 1 RCT		 Overall treatment satisfaction
84/90 (93%) with oestrogen ring (50 micrograms)
56/69 (81%) with placebo
OR 0.31
95% CI 0.11 to 0.86 		Moderate effect size oestrogen ring (50 micrograms)
[25]
Systematic review		 159 women
Data from 1 RCT		 Overall treatment satisfaction
88/89 (99%) with oestrogen ring (100 micrograms)
56/69 (81%) with placebo
OR 0.05
95% CI 0.01 to 0.38 		Large effect size oestrogen ring (100 micrograms)
Tolerability
[25]
Systematic review		 143 women
Data from 1 RCT		 Pain during intercourse
23/82 (28%) with oestrogen ring (50 micrograms)
15/61 (25%) with placebo
OR 0.58
95% CI 0.17 to 2.01 		Not significant
[25]
Systematic review		 143 women
Data from 1 RCT		 Pain during intercourse
17/75 (23%) with oestrogen ring (100 micrograms)
15/61 (25%) with placebo
OR 0.43
95% CI 0.11 to 1.64 		Not significant
Improvement in urogenital symptoms
[27]
RCT
4-armed trial 		622 postmenopausal women Mean change from baseline in severity of most bothersome symptom from Vaginal Atrophy/Sexual Function Questionnaire 12 weeks
–1.71 with synthetic conjugated oestrogens (SCE) 1 g cream
–1.11 with placebo
Absolute results reported graphically
P <0.0001 		Effect size not calculated synthetic conjugated oestrogens 1 g cream
[23]
RCT		 165 postmenopausal women Improvement in urogenital symptoms (vaginal dryness, pollakisuria, involuntary urination, dyspareunia) 12 weeks
with transdermal micro-dose oestradiol 0.014 mg daily
with placebo
P value not reported
Reported as not significant 		Not significant
[28]
RCT
4-armed trial 		423 postmenopausal women Change in severity score of participant-rated most bothersome vaginal symptoms 12 weeks
–1.3 points with conjugated oestrogen cream 0.3 mg once daily, 21 days on/7 days off
–0.8 points with placebo
P less than or equal to 0.001 		Effect size not calculated conjugated oestrogen cream 0.3 mg
[28]
RCT
4-armed trial 		423 postmenopausal women Change in severity score of participant-rated most bothersome vaginal symptoms 12 weeks
–1.4 points with conjugated oestrogen cream 0.3 mg twice weekly
–0.7 points with placebo
P less than or equal to 0.001 		Effect size not calculated conjugated oestrogen cream 0.3 mg
Open in a new tab

No data from the following reference on this outcome.[15] [16] [18] [19] [20] [21] [22] [29] [30] [31] [32] [33] [34] [35] [36] [38] [39] [40] [41]

Psychological symptoms

Compared with placebo We don't know whether oestrogen is more effective at improving cognitive scores. Oestrogen may be more effective at reducing depressed mood in women without a pre-existing diagnosis of depression; however, evidence is weak (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Mood
[29]
Systematic review		 Population details not reported Depressed mood (measured using different scales)
with oestrogen
with placebo or no treatment
Absolute results not reported
P <0.0001 		Effect size not calculated oestrogen
Cognitive function
[31]
Systematic review		 115 women
Data from 1 RCT		 Mean difference in Cambridge Cognitive Examination for Mental Disorders of the Elderly (CAMCOG) score 20 weeks
with oestrogen
with placebo
Absolute results not reported
Mean difference +0.60
95% CI –0.62 to +1.82 		Not significant
[31]
Systematic review		 Number of women in this analysis not reported
Data from 1 RCT		 Mean difference in Modified Mini-Mental State Examination (3MSE) score 6 years
with oestrogen
with placebo
Absolute results not reported
Mean difference –0.45
95% CI –0.99 to +0.09 		Not significant
[31]
Systematic review		 373 women
Data from 1 RCT		 Mean difference in Folstein Mini-Mental State Examination score 3 years
with oestrogen
with placebo
Absolute results not reported
Mean difference –0.10
95% CI –0.34 to +0.14 		Not significant
[31]
Systematic review		 Number of women in this analysis not reported
Data from 1 RCT		 Modified Mini-Mental State Examination (3MSE) score 1 year
with oestrogen
with placebo
Absolute results not reported
WMD –0.44
95% CI –0.73 to –0.16 		Effect size not calculated oestrogen
[31]
Systematic review		 2942 women
Data from 1 RCT		 Proportion of women with a diagnosis of mild cognitive impairment 5 years
76/1463 (5%) with oestrogen
58/1479 (4%) with placebo
OR 1.34
95% CI 0.95 to 1.90 		Not significant
Open in a new tab

No data from the following reference on this outcome.[15] [16] [17] [18] [19] [20] [21] [23] [22] [24] [26] [27] [23] [28] [32] [33] [34] [35] [36] [38] [39] [40] [41]

Quality of life

Compared with placebo Oestrogen (oral or transdermal) seems more effective at improving quality-of-life scores at 12 to 16 weeks (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life
[32]
RCT		 242 postmenopausal women Quality of life (measured by change in Nottingham Health Profile scores) 12 weeks
−58.2 with oestradiol transdermal patches (50 micrograms/24 hours)
−17.3 with placebo patches
P = 0.0003 		Effect size not calculated oestradiol transdermal patches
[33]
RCT		 82 women aged 40 to 60 years Quality of life (Kupperman Index score) 16 weeks
8.6 with oral oestradiol
18.1 with placebo
P = 0.0015 		Effect size not calculated oral oestradiol
[33]
RCT		 82 women aged 40 to 60 years Quality of life (Greene Climacteric Scale psychological subscore) 16 weeks
8.0 with oral oestradiol
16.7 with placebo
P = 0.0037 		Effect size not calculated oral oestradiol
[33]
RCT		 82 women aged 40 to 60 years Quality of life (Greene Climacteric Scale somatic subscore) 16 weeks
3.3 with oral oestradiol
5.4 with placebo
P = 0.0026 		Effect size not calculated oral oestradiol
[33]
RCT		 82 women aged 40 to 60 years Quality of life (Greene Climacteric Scale vasomotor subscore) 16 weeks
4.5 with oral oestradiol
9.4 with placebo
P = 0.0003 		Effect size not calculated oral oestradiol
[23]
RCT		 165 postmenopausal women Changes in Menopause QoL Questionnaire scores 12 weeks
–1.0 with transdermal micro-dose oestradiol 0.014 mg daily
–1.0 with placebo
P value not reported
Reported as not significant 		Not significant
Open in a new tab

No data from the following reference on this outcome.[15] [16] [17] [18] [19] [20] [21] [22] [24] [26] [27] [28] [29] [30] [31] [34] [35] [36] [37] [38] [39] [40] [41]

Adverse effects

Compared with placebo Oestrogen seems associated with an increased risk of endometrial hyperplasia (in women who have not had a hysterectomy), breast cancer, venous thromboembolism, and stroke with long-term use (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects (any)
[17] [24] [25] [26] Adverse effects
with oestrogens
[27]
RCT
4-armed trial 		622 postmenopausal women Withdrawals due to adverse effects
3/150 (2.0%) with synthetic conjugated oestrogens (SCE) 1 g cream
2/155 (1.3%) with placebo
Absolute results reported graphically
Significance not assessed
[22]
RCT
4-armed trial 		495 postmenopausal women Proportion of people with treatment-related adverse effects
43/125 (34%) with 1 g transdermal oestradiol gel 0.1%
26/123 (21%) with 0.5 g transdermal oestradiol gel 0.1%
23/122 (19%) with 0.25 g transdermal oestradiol gel 0.1%
15/125 (12%) with placebo
Absolute results reported graphically
Significance not assessed
[23]
RCT		 165 postmenopausal women Adverse effects
with transdermal micro-dose oestradiol 0.014 mg daily
with placebo
Significance not assessed
[28]
RCT
4-armed trial 		423 postmenopausal women Adverse effects 12 weeks
with conjugated oestrogen cream 0.3 mg
with placebo
Significance not assessed
Weight gain
[42]
Systematic review		 10,194 women
9 RCTs in this analysis		 Body weight 3 months to 4 years
with oestrogen
with placebo
Absolute results not reported
WMD +0.03 kg
95% CI –0.61 kg to +0.67 kg 		Not significant
Endometrial hyperplasia and cancer
[34]
Systematic review		 1499 postmenopausal women
4 RCTs in this analysis		 Endometrial hyperplasia 12 months
13/980 (1.3%) with low-dose oestrogen
2/519 (0.4%) with placebo
OR 2.84
95% CI 0.97 to 8.29 		Not significant
[34]
Systematic review		 893 postmenopausal women
6 RCTs in this analysis		 Endometrial hyperplasia 18 to 24 months
34/627 (5%) with low-dose oestrogen
5/266 (2%) with placebo
OR 2.42
95% CI 1.19 to 4.92 		Moderate effect size placebo
[34]
Systematic review		 1244 postmenopausal women
5 RCTs in this analysis		 Endometrial hyperplasia 12 months
89/606 (15%) with moderate-dose oestrogen
2/638 (<1%) with placebo
OR 8.4
95% CI 5.5 to 12.9 		Large effect size placebo
[34]
Systematic review		 627 postmenopausal women
6 RCTs in this analysis		 Endometrial hyperplasia 18 to 24 months
103/290 (36%) with moderate-dose oestrogen
4/337 (1%) with placebo
OR 11.9
95% CI 7.8 to 18.1 		Large effect size placebo
[34]
Systematic review		 238 postmenopausal women
Data from 1 RCT		 Endometrial hyperplasia 3 years
74/119 (62%) with moderate-dose oestrogen
2/119 (2%) with placebo
OR 16
95% CI 9.3 to 27.5 		Large effect size placebo
[34]
Systematic review		 120 postmenopausal women
Data from 1 RCT		 Endometrial hyperplasia 12 months
26/60 (43%) with high-dose oestrogen
1/60 (2%) with placebo
OR 10.7
95% CI 4.6 to 25.1 		Large effect size placebo
[34]
Systematic review		 120 postmenopausal women
Data from 1 RCT		 Endometrial hyperplasia 18 to 24 months
32/60 (53%) with high-dose oestrogen
1/60 (2%) with placebo
OR 13.1
95% CI 5.9 to 29 		Large effect size placebo
[34]
Systematic review		 Population details not reported Endometrial cancer
with oestrogen
with placebo
[36]
Non-systematic review		 More than 20,000 women
4 RCTs in this analysis		 Endometrial cancer
with combined HRT
with placebo
Absolute results not reported
RR 0.76
95% CI 0.45 to 1.31 		Not significant
Breast cancer
[35]
Systematic review		 More than 160,000 women
51 RCTs in this analysis		 Breast cancer
with HRT (oestrogen alone or oestrogen plus progestogen)
with placebo
RR of developing breast cancer: 2.3% per year
95% CI 1.1% to 3.6% 		Effect size not calculated placebo
[36]
Non-systematic review		 More than 20,000 women
4 RCTs in this analysis		 Breast cancer
with combined HRT or oestrogen-only HRT
with placebo
Absolute results not reported
RR 1.27
95% CI 1.03 to 1.56 		Small effect size placebo
[37]
RCT		 10,739 postmenopausal women aged 50 to 79 years who had undergone hysterectomy, with or without oophorectomy Breast cancer mean follow-up of 7.1 years
129/5310 (2%) with conjugated equine oestrogens (CEE) 0.625 mg daily
161/5429 (3%) with placebo
HR 0.82
95% CI 0.62 to 1.04
P = 0.09 		Not significant
Colorectal cancer
[36]
Non-systematic review		 More than 20,000 women
4 RCTs in this analysis		 Colorectal cancer
with combined HRT or oestrogen-only HRT
with placebo
Absolute results not reported
RR 0.64
95% CI 0.45 to 0.92 		Small effect size combined HRT or oestrogen-only HRT
Fractures
[36]
Non-systematic review		 More than 20,000 women
4 RCTs in this analysis		 Fractured neck of femur
with combined HRT or oestrogen-only HRT
with placebo
Absolute results not reported
RR 0.72
95% CI 0.52 to 0.98 		Small effect size combined HRT or oestrogen-only HRT
Cardiovascular adverse effects
[39]
Systematic review		 39,769 people
28 RCTs in this analysis		 Proportion of people with any type of stroke
534/19,735 (3%) with combined HRT or oestrogen-only HRT
406/20,034 (2%) with no HRT
OR 1.29
95% CI 1.13 to 1.47 		Small effect size no HRT
[39]
Systematic review		 39,769 people
28 RCTs in this analysis		 Ischaemic stroke
with combined HRT or oestrogen-only HRT
with no HRT
Absolute results not reported
OR 1.29
95% CI 1.06 to 1.56 		Small effect size no HRT
[39]
Systematic review		 39,769 people
28 RCTs in this analysis		 Haemorrhagic stroke
with combined HRT or oestrogen-only HRT
with no HRT
Absolute results not reported
OR 1.07
95% CI 0.65 to 1.75 		Not significant
[39]
Systematic review		 39,769 people, three RCTs included men
28 RCTs in this analysis		 Stroke severity (death or dependency after a stroke)
with combined HRT or oestrogen-only HRT
with no HRT
Absolute results not reported
OR 1.56
95% CI 1.11 to 2.20 		Small effect size no HRT
[40]
Systematic review		 41,113 women
31 RCTs in this analysis		 Proportion of women with a cerebrovascular event (stroke or TIA)
581/23,116 (3%) with combined HRT or oestrogen-only HRT
453/20,433 (2%) with control
OR 1.24
95% CI 1.09 to 1.41 		Small effect size control
[40]
Systematic review		 41,113 women
31 RCTs in this analysis		 Proportion of women with a venous thromboembolism
360/22,540 (2%) with combined HRT or oestrogen-only HRT
187/19,841 (1%) with control
OR 2.05
95% CI 1.44 to 2.92 		Moderate effect size control
[40]
Systematic review		 41,113 women
31 RCTs in this analysis		 Proportion of women with CHD event (including MI)
841/22,945 (4%) with combined HRT or oestrogen-only HRT
795/20,214 (4%) with control
OR 1.00
95% CI 0.90 to 1.11 		Not significant
[41]
Systematic review		 38,779 women
9 RCTs in this analysis		 Venous thromboembolism
with combined HRT or oestrogen-only HRT
with placebo
Absolute results not reported
OR 2.1
95% CI 1.4 to 3.1
P = 0.03 		Moderate effect size placebo
[41]
Systematic review		 Number of women in analysis not clear
2 RCTs in this analysis
Subgroup analysis		 Venous thromboembolism
with oestrogen-only HRT
with placebo
Absolute results not reported
OR 3.5
95% CI 0.2 to 11.1 		Not significant
[41]
Systematic review		 Number of women in analysis not clear
2 RCTs in this analysis
Subgroup analysis		 Venous thromboembolism
with oestrogen-only HRT
with placebo
Absolute results not reported
OR 3.3
95% CI 1.9 to 5.6 		Moderate effect size placebo
Gallbladder disease
[38]
RCT		 22,579 women Gallbladder disease
with oestrogen alone
with placebo
Absolute results not reported
HR 1.67
95% CI 1.35 to 2.06 		Small effect size placebo
Open in a new tab

No data from the following reference on this outcome.[15] [16] [17] [18] [19] [20] [21] [22] [24] [26] [27] [23] [28] [29] [30] [31] [32] [33] [34]

Different oestrogen preparations versus each other:

We found one systematic review (search date 2006, 19 RCTs, 4162 women),[25] which performed an analysis of the effects of various vaginal preparations on urogenital symptoms, and one subsequent RCT comparing the effect of different delivery systems of hormone therapy on psychological symptoms in surgically postmenopausal women.[43]

Urogenital symptoms

Different oestrogen preparations compared with each other Oestrogen tablets may be more effective than oestrogen rings at reducing vaginal dryness and dyspareunia, but not in reducing vaginal atrophy. Oestrogen rings may be more effective than oestrogen cream at improving pruritus, but not vaginal dryness or dyspareunia. Oestrogen tablets may be more effective than oestrogen cream at improving vaginal dryness, but not in improving dyspareunia (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Dyspareunia
[25]
Systematic review		 567 women
3 RCTs in this analysis		 Proportion of women with improvement or cure of dyspareunia (patient-assessed)
200/347 (58%) with oestrogen ring
147/220 (67%) with oestrogen tablet
OR 0.53
95% CI 0.36 to 0.78 		Small effect size oestrogen tablet
[25]
Systematic review		 341 women
2 RCTs in this analysis		 Proportion of women with improvement or cure of dyspareunia (patient-assessed)
145/203 (71%) with oestrogen ring
108/138 (78%) with oestrogen cream
OR 0.69
95% CI 0.41 to 1.14 		Not significant
[25]
Systematic review		 48 women
Data from 1 RCT		 Proportion of women with improvement or cure of dyspareunia (patient-assessed)
8/24 (33%) with oestrogen tablet
3/24 (13%) with oestrogen cream
OR 3.50
95% CI 0.11 to 2.58 		Not significant
Vaginal dryness
[25]
Systematic review		 397 women
2 RCTs in this analysis		 Proportion of women with improvement or cure of vaginal dryness (patient-assessed)
155/235 (66%) with oestrogen ring
124/162 (77%) with oestrogen tablet
OR 0.40
95% CI 0.24 to 0.64 		Moderate effect size oestrogen tablet
[25]
Systematic review		 341 women
2 RCTs in this analysis		 Proportion of women with improvement of vaginal dryness (patient-assessed)
165/203 (81%) with oestrogen ring
107/138 (76%) with oestrogen cream
OR 1.29
95% CI 0.75 to 2.22 		Not significant
[25]
Systematic review		 48 women
Data from 1 RCT		 Proportion of women with improvement or cure of vaginal dryness (patient-assessed)
12/24 (50%) with oestrogen tablet
3/24 (13%) with oestrogen cream
OR 7.00
95% CI 1.64 to 29.85 		Large effect size oestrogen tablet
Vaginal atrophy
[25]
Systematic review		 170 women
Data from 1 RCT		 Proportion of women with absence of vaginal atrophy symptoms
47/112 (42%) with oestrogen ring
22/58 (38%) with oestrogen tablet
OR 1.18
95% CI 0.62 to 2.27 		Not significant
Pruritus
[25]
Systematic review		 341 women
2 RCTs in this analysis		 Improvement in pruritus
159/203 (78%) with oestrogen ring
81/138 (59%) with oestrogen cream
OR 2.71
95% CI 1.66 to 4.43 		Moderate effect size oestrogen ring
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No data from the following reference on this outcome.[43]

Vasomotor symptoms

Different oestrogen preparations compared with each other We don't know whether different oestrogen delivery systems (oral, intranasal, or percutaneous) differ in effectiveness in reducing vasomotor symptoms (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Vasomotor symptoms
[43]
RCT
4-armed trial 		132 surgically postmenopausal women (minimum 1 month post hysterectomy) Change from baseline in menopausal symptoms (Kupperman Index scores) 12 months
14.83 to 8.38 with oral conjugated oestrogen 0.625 mg daily
13.64 to 8.29 with intranasal oestradiol hemihydrate 300 micrograms daily
13.19 to 9.38 with percutaneous oestradiol hemihydrate 1.5 mg daily
Reported as "no difference between groups"
P value not reported 		Not significant
Open in a new tab

No data from the following reference on this outcome.[25]

Psychological symptoms

Different oestrogen preparations compared with each other We don't know whether different oestrogen delivery systems (oral, intranasal, or percutaneous) differ in effectiveness at improving psychological symptoms (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Psychological symptoms
[43]
RCT
4-armed trial 		132 surgically postmenopausal women (minimum 1 month post hysterectomy) Change from baseline in severity of depressive symptoms (Hamilton Depression Rating Scale) 12 months
10.63 to 4.79 with oral conjugated oestrogen 0.625 mg daily
11.07 to 8.00 with intranasal oestradiol hemihydrate 300 micrograms daily
P = 0.001 for oral v intranasal treatment 		Effect size not calculated oral conjugated oestrogen 0.625 mg daily
[43]
RCT
4-armed trial 		132 surgically postmenopausal women (minimum 1 month post hysterectomy) Change from baseline in severity of depressive symptoms (Hamilton Depression Rating Scale) 12 months
10.63 to 4.79 with oral conjugated oestrogen 0.625 mg daily
11.25 to 7.13 with percutaneous oestradiol hemihydrate 1.5 mg daily
P = 0.015 for oral v percutaneous treatment 		Effect size not calculated oral conjugated oestrogen 0.625 mg daily
[43]
RCT
4-armed trial 		132 surgically postmenopausal women (minimum 1 month post hysterectomy) Change from baseline in severity of depressive symptoms (Hamilton Depression Rating Scale) 12 months
11.07 to 8.00 with intranasal oestradiol hemihydrate 300 micrograms daily
11.25 to 7.13 with percutaneous oestradiol hemihydrate 1.5 mg daily
P = 0.735 for percutaneous v intranasal treatment 		Not significant
[43]
RCT
4-armed trial 		132 surgically postmenopausal women (minimum 1 month post hysterectomy) Change from baseline in severity of psychic-anxiety scores (Hamilton Anxiety Rating Scale) 12 months
8.46 to 5.21 with oral conjugated oestrogen 0.625 mg daily
7.57 to 5.43 with intranasal oestradiol hemihydrate 300 micrograms daily
9.06 to 6.00 with percutaneous oestradiol hemihydrate 1.5 mg daily
P less than or equal to 0.001 for all active treatments compared with baseline 		Not significant
[43]
RCT
4-armed trial 		132 surgically postmenopausal women (minimum 1 month post hysterectomy) Change from baseline in severity of somatic-anxiety symptoms (Hamilton Anxiety Rating Scale) 12 months
7.83 to 4.42 with oral conjugated oestrogen 0.625 mg daily
6.79 to 4.79 with intranasal oestradiol hemihydrate 300 micrograms daily
8.75 to 5.94 with percutaneous oestradiol hemihydrate 1.5 mg daily
P less than or equal to 0.002 for all active treatments compared with baseline 		Not significant
Open in a new tab

No data from the following reference on this outcome.[25]

Quality of life

No data from the following reference on this outcome.[25] [43]

Oestrogens alone versus progestogens:

We found one RCT that compared oral oestrogen alone versus progestogen.[44]

Vasomotor symptoms

Compared with progestogens We don't know how oestrogens and progestogens compare at reducing vasomotor symptoms (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Vasomotor symptoms (all)
[44]
RCT		 43 women with menopausal symptoms Reduction in vasomotor symptoms 3 months
with oral oestrogen
with progestogen (medroxyprogesterone 150 mg depot for 25 days/month)
Absolute results reported graphically
Significance not assessed
Open in a new tab

Urogenital symptoms

No data from the following reference on this outcome.[44]

Psychological symptoms

No data from the following reference on this outcome.[44]

Quality of life

No data from the following reference on this outcome.[44]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
General adverse effects
[44]
RCT		 43 women with menopausal symptoms Adverse effects
with oral oestrogen
with progestogen (medroxyprogesterone 150 mg depot for 25 days/month)
Absolute results not reported
Open in a new tab

Oestrogens alone versus phyto-oestrogens:

See option on phyto-oestrogens.

Further information on studies

Eight smaller RCTs identified by the review and comparing oestrogen alone versus placebo were analysed separately and examined different types of cognitive function test (verbal memory and language tests, visual tests, and speed and dexterity tests). Most of these analyses showed no significant difference in test scores between oestrogen and placebo; however, the authors stated that there were too few people in the analyses to determine whether HRT has a beneficial or a harmful effect.

The review found no significant differences between groups (ring v cream, ring v tablets, tablets v cream, and tablets v placebo) in dysuria, nocturia, urgency, urge incontinence, soreness and irritation, loss of libido, vaginitis, endometrial hyperplasia, proliferation of the endometrium, or increasing endometrial thickness as assessed by ultrasound.

Comment

Clinical guide:

Based on the evidence of important adverse effects, there has been a change in prescribing attitude towards HRT. Before starting HRT, it is now considered important for prescribers to discuss with women the excess risks associated with HRT. Based on the evidence presented under adverse effects, above, it remains important that women with an intact uterus who are prescribed any form of systemic oestrogen take either continuous or cyclical progestogens.

Substantive changes

Oestrogens alone New evidence added.[22] [23] [27] [28] [34] [43] Categorisation unchanged (Trade-off between benefits and harms).

BMJ Clin Evid. 2011 Jun 15;2011:0804.

Oestrogens plus progestogens

Summary

Oestrogens, used alone or with progestogens, reduce vasomotor and urogenital symptoms, and improve quality of life compared with placebo over 3 to 6 months.

However, oestrogens increase the risk of breast cancer, endometrial cancer, stroke, and venous thromboembolism.

Progestogens, used alone or with oestrogens, reduce vasomotor symptoms in perimenopausal women.

CAUTION: Women with an intact uterus who are prescribed oestrogen replacement therapy should also take continuous or cyclical progestogens.

Benefits and harms

Oestrogens plus progestogens versus placebo:

We found one systematic review,[15] two subsequent RCTs[16] [45] comparing oestrogens plus progestogens versus placebo, and one subsequent RCT comparing oestrogen plus drospirenone (a new progestogen preparation) versus placebo on vasomotor symptoms.[46] The systematic review (search date 2001, 21 RCTs, 2511 women, follow-up 3–36 months) included comparisons of progesterone-plus-oestrogen HRT versus placebo.[15] We found three RCTs evaluating the effects of oestrogens plus progestogens on urogenital symptoms.[47] [45] [46] For the psychological, cognitive, and sleep symptoms, we found one systematic review (search date 2006, 16 RCTs, 10,114 women) assessing the effect of oestrogen plus progestogens on cognitive function of postmenopausal women.[31] One large RCT in the review (reported in 2 publications) also assessed the effect of oestrogen plus progesterone on mental health and symptoms of depression.[48] [49] We found three systematic reviews (search date 2004, 28 RCTs, 39,769 people, 3 RCTs included men;[39] search date 2008, 31 RCTs, 41,113 women;[40] and search date 2007, 9 RCTs, 7 case control studies, and 1 prospective cohort study)[41] evaluating cardiovascular complications of HRT. We found one systematic review (search date 2008, 45 RCTs, 38,702 women) assessing the effect of oestrogen plus progesterone on the risk of endometrial hyperplasia and cancer.[34] All of the reviews compared either oestrogen alone or oestrogen plus progestogen versus placebo or no treatment. The reviews did not report results separately for combined HRT. We found a further 6 RCTs that reported on adverse effects.[50] [51] [52] [53] [54] [38]

Vasomotor symptoms

Compared with placebo Oestrogens plus progestogens are more effective at reducing hot flushes and night sweats (high-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom improvement
[15]
Systematic review		 2511 women
21 RCTs in this analysis		 Hot flushes 3 to 36 months
94/678 (14%) with progesterone plus oestrogen
126/279 (45%) with placebo
OR 0.10
95% CI 0.04 to 0.25 		Large effect size progesterone plus oestrogen
[16]
RCT		 2673 women entered, 2152 analysed Vasomotor symptoms 3 to 12 weeks
with oral conjugated equine oestrogen (0.625 mg, 0.45 mg, and 0.3 mg) plus medroxyprogesterone acetate 2.5 mg
with placebo
Absolute results not reported
P <0.05 		Effect size not calculated oral conjugated equine oestrogen plus medroxyprogesterone acetate 2.5 mg
[16]
RCT		 2673 women entered, 2152 analysed Vasomotor symptoms 3 to 12 weeks
with oral conjugated equine oestrogen (0.625 mg, 0.45 mg, and 0.3 mg) plus medroxyprogesterone acetate 1.5 mg
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[45]
RCT		 16,608 postmenopausal women with an intact uterus aged 50 to 79 years Proportion of women with relief from hot flushes
86% with oral conjugated equine oestrogen 0.625 mg daily plus medroxyprogesterone acetate 2.5 mg
58% with placebo
Absolute numbers not reported
OR 4.40
95% CI 3.40 to 5.71 		Moderate effect size oestrogen plus medroxyprogesterone
[45]
RCT		 16,608 postmenopausal women with an intact uterus aged 50 to 79 years Proportion of women with relief from night sweats
78% with oral conjugated equine oestrogen 0.625 mg daily plus medroxyprogesterone acetate 2.5 mg
57% with placebo
Absolute numbers not reported
OR 2.58
95% CI 2.04 to 3.26 		Moderate effect size oestrogen plus medroxyprogesterone
[46]
RCT		 90 postmenopausal women Reduction in number of hot flushes 3 to 16 weeks
84% with oestradiol plus drospirenone
48% with placebo
Absolute numbers not reported
P <0.001 		Effect size not calculated oestrogen plus drospirenone
Open in a new tab

No data from the following reference on this outcome.[47] [31] [48] [49] [39] [40] [41] [34] [50] [51] [52] [53] [54] [38]

Urogenital symptoms

Compared with placebo Oestrogens plus progestogens seem more effective at reducing vaginal dryness, but we don't know about urinary frequency or nocturia (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Vaginal dryness
[47]
RCT		 136 women Vaginal dryness (measured on a 100-mm visual analogue scale) 6 months
32.4 mm with low-dose transdermal oestrogen 25 micrograms daily plus norethisterone acetate
50.5 mm with placebo
P <0.001 		Effect size not calculated transdermal oestrogen plus norethisterone acetate
[45]
RCT		 16,608 postmenopausal women with an intact uterus aged 50 to 79 years Proportion of women with improvement in vaginal dryness
74% with oral conjugated equine oestrogen 0.625 mg daily plus medroxyprogesterone acetate 2.5 mg
55% with placebo
Absolute numbers not reported
OR 2.40
95% CI 1.90 to 3.02 		Moderate effect size oestrogen plus medroxyprogesterone
Dyspareunia
[47]
RCT		 136 women Dyspareunia (measured on a 100-mm visual analogue scale) 6 months
20.5 mm with low-dose transdermal oestrogen 25 micrograms daily plus norethisterone acetate
34.2 mm with placebo
P <0.001 		Effect size not calculated transdermal oestrogen plus norethisterone acetate
Urinary frequency
[46]
RCT		 90 postmenopausal women Proportion of women with frequent urge to urinate (change from baseline) 3 to 16 weeks
from 40% to 17% with oestradiol plus drospirenone
from 30% to 16% with placebo
Absolute numbers not reported
Significance not assessed
Nocturia
[46]
RCT		 90 postmenopausal women Proportion of women with nocturia (change from baseline) 3 to 16 weeks
from 29% to 14% with oestradiol plus drospirenone
from 22% to 14% with placebo
Absolute numbers not reported
Significance not assessed
Open in a new tab

No data from the following reference on this outcome.[15] [16] [31] [48] [49] [39] [40] [41] [34] [50] [51] [52] [53] [54] [38]

Psychological symptoms

Compared with placebo We don't know whether oestrogens plus progestogens are more effective at improving cognitive scores, reducing new diagnoses of mild cognitive impairment, or improving mental health or depressive symptom scores (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Cognitive function
[31]
Systematic review		 4344 women
Data from 1 RCT		 Modified Mini-Mental State Examination (3MSE) score (lower scores were worse) 1 year
with oestrogen plus progestogen
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[31]
Systematic review		 4344 women
Data from 1 RCT		 Modified Mini-Mental State Examination (3MSE) score (lower scores were worse) 2 years
with oestrogen plus progestogen
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[31]
Systematic review		 4344 women
Data from 1 RCT		 Modified Mini-Mental State Examination (3MSE) score (lower scores were worse) 3 years
with oestrogen plus progestogen
with placebo
Absolute results not reported
WMD −0.36
95% CI –0.61 to –0.11
P = 0.0046 		Effect size not calculated placebo
[31]
Systematic review		 4344 women
Data from 1 RCT		 Modified Mini-Mental State Examination (3MSE) score (lower scores were worse) 4 years
with oestrogen plus progestogen
with placebo
Absolute results not reported
WMD –0.52
95% CI –0.81 to –0.23
P = 0.00042 		Effect size not calculated placebo
[31]
Systematic review		 4344 women
Data from 1 RCT		 Modified Mini-Mental State Examination (3MSE) score (lower scores were worse) 5 years
with oestrogen plus progestogen
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[31]
Systematic review		 4344 women
Data from 1 RCT		 Proportion of people with a diagnosis of mild cognitive impairment 4 years
56/2229 (3%) with oestrogen plus progestogen
55/2303 (2%) with placebo
OR 1.05
95% CI 0.75 to 1.54 		Not significant
Mood
[48] [49]
RCT		 16,608 postmenopausal women with an intact uterus aged 50 to 79 years
In review [31] 		Change in mental health or depressive symptoms from baseline (assessed using the RAND 36-Item Health Survey) 1 year
from –0.1 to +0.6 with conjugated equine oestrogens (CEE) 0.625 mg daily plus medroxyprogesterone acetate 2.5 mg
from –0.1 to +0.7 with placebo
P = 0.40–0.81
Applicability of the RCT may be limited because the average age of women enrolled in the study (63.3 years) was much older than that of women who typically start HRT 		Not significant
Sleep
[49] [48]
RCT		 16,608 postmenopausal women with an intact uterus aged 50 to 79 years
In review [31] 		Mean change in sleep disturbance scores from baseline 1 year
0.5 with CEE 0.625 mg daily plus medroxyprogesterone acetate 2.5 mg
0.1 with placebo
P <0.001
Applicability of the RCT may be limited because the average age of women enrolled in the study (63.3 years) was much older than that of women who typically start HRT 		Effect size not calculated oestrogen plus progestogen
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No data from the following reference on this outcome.[15] [16] [45] [46] [47] [39] [40] [41] [34]

Quality of life

Compared with placebo We don't know whether oestrogens plus progestogens are more effective at improving quality-of-life scores (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life
[49]
RCT		 16,608 postmenopausal women with an intact uterus aged 50 to 79 years
Further report of reference [48] 		Range of RAND quality-of-life subscores in general health, social functioning, vitality, or sexual satisfaction (expressed as a change from baseline) 1 year
–1.9 to +0.2 with conjugated equine oestrogens (CEE) 0.625 mg daily plus medroxyprogesterone acetate 2.5 mg
–2.3 to 0 with placebo
P = 0.08–0.76
Applicability of the RCT may be limited because the average age of women enrolled in the study (63.3 years) was much older than that of women who typically start HRT 		Not significant
[49]
RCT		 16,608 postmenopausal women with an intact uterus aged 50 to 79 years
Further report of reference [48] 		Mean change in RAND physical functioning subscore 1 year
−0.6 with CEE 0.625 mg daily plus medroxyprogesterone acetate 2.5 mg
−1.4 with placebo
P <0.001
Applicability of the RCT may be limited because the average age of women enrolled in the study (63.3 years) was much older than that of women who typically start HRT 		Effect size not calculated oestrogen plus progestogen
[49]
RCT		 16,608 postmenopausal women with an intact uterus aged 50 to 79 years
Further report of reference [48] 		Mean change in RAND bodily pain subscore 1 year
+0.1 with CEE 0.625 mg daily plus medroxyprogesterone acetate 2.5 mg
−1.8 with placebo
P <0.001
Applicability of the RCT may be limited because the average age of women enrolled in the study (63.3 years) was much older than that of women who typically start HRT 		Effect size not calculated oestrogen plus progestogen
Open in a new tab

No data from the following reference on this outcome.[15] [16] [45] [46] [47] [39] [40] [41] [34] [50] [51] [52] [53] [54] [38]

Adverse effects

Compared with placebo Long-term use of oestrogens plus progestogens seems to be associated with an increased risk of breast cancer, stroke, thromboembolism, and gallbladder disease (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Minor/general adverse effects
[50]
RCT		 321 women who had undergone hysterectomy and were already taking conjugated equine oestrogens (CEE) General adverse effects (including weight gain and bloating)
with continuous progestogen (norgestrel)
with placebo
Absolute results not reported
Significance not assessed
[45]
RCT		 16,608 postmenopausal women with an intact uterus aged 50 to 79 years Stress incontinence 1 year
with oestrogen plus progesterone
with placebo
Absolute results not reported
RR 1.87
95% CI 1.61 to 2.18 		Small effect size placebo
[45]
RCT		 16,608 postmenopausal women with an intact uterus aged 50 to 79 years Proportion of women with breast tenderness 1 year
9% with oestrogen plus progesterone
2% with placebo
Absolute numbers not reported
OR 4.26
95% CI 3.59 to 5.04 		Moderate effect size placebo
[45]
RCT		 16,608 postmenopausal women with an intact uterus aged 50 to 79 years Proportion of women with genital discharge 1 year
4% with oestrogen plus progesterone
1% with placebo
Absolute numbers not reported
OR 4.47
95% CI 3.44 to 5.81 		Moderate effect size placebo
[45]
RCT		 16,608 postmenopausal women with an intact uterus aged 50 to 79 years Proportion of women with headache 1 year
6% with oestrogen plus progesterone
5% with placebo
Absolute numbers not reported
OR 1.26
95% CI 1.08 to 1.46 		Small effect size placebo
Endometrial cancer
[51]
RCT		 16,608 postmenopausal women
In review [34] 		Endometrial cancer 5 or more years
27/8506 (0.3%) with continuous combined HRT (oestrogen plus continuous progestogen)
31/8102 (0.4%) with placebo
OR 0.81
95% CI 0.48 to 1.36 		Not significant
[34]
Systematic review		 Total number of women not reported
Data from 1 RCT		 Endometrial cancer 3 years
0/118 (0%) with cyclical combined HRT (oestrogen plus cyclical medroxyprogesterone acetate 10 mg)
1/119 (1%) with placebo
OR 0.33
95% CI 0.01 to 8.27 		Not significant
[34]
Systematic review		 Total number of women not reported
Data from 1 RCT		 Endometrial cancer 3 years
0/120 (0%) with cyclical combined HRT (oestrogen plus cyclical progesterone 200 mg)
1/119 (1%) with placebo
OR 0.33
95% CI 0.01 to 8.13 		Not significant
[34]
Systematic review		 Total number of women not reported
Data from 1 RCT		 Endometrial hyperplasia
with combined HRT (oestrogens plus either cyclical or continuous progestogens)
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
Breast cancer
[52]
RCT		 16,608 postmenopausal women
Further report of reference [48] [49] 		Breast cancer (total)
245/8506 (3%) with oestrogen plus progesterone
185/8102 (2%) with placebo
HR 1.24
95% CI 1.02 to 1.50 		Small effect size placebo
[52]
RCT		 16,608 postmenopausal women
Further report of reference [48] [49] 		Invasive breast cancer
199/8506 (2.3%) with oestrogen plus progesterone
150/8102 (1.9%) with placebo
HR 1.24
95% CI 1.01 to 1.54 		Small effect size placebo
[52]
RCT		 16,608 postmenopausal women
Further report of reference [48] [49] 		In situ cancers
47/8506 (0.6%) with oestrogen plus progesterone
37/8102 (0.5%) with placebo
HR 1.18
95% CI 0.77 to 1.82 		Not significant
[52]
RCT		 16,608 postmenopausal women
Further report of reference [48] [49] 		Disease severity in women who developed breast cancer: increase in tumour size
1.7 cm with oestrogen plus progesterone
1.5 cm with placebo
P = 0.04 		Effect size not calculated placebo
[52]
RCT		 16,608 postmenopausal women
Further report of reference [48] [49] 		Disease severity in women who developed breast cancer: risk of tumour spread
25% with oestrogen plus progesterone
16% with placebo
Absolute numbers not reported
P = 0.04 		Effect size not calculated placebo
Ovarian cancer
[55]
RCT		 16,608 postmenopausal women
Further report of reference [48] [49] 		Ovarian cancer (total)
20/8506 (0.2%) with oestrogen plus progesterone
12/8102 (0.1%) with placebo
HR 1.58
95% CI 0.77 to 3.24 		Not significant
Endometrial cancer
[55]
RCT		 16,608 postmenopausal women
Further report of reference [48] [49] 		Endometrial cancer (total)
27/8506 (0.3%) with oestrogen plus progesterone
31/8102 (0.4%) with placebo
HR 0.81
95% CI 0.48 to 1.36 		Not significant
Cardiovascular adverse effects
[39] [40] [41]
Systematic review		 Adverse effects
with oestrogen plus progestogen or oestrogen alone
with placebo or no treatment
[53]
RCT		 16,608 postmenopausal women
Further report of reference [48] [49] 		Stroke (total)
151/8506 (2%) with oestrogen plus progesterone
107/8102 (1%) with placebo
HR 1.31
95% CI 1.02 to 1.68 		Small effect size placebo
[53]
RCT		 16,608 postmenopausal women
Further report of reference [48] [49] 		Ischaemic stroke
125/8506 (1.5%) with oestrogen plus progesterone
81/8102 (1.0%) with placebo
HR 1.44
95% CI 1.09 to 1.90 		Small effect size placebo
[53]
RCT		 16,608 postmenopausal women
Further report of reference [48] [49] 		Haemorrhagic stroke
18/8506 (0.2%) with oestrogen plus progesterone
20/8102 (0.2%) with placebo
HR 0.82
95% CI 0.43 to 1.56 		Not significant
[53]
RCT		 16,608 postmenopausal women
Further report of reference [48] [49] 		Non-fatal MI and death due to CHD
164/8506 (0.4%) with oestrogen plus progesterone
122/8102 (0.3%) with placebo
HR 1.29
95% CI 1.02 to 1.63 		Small effect size placebo
Thromboembolic disease
[54]
RCT		 16,608 postmenopausal women
Further report of reference [48] [49] 		DVT
123/8506 (1.4%) with oestrogen plus progesterone
59/8102 (0.7%) with placebo
HR 1.95
95% CI 1.43 to 2.67 		Small effect size placebo
[54]
RCT		 16,608 postmenopausal women
Further report of reference [48] [49] 		Pulmonary embolism
86/8506 (1.0%) with oestrogen plus progesterone
38/8102 (0.4%) with placebo
HR 2.13
95% CI 1.39 to 3.25 		Moderate effect size placebo
Gallbladder disease
[38]
RCT		 22,579 women Gallbladder disease
with oestrogen plus progesterone
with placebo
Absolute results not reported
HR 1.59
95% CI 1.28 to 1.97 		Small effect size placebo
Open in a new tab

No data from the following reference on this outcome.[15] [16] [31] [46] [47] [49] [48]

Different preparations of oestrogens plus progestogens versus each other:

We found one RCT comparing oral conjugated equine oestrogens (CEE) plus medroxyprogesterone acetate versus continuous transdermal oestradiol-17beta plus medroxyprogesterone acetate,[56] and one RCT comparing different dose combinations of oestradiol valerate and medroxyprogesterone acetate.[57] We found one RCT comparing the effect of different dose combinations of oestrogen plus progesterone HRT on health-related quality of life in early postmenopausal women.[58]

Quality of life

Different preparations of oestrogens plus progestogens compared with each other We don't know whether different preparations of oestrogens plus progestogens differ in effectiveness at improving quality-of-life scores (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life
[56]
RCT		 74 women with an intact uterus and ovaries, 2 to 7 years after menopause Quality of life
with oral conjugated equine oestrogens (CEE) (0.625 mg/day for four 4-week cycles) plus medroxyprogesterone acetate (10 mg for the last 12 days of each cycle)
with transdermal oestradiol-17beta (50 micrograms twice weekly for four 4-week cycles) plus medroxyprogesterone acetate (10 mg for the last 12 days of each cycle)
Absolute results not reported
Significance not assessed
[58]
RCT
3-armed trial 		459 postmenopausal women
Further report of reference [57] 		Health-related quality of life (HRQoL) assessed using Women's Health Questionnaire (WHQ) 52 weeks
with oestradiol valerate (E2V) 1 mg plus medroxyprogesterone acetate (MPA) 2.5 mg
with E2V 1 mg plus MPA 5 mg
with E2V 2 mg plus MPA 5 mg
Absolute results reported graphically
Reported as not significant among groups
P value not reported 		Not significant
[58]
RCT
3-armed trial 		459 postmenopausal women
Further report of reference [57] 		HRQoL assessed using 15D questionnaire 52 weeks
with E2V 1 mg plus MPA 2.5 mg
with E2V 1 mg plus MPA 5 mg
with E2V 2 mg plus MPA 5 mg
Absolute results reported graphically
Reported as not significant among groups
P value not reported 		Not significant
[58]
RCT
3-armed trial 		459 postmenopausal women
Further report of reference [57] 		HRQoL assessed using visual analogue scale (VAS) indices 52 weeks
with E2V 1 mg plus MPA 2.5 mg
with E2V 1 mg plus MPA 5 mg
with E2V 2 mg plus MPA 5 mg
Absolute results reported graphically
Reported as not significant among groups
P value not reported 		Not significant
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Vasomotor symptoms

Different preparations of oestrogen plus progestogen compared with each other We don't know whether any one preparation of oestrogens plus progestogens is consistently more effective at reducing the frequency of moderate to severe hot flushes at 52 weeks (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Vasomotor symptoms
[57]
RCT
3-armed trial 		459 postmenopausal women Change from baseline in frequency of moderate to severe hot flushes 52 weeks
with oestradiol valerate (E2V) 1 mg plus medroxyprogesterone acetate (MPA) 2.5 mg
with E2V 1 mg plus MPA 5 mg
with E2V 2 mg plus MPA 5 mg
Absolute results reported graphically
Reported as no significance between groups
P value not reported 		Not significant
Open in a new tab

No data from the following reference on this outcome.[56]

Urogenital symptoms

No data from the following reference on this outcome.[56] [57]

Psychological symptoms

No data from the following reference on this outcome.[56] [57]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[57]
RCT
3-armed trial 		459 postmenopausal women Total number of adverse events 52 weeks
181 (in 152 women) with oestradiol valerate (E2V) 1 mg plus medroxyprogesterone acetate (MPA) 2.5 mg
174 (in 153 women) with E2V 1 mg plus MPA 5 mg
250 (in 154 women) with E2V 2 mg plus MPA 5 mg
P = 0.0002 for E2V 2 mg plus MPA 5 mg v other regimens 		Effect size not calculated regimens containing E2V 1 mg
Open in a new tab

No data from the following reference on this outcome.[56] [58]

Oestrogens plus progestogens versus tibolone:

See option on tibolone.

Oestrogens plus progestogens versus phyto-oestrogens:

See option on phyto-oestrogens.

Further information on studies

Two other RCTs identified by the review were analysed separately and examined disparate types of cognitive test (verbal memory and language tests, visual tests, and speed and dexterity tests). Most of these analyses showed no significant difference in test scores between oestrogen and placebo; however, the authors stated that these provided insufficient evidence to determine whether HRT has a beneficial or a harmful effect.

The review also found that oestrogens plus progestogens (either cyclical or continuous) significantly reduced endometrial hyperplasia compared with oestrogens alone.

Comment

Clinical guide:

Based on the evidence for harms associated with oestrogen (see option on oestrogens alone), it remains important that women with an intact uterus who are prescribed any form of oestrogen take either continuous or cyclical progestogens. Applicability of the large RCT may be limited, because the average age of women enrolled in the study (63.3 years) is much older than that of women who typically start HRT.[48]

Mortality

We found one meta-analysis (search date 2008, 19 RCTs, 16,000 women aged <60 years) assessing the effect of HRT on total mortality in younger postmenopausal women.[59] The meta-analysis found that, at 5 years, oestrogen plus progestogens decreased total mortality compared with no treatment (mean age 54.5 years; total mortality at 5 years: 156/8669 [1.8%] women with hormone treatment v 211/7594 [2.8%] women with no treatment; RR 0.73, 95% CI 0.52 to 0.96).[59]

Substantive changes

Oestrogens plus progestogens New evidence added.[34] [57] [58] Categorisation unchanged (Trade-off between benefits and harms).

BMJ Clin Evid. 2011 Jun 15;2011:0804.

Progestogens alone

Summary

Progestogens reduce menopausal vasomotor symptoms compared with placebo. However, the clinical usefulness of progestogens given alone for menopausal symptoms is limited by the unwanted adverse effects of the relatively high doses needed to achieve relief of menopausal symptoms.

We don't know whether progestogens alone improve psychological symptoms or quality-of-life scores.

We found no direct information from RCTs about the effects of progestogens alone in the treatment of urogenital symptoms in women with menopausal symptoms.

Benefits and harms

Progestogens versus placebo:

We found no systematic review. We found three RCTs comparing oral progestogens versus placebo,[60] [61] [62] and three RCTs comparing transdermal progesterone versus placebo.[63] [64] [65]

Vasomotor symptoms

Compared with placebo Oral progestogens may be more effective in reducing vasomotor symptoms, but we don't know about progestogen cream (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom improvement
[60]
RCT
Crossover design 		97 women Proportion of women with 50% reduction in daily hot flush frequency 4 weeks (pre-crossover)
34/48 (71%) with medroxyprogesterone acetate (200 mg twice daily)
12/49 (24%) with placebo
RR 2.9
95% CI 1.71 to 4.89
NNT 3
95% CI 2 to 4 		Moderate effect size medroxyprogesterone acetate
[61]
RCT
Crossover design 		21 women Proportion of women free from hot flushes 24 weeks
18/21 (86%) with medroxyprogesterone acetate (100 mg twice daily)
7/21 (33%) with placebo
RR for no flushes 2.60
95% CI 1.37 to 4.83
NNT 2
95% CI 2 to 3
The RCT reported results post-crossover, which makes it difficult to draw conclusions 		Moderate effect size medroxyprogesterone acetate
[61]
RCT
Crossover design 		21 women Proportion of women free from sweating
18/21 (86%) with medroxyprogesterone acetate (100 mg twice daily)
3/21 (14%) with placebo
RR for no sweating 6.0
95% CI 2.1 to 17.4
NNT 2
95% CI 1 to 2
The RCT reported results post-crossover, which makes it difficult to draw conclusions 		Large effect size medroxyprogesterone acetate
[62]
RCT
Crossover design 		27 women Percentage reduction in hot flushes 12 weeks (crossover to alternative treatment)
74% with medroxyprogesterone acetate 20 mg daily
26% with placebo
Absolute numbers not reported
P <0.05 		Effect size not calculated medroxyprogesterone acetate
[63]
RCT		 102 women Proportion of women with improvement or resolution of vasomotor symptoms as determined by review of weekly symptom diaries 1 year
25/30 (83%) with transdermal progesterone cream 20 mg
5/26 (19%) with placebo
RR 1.5
95% CI 1.1 to 2.0
NNT 4
95% CI 2 to 9 		Small effect size transdermal progesterone
[64]
RCT		 80 women Median change in Greene Climacteric Scale (vasomotor symptoms) from baseline 12 weeks
–1.0 with transdermal progesterone cream 32 mg daily
0 with placebo
P = 0.07 		Not significant
[65]
RCT
5-armed trial 		230 postmenopausal women Changes in Greene Climacteric Scale (vasomotor symptoms) 24 weeks
with progesterone cream 60 mg
with placebo
P = 0.14
Difference from placebo –0.5
95% CI –1.2 to +0.2 		Not significant
[65]
RCT
5-armed trial 		230 postmenopausal women Changes in Greene Climacteric Scale (vasomotor symptoms) 24 weeks
with progesterone cream 40 mg
with placebo
P = 0.12
Difference from placebo –0.5
95% CI –1.2 to +0.1 		Not significant
[65]
RCT
5-armed trial 		230 postmenopausal women Changes in Greene Climacteric Scale (vasomotor symptoms) 24 weeks
with progesterone cream 20 mg
with placebo
P = 0.28
Difference from placebo –0.4
95% CI –1.0 to +0.3 		Not significant
[65]
RCT
5-armed trial 		230 postmenopausal women Changes in Greene Climacteric Scale (vasomotor symptoms) 24 weeks
with progesterone cream 5 mg
with placebo
P = 0.33
Difference from placebo –0.3
95% CI –0.9 to +0.3 		Not significant
[65]
RCT
5-armed trial 		230 postmenopausal women Changes from baseline in weekly incidence of hot flushes and night sweats 24 weeks
–29.2 with progesterone cream 60 mg
–21.1 with placebo
P = 0.07
Difference from placebo –8.0
95% CI –16.8 to +0.7 		Not significant
[65]
RCT
5-armed trial 		230 postmenopausal women Changes from baseline in weekly incidence of hot flushes and night sweats 24 weeks
–26.0 with progesterone cream 40 mg
–21.1 with placebo
P = 0.26
Difference from placebo –0.49
95% CI –13.3 to +3.6 		Not significant
[65]
RCT
5-armed trial 		230 postmenopausal women Changes from baseline in weekly incidence of hot flushes and night sweats 24 weeks
–25.1 with progesterone cream 20 mg
–25.1 with placebo
P = 0.35
Difference from placebo –0.4
95% CI –12.2 to +4.3 		Not significant
[65]
RCT
5-armed trial 		230 postmenopausal women Changes from baseline in weekly incidence of hot flushes and night sweats 24 weeks
–24.7 with progesterone cream 5 mg
–21.1 with placebo
P = 0.39
Difference from placebo –3.6
95% CI –11.7 to +4.6 		Not significant
Open in a new tab

Psychological symptoms

Compared with placebo We don't know whether transdermal progestogens are more effective at reducing psychological and sleep symptoms (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Psychological symptom change
[64]
RCT		 80 women Depression or anxiety symptoms 12 weeks
with transdermal progesterone
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[65]
RCT
5-armed trial 		230 postmenopausal women Changes in Greene Climacteric Scale (psychological components) 24 weeks
with progesterone cream 60 mg
with placebo
P = 0.71
Difference from placebo +0.3
95% CI –1.3 to +1.9 		Not significant
[65]
RCT
5-armed trial 		230 postmenopausal women Changes in Greene Climacteric Scale (psychological components) 24 weeks
with progesterone cream 40 mg
with placebo
P = 0.53
Difference from placebo –0.5
95% CI –2.1 to +1.1 		Not significant
[65]
RCT
5-armed trial 		230 postmenopausal women Changes in Greene Climacteric Scale (psychological components) 24 weeks
with progesterone cream 20 mg
with placebo
P = 0.51
Difference from placebo +0.5
95% CI –1.0 to +2.1 		Not significant
[65]
RCT
5-armed trial 		230 postmenopausal women Changes in Greene Climacteric Scale (psychological components) 24 weeks
with progesterone cream 5 mg
with placebo
P = 0.78
Difference from placebo +0.2
95% CI –1.3 to +1.7 		Not significant
[65]
RCT
5-armed trial 		230 postmenopausal women Changes in Greene Climacteric Scale (somatic components) 24 weeks
with progesterone cream 60 mg
with placebo
P = 0.93
Difference from placebo 0
95% CI –0.8 to +0.8 		Not significant
[65]
RCT
5-armed trial 		230 postmenopausal women Changes in Greene Climacteric Scale (somatic components) 24 weeks
with progesterone cream 40 mg
with placebo
P = 0.95
Difference from placebo 0
95% CI –0.8 to +0.8 		Not significant
[65]
RCT
5-armed trial 		230 postmenopausal women Changes in Greene Climacteric Scale (somatic components) 24 weeks
with progesterone cream 20 mg
with placebo
P = 0.25
Difference from placebo +0.5
95% CI –0.3 to +1.2 		Not significant
[65]
RCT
5-armed trial 		230 postmenopausal women Changes in Greene Climacteric Scale (somatic components) 24 weeks
with progesterone cream 5 mg
with placebo
P = 0.71
Difference from placebo +0.1
95% CI –0.6 to +0.9 		Not significant
Open in a new tab

No data from the following reference on this outcome.[60] [61] [62] [63]

Quality of life

Compared with placebo We don't know whether transdermal progestogens are more effective at improving quality of life (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality-of-life
[64]
RCT		 80 women Quality of life as assessed using Menopause Quality of Life Questionnaire 12 weeks
with transdermal progesterone
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
Open in a new tab

No data from the following reference on this outcome.[60] [61] [62] [63] [65]

Urogenital symptoms

No data from the following reference on this outcome.[60] [61] [62] [63] [64] [65]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[65]
RCT
5-armed trial 		230 postmenopausal women Changes in Greene Climacteric Scale (somatic components) 24 weeks
with progesterone cream 60 mg, 40 mg, 20 mg, or 5 mg
with placebo
P = 0.71
Difference from placebo +0.1
95% CI –0.6 to +0.9 		Not significant
Open in a new tab

No data from the following reference on this outcome.[60] [61] [62] [63] [64]

Progestogens versus oestrogens:

See option on oestrogens alone.

Further information on studies

None.

Comment

Clinical guide:

Progestogens are seldom given alone, which makes it difficult to isolate their effects. When given without oestrogen, doses of progestogens were high, the lowest dose being medroxyprogesterone acetate 20 mg daily. The adverse effects associated with these high doses of progestogens limit the clinical usefulness of progestogens given alone for menopausal symptoms.

Substantive changes

Progestogens alone New evidence added.[65]Categorisation unchanged (Trade-off between benefits and harms).

BMJ Clin Evid. 2011 Jun 15;2011:0804.

Antidepressants

Summary

Antidepressants may be more effective than placebo at relieving vasomotor symptoms in postmenopausal women in the short term. However, we don't know whether they are effective in the long term.

We found no direct information from RCTs about the effects of antidepressants in the treatment of urogenital symptoms; psychological, cognitive, and sleep symptoms; or quality of life, in women with menopausal symptoms.

Benefits and harms

Antidepressants versus placebo:

We found one systematic review[66] and one subsequent RCT,[67] which assessed the effects of antidepressants on the number and severity of hot flushes. The systematic review (search date 2005, 10 RCTs, 998 women) carried out a meta-analysis of SSRIs or serotonin noradrenaline (norepinephrine) reuptake inhibitors (SNRIs).

Vasomotor symptoms

Compared with placebo Antidepressants (SSRIs, selective noradrenaline reuptake inhibitors [SNRIs], veralipride, and desvenlafaxine) may be more effective at reducing vasomotor symptom severity in the short term. However, the significance of the effect for some antidepressants depended on the analysis undertaken (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom improvement
[66]
Systematic review		 744 women in this analysis
6 RCTs in this analysis		 Mean number of daily hot flushes
with SSRIs/SNRIs, with or without selective oestrogen receptor modulator
with placebo
Absolute results not reported
WMD –1.13
95% CI –1.70 to –0.57 		Effect size not calculated SSRIs/SNRIs, with or without selective oestrogen receptor modulator
[66]
Systematic review		 180 women
2 RCTs in this analysis
Subgroup analysis		 Mean number of daily hot flushes
with SSRIs/SNRIs alone
with placebo
Absolute results not reported
WMD –0.17
95% CI –1.41 to +1.07 		Not significant
[66]
Systematic review		 564 women
4 RCTs in this analysis
Subgroup analysis		 Mean number of daily hot flushes
with SSRIs/SNRIs plus selective oestrogen receptor
with placebo
Absolute results not reported
WMD –1.40
95% CI –1.97 to –0.82 		Effect size not calculated SSRIs/SNRIs plus selective oestrogen receptor
[66]
Systematic review		 50 women
Data from 1 RCT		 Frequency and severity of hot flushes
with veralipride 100 mg daily
with placebo
Absolute results not reported
P <0.05 		Effect size not calculated veralipride
[66]
Systematic review		 40 women
Data from 1 RCT		 Frequency and severity of hot flushes
with veralipride 100 mg daily
with placebo
Absolute results not reported
P <0.05 		Effect size not calculated veralipride
[66]
Systematic review		 30 women
Data from 1 RCT		 Frequency and severity of hot flushes
with veralipride 100 mg daily
with placebo
Absolute results not reported
Between-group difference reported as not significant
P value not reported 		Not significant
[67]
RCT
3-armed trial 		458 postmenopausal women Change in number of moderate and severe hot flushes/day 12 weeks
−7.1 with desvenlafaxine 100 mg
−5.8 with placebo
P = 0.005 for desvenlafaxine 100 mg v placebo 		Effect size not calculated desvenlafaxine 100 mg
[67]
RCT
3-armed trial 		458 postmenopausal women Change in number of moderate and severe hot flushes/day 12 weeks
−7.0 with desvenlafaxine 150 mg
−5.8 with placebo
P = 0.012 for desvenlafaxine 150 mg v placebo 		Effect size not calculated desvenlafaxine 150 mg
[67]
RCT
3-armed trial 		458 postmenopausal women Change in daily hot flush severity score (possible range not reported) 12 weeks
–0.65 with desvenlafaxine 100 mg
–0.33 with placebo
P <0.001 for desvenlafaxine 100 mg v placebo 		Effect size not calculated desvenlafaxine 100 mg
[67]
RCT
3-armed trial 		458 postmenopausal women Change in daily hot flush severity score (possible range not reported) 12 weeks
–0.66 with desvenlafaxine 150 mg
–0.33 with placebo
P <0.001 for desvenlafaxine 150 mg v placebo 		Effect size not calculated desvenlafaxine 150 mg
Open in a new tab

Urogenital symptoms

No data from the following reference on this outcome.[66] [67]

Psychological symptoms

No data from the following reference on this outcome.[66] [67]

Quality of life

No data from the following reference on this outcome.[66] [67]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
General adverse effects
[66]
Systematic review		 744 women in this analysis
6 RCTs in this analysis		 Adverse effects
with SSRIs/SNRIs, with or without selective oestrogen receptor modulator
with placebo
[67]
RCT
3-armed trial 		458 postmenopausal women Proportion of people with nausea 12 weeks
76/301 (25%) with desvenlafaxine (100 mg/day and 150 mg/day)
11/151 (7%) with placebo
P <0.001 		Effect size not calculated placebo
[67]
RCT
3-armed trial 		458 postmenopausal women Adverse effects
with desvenlafaxine (100 mg/day and 150 mg/day)
with placebo
Adverse effects
with antidepressants
with placebo
Open in a new tab

Further information on studies

The review found that the most common adverse effects reported with SSRIs or SNRIs were dry mouth, decreased appetite, nausea, constipation, and drowsiness (no other details reported). The review reported that GI adverse effects, mastodynia, and galactorrhoea were more common with veralipride than with placebo.

Comment

Clinical guide:

The SSRI/SNRI classes of antidepressants may alleviate severe menopausal symptoms in women unable or unwilling to take hormonal medications. Evidence suggests that there is no long-term effect, and so the short-term benefits should be balanced against the adverse effect of these drugs.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jun 15;2011:0804.

Clonidine

Summary

We don't know whether clonidine reduces menopausal symptoms.

We found no direct information from RCTs about the effects of clonidine on sexual function, psychological symptoms, or quality of life.

Benefits and harms

Clonidine versus placebo:

We found one systematic review (search date 2005, 4 RCTs, 446 women with 4 weeks' follow-up, and 228 women with 8 weeks' follow-up) on the effects of clonidine on menopausal symptoms.[66]

Vasomotor symptoms

Compared with placebo We don't know whether clonidine is more effective in reducing hot flushes at 4 weeks (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom improvement
[66]
Systematic review		 446 women
4 RCTs in this analysis		 Mean number of daily hot flushes 4 weeks
with clonidine (0.05 mg to 0.15 mg daily)
with placebo
Absolute results not reported
WMD –0.95
95% CI –1.44 to –0.47 		Effect size not calculated clonidine
[66]
Systematic review		 130 women
2 RCTs in this analysis
Subgroup analysis		 Mean number of daily hot flushes 4 weeks
with clonidine (0.05 mg to 0.15 mg daily)
with placebo
Absolute results not reported
WMD –0.53
95% CI –2.09 to +1.04 		Not significant
[66]
Systematic review		 218 women
2 RCTs in this analysis		 Mean number of daily hot flushes 8 weeks
with clonidine (0.05 mg to 0.15 mg daily)
with placebo
Absolute results not reported
WMD –1.63
95% CI –2.76 to –0.5 		Effect size not calculated clonidine
Open in a new tab

Urogenital symptoms

No data from the following reference on this outcome.[66]

Psychological symptoms

No data from the following reference on this outcome.[66]

Quality of life

No data from the following reference on this outcome.[66]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Minor adverse effects
[66]
Systematic review		 446 women
4 RCTs in this analysis		 Adverse effects
with clonidine
with placebo
Open in a new tab

Further information on studies

None.

Comment

Clinical guide:

Most RCTs on the effect of clonidine on vasomotor symptoms are considered of poor or moderate quality. The length of follow-up of the individual RCTs does not support a long-term effect. Further research with high-quality RCTs is required.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jun 15;2011:0804.

Testosterone

Summary

Testosterone plus oestrogen-based HRT reduces sexual symptoms in postmenopausal women but does not seem to reduce vasomotor symptoms, compared with oestrogen HRT alone.

We found no direct information from RCTs on whether testosterone alone is better than no active treatment, or on the effects of testosterone on quality of life in women with menopausal symptoms.

Benefits and harms

Testosterone versus placebo:

We found no systematic review or RCTs.

Testosterone plus oestrogen versus placebo:

We found no systematic review or RCTs.

Testosterone plus oestrogen-containing HRT versus oestrogen-containing HRT alone:

We found one systematic review (search date 2008, 9 RCTs, 2215 peri- and postmenopausal women)[68] comparing testosterone plus oestrogen-containing HRT versus oestrogen-containing HRT alone. The review found two RCTs assessing vasomotor symptoms and performed a meta-analysis of the data from these two RCTs.[68]

Urogenital symptoms

Testosterone plus oestrogen-containing HRT compared with oestrogen-containing HRT alone Testosterone plus oestrogen-containing HRT may be more effective in improving sexual function scores (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Sexual function
[68]
Systematic review		 1893 postmenopausal women
5 RCTs in this analysis		 Number of satisfying sexual events 6 to <12 months*
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute numbers not reported
SMD 0.29
95% CI 0.20 to 0.38
P <0.0001 		Effect size not calculated oestrogen-containing HRT plus testosterone
[68]
Systematic review		 1893 postmenopausal women
7 RCTs in this analysis		 Number of sexual activity <3 months to >12 months*
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute numbers not reported
SMD 0.25
95% CI 0.17 to 0.34
P <0.0001 		Effect size not calculated oestrogen-containing HRT plus testosterone
[68]
Systematic review		 1893 postmenopausal women
5 RCTs in this analysis		 Number of orgasms 6 to <12 months*
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute numbers not reported
SMD 0.30
95% CI 0.21 to 0.39
P <0.0001 		Effect size not calculated oestrogen-containing HRT plus testosterone
[68]
Systematic review		 2215 postmenopausal women
9 RCTs in this analysis		 Libido, desire, or interest in sex <3 to >12 months*
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute numbers not reported
SMD 0.35
95% CI 0.26 to 0.43
P <0.0001 		Effect size not calculated oestrogen-containing HRT plus testosterone
[68]
Systematic review		 1872 postmenopausal women
6 RCTs in this analysis		 Level of orgasm 6 to >12 months*
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute numbers not reported
SMD 0.28
95% CI 0.19 to 0.37
P <0.0001 		Effect size not calculated oestrogen-containing HRT plus testosterone
[68]
Systematic review		 1845 postmenopausal women
5 RCTs in this analysis		 Arousal 6 to <12 months*
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute numbers not reported
SMD 0.36
95% CI 0.27 to 0.45
P <0.0001 		Effect size not calculated oestrogen-containing HRT plus testosterone
[68]
Systematic review		 1641 postmenopausal women
6 RCTs in this analysis		 Pleasure or enjoyment of sex 6 to <12 months
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute numbers not reported
SMD 0.33
95% CI 0.22 to 0.43
P <0.0001 		Effect size not calculated oestrogen-containing HRT plus testosterone
[68]
Systematic review		 1852 postmenopausal women
5 RCTs in this analysis		 Sexual concerns 6 to <12 months*
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute numbers not reported
SMD 0.32
95% CI 0.22 to 0.41
P <0.0001 		Effect size not calculated oestrogen-containing HRT plus testosterone
[68]
Systematic review		 2171 postmenopausal women
8 RCTs in this analysis		 Sexual responsiveness <3 to >12 months*
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute numbers not reported
SMD 0.32
95% CI 0.23 to 0.40
P <0.0001 		Effect size not calculated oestrogen-containing HRT plus testosterone
[68]
Systematic review		 1839 postmenopausal women
5 RCTs in this analysis		 Sexual self-image 6 to <12 months*
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute numbers not reported
SMD 0.26
95% CI 0.16 to 0.35
P <0.0001 		Effect size not calculated oestrogen-containing HRT plus testosterone
[68]
Systematic review		 32 postmenopausal women
Data from 1 RCT		 Satisfaction at least 12 months
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute numbers not reported
SMD 0.98
95% CI 0.24 to 1.72
P = 0.009 		Effect size not calculated oestrogen-containing HRT plus testosterone
[68]
Systematic review		 32 postmenopausal women
Data from 1 RCT		 Sexual fantasy at least 12 months
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute numbers not reported
SMD 1.37
95% CI 0.59 to 2.15
P <0.0001 		Effect size not calculated oestrogen-containing HRT plus testosterone
[68]
Systematic review		 96 postmenopausal women
Data from 1 RCT		 Frequency of desire <3 months
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute numbers not reported
SMD +0.21
95% CI –0.19 to +0.61
P = 0.03 		Not significant
[68]
Systematic review		 330 postmenopausal women
3 RCTs in this analysis		 Composite sexual score <3 to >12 months*
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute numbers not reported
SMD 0.41
95% CI 0.19 to 0.63
P = 0.0002 		Effect size not calculated oestrogen-containing HRT plus testosterone
[68]
Systematic review		 1845 postmenopausal women
5 RCTs in this analysis		 Personal Distress Scale (change scores) <6 to >12 months*
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute numbers not reported
SMD –8.13
95% CI –10.59 to –5.67
P <0.0001 		Effect size not calculated oestrogen-containing HRT plus testosterone
Open in a new tab

Psychological symptoms

Testosterone plus oestrogen-containing HRT compared with oestrogen-containing HRT alone We don't know whether testosterone (oral methyltestosterone) plus oestrogen-containing HRT is more effective at improving cognition at between 12 and 24 weeks (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Cognition
[68]
Systematic review		 26 postmenopausal women
Data from 1 RCT		 Identical pictures memory 3 to <6 months
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute numbers not reported
Mean difference –2.4
95% CI –6.67 to +1.87
P = 0.27 		Not significant
[68]
Systematic review		 26 postmenopausal women
Data from 1 RCT		 Shape memory 3 to <6 months
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute numbers not reported
Mean difference +0.10
95% CI –2.19 to +2.39
P = 0.93 		Not significant
Open in a new tab

Vasomotor symptoms

Testosterone plus oestrogen-containing HRT compared with oestrogen-containing HRT alone We don't know whether testosterone (oral methyltestosterone) plus oestrogen-containing HRT is more effective at improving vasomotor symptoms at 12 weeks (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Vasomotor symptoms
[68]
Systematic review		 166 postmenopausal women
2 RCTs in this analysis		 Vasomotor symptoms <3 months
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute numbers not reported
Mean difference +0.09
95% CI –0.18 to +0.37
P = 0.5 		Not significant
Open in a new tab

Quality of life

No data from the following reference on this outcome.[68]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Androgenic adverse effects
[68]
Systematic review		 216 women
Data from 1 RCT		 Mean acne scores 16 weeks
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute results not reported
WMD +0.10
95% CI –0.03 to +0.23
P = 0.14 		Not significant
[68]
Systematic review		 2127 postmenopausal women
7 RCTs in this analysis		 Incidence of acne <3 months to <12 months*
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute results not reported
Peto odds ratio 1.51
95% CI 1.07 to 2.14
P = 0.02 		Small effect size oestrogen-containing HRT
[68]
Systematic review		 2127 postmenopausal women
7 RCTs in this analysis		 Incidence of facial and body hair growth 16 weeks
with oestrogen-containing HRT plus testosterone
with oestrogen-containing HRT
Absolute results not reported
Peto odds ratio 1.52
95% CI 1.07 to 2.17
P = 0.02 		Small effect size oestrogen-containing HRT
Open in a new tab

Further information on studies

The RCTs included in the review had inconsistent washout periods, baseline inequality, and attrition bias. Randomisation and blinding were generally considered of good quality.

Comment

None.

Substantive changes

Testosterone New evidence added.[68] Categorisation unchanged (Unknown effectiveness) because the new systematic review assessed the combination of testosterone plus oestrogen-based HRT, rather than testosterone alone, and found different results for different menopausal symptoms. There remains insufficient evidence to judge the effects of testosterone.

BMJ Clin Evid. 2011 Jun 15;2011:0804.

Agnus castus

Summary

We don't know whether agnus castus reduces menopausal symptoms, as we found no direct information from RCTs about agnus castus in the treatment of women with menopausal symptoms.

Benefits and harms

Agnus castus:

We found no systematic review or RCTs of agnus castus in women with menopausal symptoms.

Further information on studies

None.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jun 15;2011:0804.

Black cohosh

Summary

We don't know whether black cohosh reduces menopausal symptoms, as we found insufficient evidence to assess its effects.

Benefits and harms

Black cohosh:

We found one systematic review (9 RCTs, search date 2008)[69] assessing the effects of black cohosh alone or in combination with other preparations. The review performed a meta-analysis of two RCTs comparing black cohosh alone versus placebo.

Vasomotor symptoms

Compared with placebo We don't know whether black cohosh reduces vasomotor symptoms compared with placebo at 12 weeks (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Vasomotor symptoms
[69]
Systematic review		 273 women aged 45 to 60 years
2 RCTs in this analysis		 Difference between change in proportion of menopausal symptoms (including vasomotor) 12 weeks
with black cohosh
with placebo
Absolute results not reported
Rate difference 11%
95% CI 1% to 20%
P <0.05 		Effect size not calculated black cohosh
Open in a new tab

Psychological symptoms

No data from the following reference on this outcome.[69]

Quality of life

No data from the following reference on this outcome.[69]

Urogenital symptoms

No data from the following reference on this outcome.[69]

Further information on studies

None.

Comment

A temporal association between the start of treatment with black cohosh and adverse effects on the liver has been reported.[70] In the UK, the European Medicines Agency (EMA) and the Medicines and Healthcare products Regulatory Agency (MHRA) have issued guidance that women taking black cohosh who develop signs and symptoms suggestive of hepatic impairment should stop taking the drug and contact their doctor immediately.

Substantive changes

Black cohosh New evidence added.[69] Categorisation unchanged (Unknown effectiveness) because evidence remains insufficient to judge the effects of this intervention.

BMJ Clin Evid. 2011 Jun 15;2011:0804.

Phyto-oestrogens

Summary

We don't know whether phyto-oestrogens, such as those in soy flour, reduce menopausal symptoms. Phyto-oestrogens have not been shown consistently to improve symptoms, and they may increase the risk of endometrial hyperplasia in perimenopausal women.

We found no direct information from RCTs about the effects of phyto-oestrogens on quality of life in women with menopausal symptoms.

Benefits and harms

Phyto-oestrogens versus placebo:

We found one systematic review[71] and one additional RCT.[72] The systematic review (search date 2007, 31 RCTs, 2730 postmenopausal women) evaluated food products or dietary supplements containing high levels of phyto-oestrogens for management of hot flushes and night sweats.[71] Most of the RCTs identified were small pilot studies that evaluated disparate types of phyto-oestrogen with no standardised dosing, and therefore the review did not perform a meta-analysis for most comparisons. As a consequence the review was unable to draw any firm conclusions as to whether any phyto-oestrogen preparation was effective. We have reported separately the results of the included RCTs that met Clinical Evidence inclusion criteria. The review grouped the trials by whether they included soy dietary supplements (flour, powders, or drinks: 6 RCTs), soy isoflavone extracts (usually tablets: 6 RCTs), red clover extracts (tablets: 6 RCTs), or other phyto-oestrogens (extracts of genistein, pueraria lobata, hops, or flaxseed). We found two RCTs assessing the effects of phyto-oestrogens on urogenital symptoms,[73] [74] and two RCTs assessing the effects of phyto-oestrogens on psychological, cognitive, and sleep symptoms.[74] [75] We found one systematic review (search date not reported, 92 RCTs, 9629 women)[76] assessing adverse effects of phyto-oestrogens.

Vasomotor symptoms

Compared with placebo We don't know whether phyto-oestrogens (soy isoflavone extracts, soy dietary supplements, red clover, or other phyto-oestrogens) are more effective at reducing vasomotor symptoms (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom improvement: soy isoflavone supplements
[71]
Systematic review		 104 postmenopausal women, predominantly in the age range 52 to 53 years
Data from 1 RCT		 Number of flushes/day 12 weeks
with 60 g soy powder (76 mg isoflavones)
with placebo (60 g casein)
Absolute results not reported
Mean difference −1.59 flushes in favour of soy powder
95% CI −1.95 flushes to −1.2 flushes
P <0.01 		Effect size not calculated soy dietary supplements
[71]
Systematic review
3-armed trial 		241 postmenopausal women, mean age 51 years
Data from 1 RCT		 Number and severity of flushes/day 2 years
with soy drink with lower isoflavones (42 mg/day)
with soy drink with higher isoflavones (58 mg/day)
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[71]
Systematic review
Crossover design
3-armed trial 		52 postmenopausal women, predominantly in the age range 53.6 to 54.6 years
Data from 1 RCT		 Percentage reduction in number of hot flushes (pre-crossover results) 12 weeks
22% with soy diet (53 mg isoflavones/day)
41% with linseed diet (high in isoflavones, quantity not reported)
51% with placebo (wheat diet)
Absolute numbers not reported
Reported as not significant
P value not reported
It is unclear which comparison was used for assessing significance 		Not significant
[71]
Systematic review		 24 postmenopausal women, aged 45 to 60 years
Data from 1 RCT		 Number of flushes/week 12 weeks
29 with soy powder drink (60 g/day)
46 with placebo (casein powder drink)
Reported as not significant
P value not reported 		Not significant
[71]
Systematic review
3-armed trial 		99 postmenopausal women, mean age 53 years
Data from 1 RCT		 Menoquol vasomotor symptom severity score 16 weeks
with soy flour muffins (42 mg isoflavones/day)
with flaxseed muffins (50 mg lignans/day)
with placebo
Absolute results not reported
Reported as not significant
P value not reported
It is unclear which comparison was used for assessing significance 		Not significant
[71]
Systematic review
3-armed trial 		99 postmenopausal women, mean age 53 years
Data from 1 RCT		 Number of flushes/day 16 weeks
with soy flour muffins (42 mg isoflavones/day)
with flaxseed muffins (50 mg lignans/day)
with placebo
Absolute results not reported
Reported as not significant
P value not reported
It is unclear which comparison was used for assessing significance 		Not significant
[71]
Systematic review
3-armed trial 		99 postmenopausal women, mean age 53 years
Data from 1 RCT		 Flushing severity (from 1 = none to 7 = severe) 16 weeks
with soy flour muffins (42 mg isoflavones/day)
with flaxseed muffins (50 mg lignans/day)
with placebo
Absolute results not reported
Reported as not significant
P value not reported
It is unclear which comparison was used for assessing significance 		Not significant
[71]
Systematic review
3-armed trial 		69 postmenopausal women, median age 50 years
Data from 1 RCT		 Proportion of people with reduced frequency, duration, and severity of flushes 24 weeks
with higher-dose soy protein (80.4 mg isoflavones/day)
with lower-dose soy protein (4.4 mg isoflavones/day)
with placebo
Absolute results not reported
Reported as not significant
P value not reported
It is unclear which comparison was used for assessing significance 		Not significant
[71]
Systematic review
3-armed trial 		69 postmenopausal women, median age 50 years
Data from 1 RCT		 Number of flushes/week 24 weeks
with higher-dose soy protein (80.4 mg isoflavones/day)
with lower-dose soy protein (4.4 mg isoflavones/day)
with placebo
Absolute results not reported
Reported as not significant
P value not reported
It is unclear which comparison was used for assessing significance 		Not significant
[71]
Systematic review
3-armed trial 		69 postmenopausal women, median age 50 years
Data from 1 RCT		 Number of sweats/week 24 weeks
with higher-dose soy protein (80.4 mg isoflavones/day)
with lower-dose soy protein (4.4 mg isoflavones/day)
with placebo
Absolute results not reported
Reported as not significant
P value not reported
It is unclear which comparison was used for assessing significance 		Not significant
[71]
Systematic review		 75 postmenopausal women, predominantly in the age range 52 to 54 years
Data from 1 RCT		 Proportion with reduced hot flushes 25 weeks
74% with standardised soy extract (33 mg isoflavones/day)
43% with placebo
Absolute numbers not reported
P = 0.007 		Effect size not calculated soy extract
[71]
Systematic review		 75 postmenopausal women, predominantly in the age range 52 to 54 years
Data from 1 RCT		 Proportion with reduced night sweats 25 weeks
68% with standardised soy extract (33 mg isoflavones/day)
46% with placebo
Absolute numbers not reported
P = 0.049 		Effect size not calculated soy extract
[71]
Systematic review		 75 postmenopausal women, predominantly in the age range 52 to 54 years
Data from 1 RCT		 Greene Climacteric Scale vasomotor symptom severity 25 weeks
with standardised soy extract (33 mg isoflavones/day)
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[71]
Systematic review		 75 postmenopausal women, predominantly in the age range 52 to 54 years
Data from 1 RCT		 Symptom severity 25 weeks
with standardised soy extract (33 mg isoflavones/day)
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[71]
Systematic review
Crossover design 		36 postmenopausal women, mean age 51 years
Data from 1 RCT		 Number of flushes/week (pre-crossover results) 12 weeks
with standardised soy extract capsules (60 mg isoflavones/day)
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[71]
Systematic review		 36 postmenopausal women, predominantly in the age range 57 to 59 years
Data from 1 RCT		 Greene Climacteric Scale vasomotor symptom severity score 12 weeks
with soy supplement capsules (60 mg isoflavones/day)
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[71]
Systematic review		 75 postmenopausal women, predominantly in the age range 53 to 53.9 years
Data from 1 RCT		 Reduction in number of flushes/day 16 weeks
61% with soy extract capsules (70 mg isoflavones/day)
21% with placebo
Absolute numbers not reported
Significance not assessed
[71]
Systematic review		 75 postmenopausal women, predominantly in the age range 53 to 53.9 years
Data from 1 RCT		 Proportion who responded to treatment (those with at least 50% reduction in number of flushes/day) 16 weeks
66% with soy extract capsules (70 mg isoflavones/day)
34% with placebo
Absolute numbers not reported
P <0.005 		Effect size not calculated soy extract
[71]
Systematic review		 80 postmenopausal women, predominantly in the age range 48 to 49 years
Data from 1 RCT		 Kupperman Index vasomotor symptom severity score 16 weeks
8.2 with soy capsules (100 mg isoflavones/day)
9.9 with placebo
P <0.01 		Effect size not calculated soy capsules
[71]
Systematic review		 207 postmenopausal women, predominantly in the age range 52 to 54 years
Data from 1 RCT		 Reduction in hot flush severity/week 12 weeks
34% with soy extract tablets (50 mg of genistein and daidzin/day)
21% with placebo
Absolute numbers not reported
P = 0.01 		Effect size not calculated soy extract
[71]
Systematic review		 207 postmenopausal women, predominantly in the age range 52 to 54 years
Data from 1 RCT		 Hot flush frequency 12 weeks
with soy extract tablets (50 mg of genistein and daidzin/day)
with placebo
Absolute results not reported
P = 0.078 		Not significant
[71]
Systematic review		 207 postmenopausal women, predominantly in the age range 52 to 54 years
Data from 1 RCT		 Night sweats 12 weeks
with soy extract tablets (50 mg of genistein and daidzin/day)
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
Symptom improvement: red clover extracts
[71]
Systematic review		 300 postmenopausal women, mean ages in RCTs ranged from 51.1 to 54.5 years
5 RCTs in this analysis		 Number of hot flushes/day 12 to 16 weeks
with standard red clover extract (promensil 40 mg or 80 mg)
with placebo
Absolute results not reported
WMD −0.57 flushes/day in favour of red clover extract
95% CI −1.76 flushes/day to +0.62 flushes/day 		Not significant
[71]
Systematic review		 282 postmenopausal women, mean ages in RCTs ranged from 51 to 52 years
2 RCTs in this analysis		 Reduction in number of hot flushes from baseline 12 to 16 weeks
with standard red clover extract (promensil 40 mg or 80 mg)
with placebo
Absolute results not reported
WMD +20.15
95% CI −12.08 to +52.38
The estimate of effect size is imprecise 		Not significant
[71]
Systematic review		 30 postmenopausal women, predominantly in the age range 51 to 52 years
Data from 1 RCT		 Risk of improvement in hot flush severity 16 weeks
with standard red clover extract (promensil 40 mg)
with placebo
Absolute results not reported
OR 47.7
95% CI 2.4 to 967.4
The estimate of effect size is imprecise 		Large effect size red clover extract
[71]
Systematic review		 252 postmenopausal women, mean age 52 years
Data from 1 RCT		 Vasomotor symptom severity score 12 weeks
with standard red clover extract (promensil)
with placebo
Absolute results not reported
WMD +0.1
95% CI −1.5 to +1.7 		Not significant
[71]
Systematic review
Crossover design 		60 postmenopausal women
Data from 1 RCT		 Kupperman Index score for hot flushes (severity scored as a percentage) (pre-crossover results) 12 weeks
15% with red clover extract
98% with placebo
Absolute numbers not reported
Significance not assessed
[71]
Systematic review
Crossover design 		60 postmenopausal women
Data from 1 RCT		 Kupperman Index score for night sweats (severity scored as a percentage) (pre-crossover results) 12 weeks
30% with red clover extract
93% with placebo
Absolute numbers not reported
Significance not assessed
Symptom improvement: other phyto-oestrogens versus placebo
[71]
Systematic review
3-armed trial 		90 postmenopausal women, predominantly in the age range 51 to 52 years
Data from 1 RCT		 Reduction in number of hot flushes/day 1 year
with genistein extract (54 mg isoflavones/day)
with placebo
Absolute results not reported
P <0.01 		Effect size not calculated genistein extract
[71]
Systematic review		 112 women with symptoms at the start of the RCT, predominantly in the age range 54 to 55 years
Data from 1 RCT
Subgroup analysis		 Menoquol hot flush and sweat severity scores 1 year
with flaxseed dietary supplement (in bread and ground grains, containing 21,071 micrograms lignans)
with placebo wheat-germ supplement (low in lignans)
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[71]
Systematic review
3-armed trial 		67 postmenopausal women, predominantly in the age range 52 to 53 years
Data from 1 RCT		 Kupperman Index hot flush severity score 12 weeks
with lower-dose hop extract (containing 100 micrograms lignans)
with higher-dose hop extract (containing 250 micrograms lignans)
with placebo
Absolute results not reported
Reported as not significant
P value not reported
It is unclear which comparison was used for assessing significance 		Not significant
[71]
Systematic review
Crossover design
3-armed trial 		52 postmenopausal women, predominantly in the age range 53.6 to 54.6 years
Data from 1 RCT		 Percentage reduction in number of hot flushes (pre-crossover results) 12 weeks
22% with soy diet (53 mg isoflavones/day)
41% with linseed diet (high in isoflavones, quantity not reported)
51% with placebo (wheat diet)
Absolute numbers not reported
Reported as not significant
P value not reported
It is unclear which comparison was used for assessing significance 		Not significant
[72]
RCT
Crossover design 		51 women Vasomotor symptom severity 6 weeks
with supplement containing soy protein 34 mg
with supplement containing no phyto-oestrogens
Absolute results not reported
P <0.001 		Effect size not calculated soy protein
[72]
RCT
Crossover design 		51 women Vasomotor symptom frequency 6 weeks
with supplement containing soy protein 34 mg
with supplement containing no phyto-oestrogens
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
Open in a new tab

No data from the following reference on this outcome.[73] [74] [75]

Urogenital symptoms

Compared with placebo We don't know whether phyto-oestrogens (soy protein or red clover extract) are more effective at improving vaginal dryness or libido (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Sexual functioning
[74]
RCT		 94 women Vaginal dryness 3 months
with soy protein
with placebo
Absolute results not reported
P = 0.1 		Not significant
[74]
RCT		 94 women Libido 3 months
with soy protein
with placebo
Absolute results not reported
P = 0.38 		Not significant
[73]
RCT
Crossover design 		60 women Vaginal cytology (mean karyopyknotic score [baseline of 6.1]) 90 days
45.6 with red clover isoflavone
3.6 with placebo
P <0.05 		Effect size not calculated red clover isoflavone
Open in a new tab

No data from the following reference on this outcome.[71] [72] [75]

Psychological symptoms

Compared with placebo We don't know whether phyto-oestrogens are more effective in improving psychological symptoms or cognitive function at 3 to 6 months (very low-quality evidence)

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Psychological symptoms
[74]
RCT		 94 women Psychological symptoms (including irritability, depression, anxiousness, and sleeplessness) 3 months
with soy protein
with placebo
Absolute results not reported
Reported as not significant
P values not reported 		Not significant
[75]
RCT
Crossover design 		78 women Beck Depression Inventory score
7.6 with red clover
9.7 with placebo
P = 0.01 		Effect size not calculated red clover
[75]
RCT
Crossover design 		78 women Global score for the Profile of Mood States
34 with red clover
41 with placebo
P = 0.01 		Effect size not calculated red clover
Cognition
[75]
RCT
Crossover design 		78 women Pairs recalled correctly in pairs recall test
6.5 with red clover
6.2 with placebo
P = 0.04 		Effect size not calculated red clover
[75]
RCT
Crossover design 		78 women Backwards recall of digits
5.9 with red clover
5.4 with placebo
P = 0.05 		Not significant
[75]
RCT
Crossover design 		78 women Forwards recall of digits
6.5 with red clover
6.5 with placebo
P = 0.98 		Not significant
[75]
RCT
Crossover design 		78 women Other domains of cognitive function (including the digit symbol, digit span, or visual scanning test)
with red clover
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
Open in a new tab

No data from the following reference on this outcome.[71] [72] [73]

Quality of life

No data from the following reference on this outcome.[71] [72] [73] [74] [75]

Endometrial hyperplasia

Phyto-oestrogens compared with placebo Isoflavone may be associated with an increased risk of endometrial hyperplasia in women at 5 years (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Endometrial hyperplasia
[77]
RCT		 376 women Proportion of women with endometrial hyperplasia 5 years
6/154 (4%) with isoflavone 150 mg daily
0/165 (0%) with placebo
P <0.05 		Effect size not calculated placebo
[77]
RCT		 376 women Proportion of women with complex hyperplasia 5 years
1/154 (1%) with isoflavone 150 mg daily
0/165 (0%) with placebo
Reported as not significant
P value not reported 		Not significant
[71]
Systematic review		 80 postmenopausal women, predominantly in the age range 48 to 49 years
Data from 1 RCT		 Endometrial thickness
with soy capsules (100 mg isoflavones/day)
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[76]
Systematic review		 298 women
Data from 1 RCT		 Incidence of endometrial hyperplasia 5 years
with phyto-oestrogens
with control
Significance not assessed
Open in a new tab

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects (general)
[71]
Systematic review		 104 postmenopausal women, predominantly in the age range 52 to 53 years
Data from 1 RCT		 Adverse effects 12 weeks
with 60 g soy powder (76 mg isoflavones)
with placebo (60 g casein)
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[71]
Systematic review
Crossover design
3-armed trial 		52 postmenopausal women, predominantly in the age range 53.6 to 54.6 years
Data from 1 RCT		 Increase in vaginal maturation index (pre-crossover results)
103% with soy diet (53 mg isoflavones/day)
6% with linseed diet (high in isoflavones, quantity not reported)
11% with placebo (wheat diet)
Absolute numbers not reported
Significance not assessed
[71]
Systematic review		 24 postmenopausal women, aged 45 to 60 years
Data from 1 RCT		 Adverse effects 12 weeks
75% with soy powder drink (60 g/day)
17% with placebo (casein powder drink)
Absolute numbers not reported
P = 0.001 		Effect size not calculated placebo
[71]
Systematic review		 75 postmenopausal women, predominantly in the age range 52 to 54 years
Data from 1 RCT		 Vaginal maturation index 25 weeks
with standardised soy extract (33 mg isoflavones/day)
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[71]
Systematic review
Crossover design 		36 postmenopausal women, mean age 51 years
Data from 1 RCT		 Vaginal maturation index
with standardised soy extract capsules (60 mg isoflavones/day)
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[71]
Systematic review		 75 postmenopausal women, predominantly in the age range 53 to 53.9 years
Data from 1 RCT		 Adverse effects
with soy extract capsules (70 mg isoflavones/day)
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[71]
Systematic review
3-armed trial 		90 postmenopausal women, predominantly in the age range 51 to 52 years
Data from 1 RCT		 Endometrial thickness 1 year
with genistein extract (54 mg isoflavones/day)
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[76]
Systematic review		 9629 women
92 RCTs in this analysis		 Overall incidence of adverse effects
2019/5502 (37%) with phyto-oestrogens
1824/4806 (39%) with control
P = 0.2
Incidence rate ratio (IRR) 1.01
95% CI 0.95 to 1.08 		Not significant
[76]
Systematic review		 9629 women
92 RCTs in this analysis		 Incidence of GI adverse effects
with phyto-oestrogens
with control
Absolute numbers not reported
P = 0.003
IRR 1.28
95% CI 1.08 to 1.50 		Effect size not calculated control
[76]
Systematic review		 9629 women
92 RCTs in this analysis		 Incidence of gynaecological or urinary adverse effects
with phyto-oestrogens
with control
P = 0.61
IRR 0.94
95% CI 0.74 to 1.20 		Not significant
[76]
Systematic review		 9629 women
92 RCTs in this analysis		 Incidence of musculoskeletal adverse effects
with phyto-oestrogens
with control
P = 0.14
IRR 1.20
95% CI 0.94 to 1.53 		Not significant
[76]
Systematic review		 9629 women
92 RCTs in this analysis		 Incidence of neurological or sensory adverse effects
with phyto-oestrogens
with control
P = 0.48
IRR 0.91
95% CI 0.70 to 1.19 		Not significant
[76]
Systematic review		 9629 women
92 RCTs in this analysis		 Incidence of non-specific adverse effects
with phyto-oestrogens
with control
P = 0.19
IRR 0.95
95% CI 0.88 to 1.03 		Not significant
[76]
Systematic review		 9629 women
92 RCTs in this analysis		 Incidence of breast cancer
11/5502 (0.2%) with phyto-oestrogens
5/4806 (0.1%) with control
P = 0.9 		Not significant
Open in a new tab

No data from the following reference on this outcome.[72] [73] [74] [75]

Phyto-oestrogens versus oestrogen alone:

We found one systematic review (search date 2007, 31 RCTs, 2730 postmenopausal women), which identified one RCT comparing phyto-oestrogen (soy extract) versus oestrogen plus placebo.[71]

Vasomotor symptoms

Compared with oestrogen alone We don't know how phyto-oestrogen (soy extract) and oestrogen alone compare at reducing vasomotor symptoms (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom improvement
[71]
Systematic review		 79 postmenopausal women, mean age 54 years
Data from 1 RCT		 Proportion of women reporting reduced symptoms 24 weeks
with soy extract capsules (120 mg isoflavones/day)
with oestrogen plus placebo capsules
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
Open in a new tab

Urogenital symptoms

No data from the following reference on this outcome.[71]

Psychological symptoms

No data from the following reference on this outcome.[71]

Quality of life

No data from the following reference on this outcome.[71]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[71]
Systematic review		 79 postmenopausal women, mean age 54 years
Data from 1 RCT		 Endometrial thickness
3.0 mm with soy extract capsules (120 mg isoflavones/day)
5.9 mm with oestrogen plus placebo capsules
Reported as significant
P value not reported 		Effect size not calculated soy extract
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Phyto-oestrogens versus oestrogens plus progestogens:

We found one systematic review (search date 2007, 31 RCTs, 2730 postmenopausal women), which identified one RCT comparing phyto-oestrogen (pueraria lobata) versus oestrogen plus medroxyprogesterone acetate.[71]

Vasomotor symptoms

Compared with oestrogen plus progestogen We don't know how phyto-oestrogen (pueraria lobata) and oestrogen plus medroxyprogesterone acetate compare at reducing vasomotor symptoms (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom improvement
[71]
Systematic review
3-armed trial 		136 postmenopausal women, predominantly in the age range 56 to 57 years
Data from 1 RCT		 Vasomotor symptom scores (from symptom severity questionnaire) 12 weeks
with pueraria lobata
with oestrogen plus cyclical medroxyprogesterone acetate
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
Open in a new tab

Urogenital symptoms

No data from the following reference on this outcome.[71]

Psychological symptoms

No data from the following reference on this outcome.[71]

Quality of life

No data from the following reference on this outcome.[71]

Adverse effects

No data from the following reference on this outcome.[71]

Further information on studies

The RCT was a crossover study of two 6-month treatment phases of isoflavone 60 mg or placebo, with a 1-month washout phase between treatments.

Comment

Few studies have specifically investigated adverse effects of phyto-oestrogens. Results of studies are difficult to interpret because phyto-oestrogen preparations are not standardised.

Substantive changes

Phyto-oestrogens New evidence added.[76] Categorisation unchanged (Unknown effectiveness) because new evidence only assessed adverse effects of phyto-oestrogens, and there remains insufficient evidence to judge the effects of this intervention in improving menopausal symptoms.

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