Menopausal symptoms can range from the very mild, to severe and disabling.
Vasomotor symptoms – hot flushes and sweats – are the commonest symptom, but are frequently accompanied by others such as fatigue, mood changes, insomnia, reduced libido, urinary and vaginal symptoms.
HRT (hormone replacement therapy) improves these symptoms, with the strongest evidence of its effect being on vasomotor symptoms.
Menopausal symptoms will improve or disappear over time, though there is huge variation in their duration:
In a study of 881 women in the US, the median duration of hot flushes was 7.4 years.
HRT has some other associated long-term benefits and harms. Most of these are small in absolute terms, with breast cancer risk being the most significant.
The choice to take HRT (and how long to take it for) involves a consideration of the benefits on symptom relief against potential long-term benefits and harms, and is very much down to the individual.
Individuals will have differing frequency and severity of hot flushes, and differing response to HRT.
On average, randomised controlled trials show that:
Figures derived from:
Both compared oestrogen-containing (with or without progesterone) HRT to placebo.
References
1)Avis NE, Crawford SL, Greendale G et al. Study of Women’s Health Across the Nation. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med 2015; 175(4): 531-539
2)National Institute for Health and Care Excellence. Menopause: diagnosis and management [Internet]. [London]: NICE; 2015 [updated 2019]. (NICE Guidleine [NG23])
3)MacLennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD002978
| This research provides some indication of the treatment effect.
There is a high possibility that the true effect is smaller or greater. |
NICE rated this evidence as LOW quality1:
Reference
1)National Institute for Health and Care Excellence. Menopause: diagnosis and management [Internet]. [London]: NICE; 2015 [updated 2019]. (NICE Guidleine [NG23])
The studies reported in the Cochrane review1 had the following characteristics:
The NICE review did not summarise the population characteristics.
Reference
1)MacLennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD002978
Menopause is associated with a wide range of symptoms in addition to hot flushes.
Despite anecdotal evidence that HRT can improve many symptoms, there is limited RCT evidence to support this. This may well be due to under-research and lower quality trials.
Anxiety and low mood
The NICE evidence review found one MODERATE quality trial reporting a statistically significant improvement in anxiety and low mood:
A number of smaller and lower quality trials did not find any benefit on these outcomes.
Musculoskeletal symptoms
The NICE evidence review found two trials of MODERATE quality which did not show any benefit from HRT compared to placebo on this outcome:
Sexual function
A 2013 Cochrane review2 found that for women with menopausal symptoms, oestrogen (with or without progesterone) provided:
References
1)National Institute for Health and Care Excellence. Menopause: diagnosis and management [Internet]. [London]: NICE; 2015 [updated 2019]. (NICE Guidleine [NG23])
2)Nastri CO, Lara LA, Ferriani RA et al. Hormone therapy for sexual function in perimenopausal and postmenopausal women. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD009672
Side effects were poorly reported in the RCTs in the Cochrane review1, and they were unable to give summary statistics for these.
Breast tenderness was the commonest reported side effect, with very roughly 1 in 5 women reporting this with HRT.
Oedema, joint pain and psychiatric symptoms were reported as “recurrent” reasons for treatment withdrawal, however:
No serious adverse events were reported.
Data on long-term risks are presented in the sections below.
Reference
1)MacLennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD002978
HRT increases the risk of breast cancer. Absolute risk can be small, but this depends on the type and duration of HRT use:
Though the incidence of breast cancer is increased, no increase in breast cancer mortality has been associated with HRT use.
Figures derived from a 2019 Medicines & Healthcare products Regulatory Agency (MHRA) drug safety update1.
This was based on the results of a large epidemiological study2, and resulted in an update of the NICE menopause guideline to include these new figures3.
The original study, published in 20192 was:
References
1)MHRA. Hormone replacement therapy (HRT): further information on the known increased risk of breast cancer with HRT and its persistence after stopping. Drug Safety Update. Aug 2019. Accessed online Jan 2023
2)Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019; 394(10204): 1159-1168
3)National Institute for Health and Care Excellence. Surveillance of menopause: diagnosis and management (NICE guideline NG23). Surveillance decision 2019. Accessed online Jan 2023
| Though there is historic and ongoing controversy about the risk of breast cancer associated with HRT, these figures are good enough to use to support shared-decision making with women.
Previous and other estimates of risk have been slightly lower, but are essentially in the same ballpark as these figures1-3. The nature of the evidence base means there will always be some uncertainty about the exact size of this risk, but the overall size and patterns of risk can be regarded as reliable. |
References
1)National Institute for Health and Care Excellence. Surveillance of menopause: diagnosis and management (NICE guideline NG23). Surveillance decision 2019. Accessed online Jan 2023.
2)National Institute for Health and Care Excellence. Menopause: diagnosis and management [Internet]. [London]: NICE; 2015. Ch.11.5.7 (NICE Guideline [NG23])
3)Brusselaers N, Tamimi R, Konings P et al. Different menopausal hormone regimens and risk of breast cancer. Annals of Oncology 2018; 29: 1771-1776
The population characteristics in this epidemiological study1 were:
Reference
1)Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019; 394(10204): 1159-1168
When thinking about breast cancer risk with HRT, it may be useful to put this risk into perspective.
A 2017 British Menopause Society publication1 presented data on lifestyle factors and their impact on breast cancer risk. The magnitude of these risks is broadly similar to that associated with HRT:
|
Number of cases of breast cancer in general population without these lifestyle factors: 23 per 1000 women over 5 years |
||||
| Lifestyle factor | Alcohol consumption
>2 units per day |
Smoking | Obesity
BMI >30kg/m2 |
Moderate exercise >2 1/2 hours per week |
| Change in number of cases per 1000 women over 5 years with this lifestyle factor |
+5 | +3 | +24* | -7 |
| Number of cases of breast cancer in population with this lifestyle factor per 1000 women over 5 years |
28 | 26 | 47 | 16 |
* Obesity and HRT risk. One finding from the recent epidemiological study2 providing the main figures for breast cancer risk in this section, was that:
Reference
1)British Menopause Society. Understanding the risks of breast cancer. Infographic 2017. Accessed online Jan 2023
Note: (1) We have not reviewed the evidence behind this infographic; and (2) it contains estimates for breast cancer risk which are lower and based on past evidence.
2)Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019; 394(10204): 1159-1168
There does not appear to be a significant increase in CVD associated with HRT, except for venous thromboembolic disease.
Concern that HRT might increase the risk of cardiovascular disease was raised after the publication of data from the Women’s Health Initiative study in 2003.
Risk data from the 2015 NICE guideline analysis are shown in this table.
The figures refer to women aged 50-59 (on starting HRT) over a period of 7.5 years:
| HRT Type | No HRT
Events per 1000 women |
Current HRT users
Events per 1000 women |
Absolute difference per 1000 women |
|
Absolute difference per 1000 women | |
| Coronary Heart Disease | ||||||
| Oestrogen only | 26 | 20 | 6 fewer | 20 | 6 fewer | Not statistically significant*
|
| Oestrogen and progesterone | 26 | 31 | 5 more | 26 | 4 more | Not statistically significant*
|
| Stroke | ||||||
| Oestrogen only | 11 | no difference | ||||
| Oestrogen and progesterone | 11 | 17 | 6 more | 15 | 4 more | Not statistically significant |
| Venous thromboembolism | ||||||
| Oral HRT** | 12 | 22 | 10 more | No excess risk in former users | Statistically significant | |
| Transdermal HRT | No increase in VTE risk | |||||
* A 2015 Cochrane review2 did find a statistically significant benefit of a similar magnitude in this outcome for all types of HRT.
** This risk applied to both oestrogen-only and oestrogen+progesterone oral HRT regimens.
Figures derived from a 2015 NICE evidence review1:
The figures for CHD and stroke are provided in the main guideline (section 1.5.7). Details of total number of trials and participants are not summarised.
Reference
1)National Institute for Health and Care Excellence. Menopause: diagnosis and management [Internet]. [London]: NICE; 2015. (NICE Guideline [NG23])
2)Boardman HMP, Hartley L, Eisinga A et al. Hormone therapy for preventing cardiovascular disease in post‐menopausal women. Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: CD002229
| This research provides some indication of the treatment effect.
There is a high possibility that the true effect is smaller or greater. |
NICE rated this evidence quality as LOW1:
Reference
1)National Institute for Health and Care Excellence. Menopause: diagnosis and management [Internet]. [London]: NICE; 2015. (NICE Guideline [NG23])
The population characteristics of this evidence review are not summarised by NICE.
However, the review was focussed around women who started HRT around the time of the menopause. In contrast, in the Women’s Health Initiative study (which raised the original concern), the starting age was over 60.
Reference
1)National Institute for Health and Care Excellence. Menopause: diagnosis and management [Internet]. [London]: NICE; 2015. (NICE Guideline [NG23])
HRT improves bone density and reduces fracture risk whilst it is being taken, but this benefit decreases after treatment stops.
Risk data from the 2015 NICE guideline analysis1 are shown in this table.
| No HRT | Current HRT users | Absolute reduction per 1000 women | >5 years after stopping HRT | |
| Rate of fragility fracture per 1000 women over 3 years | 69 | 46 | 23 fewer | no significant difference to women not taking HRT |
Figures derived from 2015 NICE evidence review1:
Reference
1)National Institute for Health and Care Excellence. Menopause: diagnosis and management [Internet]. [London]: NICE; 2015. (NICE Guideline [NG23])
| This research provides some indication of the treatment effect.
There is a high possibility that the true effect is smaller or greater. |
NICE rated this evidence quality as LOW
Reference
1)National Institute for Health and Care Excellence. Menopause: diagnosis and management [Internet]. [London]: NICE; 2015. (NICE Guideline [NG23])
Details of the study population characteristics were not summarised in the NICE review1 except that the participants were post-menopausal women age 45-69.
Reference
1)National Institute for Health and Care Excellence. Menopause: diagnosis and management [Internet]. [London]: NICE; 2015. (NICE Guideline [NG23])
Testosterone as an addition to oestrogen-containing HRT has been shown to improve sexual function in women who report low libido or sexual dysfunction during or after menopause.
The table below summarises these improvements as compared to placebo.
| Standardised mean difference in sexual function score* | +0.25 approx | This represents a small but meaningful improvement. |
| Number of satisfactory sexual events (SSE) per month | +1 approx | In the study populations, the baseline number of SSE was about 1-3 per month |
*The most common scoring system used in the studies was the PFSF, which gathers self-reported assessments across a number of domains: desire, arousal, orgasm, pleasure, concerns, responsiveness, self-image.
There is no RCT data to show an improvement in cognition or musculoskeletal function.
There is no long term data regarding outcomes such as cardiovascular events, fracture or cancers.
Harms of testosterone therapy
Excess hair growth
2.4% of women in the RCTs developed excess hair growth due to testosterone therapy:
Acne
2.5% of women in the RCTs developed acne due to testosterone therapy:
LDL cholesterol changes
Transdermal testosterone therapy was not associated with any rise in LDL in the RCTs.
Oral testosterone therapy was associated with an average rise in LDL of 0.29mmol/mol compared to placebo.
Figures derived from a 2019 systematic revew1, which has similar findings to the 2015 NICE evidence review2:
References
1)Islam RM, Bell RJ, Green S et al. Safety and efficacy of testosterone for women: a systematic review and meta-analysis of randomised controlled trial data. The Lancet Diabetes & Endocrinology 2019; 7(10): 754-766
2)National Institute for Health and Care Excellence. Menopause: diagnosis and management [Internet]. [London]: NICE; 2015. (NICE Guideline [NG23])
| This research provides some indication of the treatment effect.
There is a high possibility that the true effect is smaller or greater. |
This evidence rates as LOW quality:
However,
Reference
1)Islam RM, Bell RJ, Green S et al. Safety and efficacy of testosterone for women: a systematic review and meta-analysis of randomised controlled trial data. The Lancet Diabetes & Endocrinology 2019; 7(10): 754-766
The population characteristics in the trials in this systematic review were, roughly:
Reference
1)Islam RM, Bell RJ, Green S et al. Safety and efficacy of testosterone for women: a systematic review and meta-analysis of randomised controlled trial data. Lancet Diabetes & Endocrinology 2019; 7(10): 754-766
Topical oestrogen preparations are effective in relieving symptoms of postmenopausal vulvovaginal atrophy.
This affects up to 50% of women and typically presents 4 to 5 years after the menopause.
Topical oestrogen may be used alone or as an adjunct to systemic HRT.
The table below summarises the number of women reporting improvement in a range of symptoms:
| Treatment duration | Placebo preparation | Topical oestrogen | |
| Overall symptoms | 3 months | 22% | 46% |
| Vaginal dryness | 1 year | 28% | 84% |
| Dyspareunia | 1 year | 27% | 73% |
| Itching and/or discomfort | 1 year | 37% | 80% |
Harms associated with topical oestrogen treatment
Systemic effects?
The British Menopause Society state that systemic absorption is minimal and vaginal oestrogen preparations can be continued indefinitely without the addition of progesterones1.
Endometrial hyperplasia?
No evidence of endometrial hyperplasia was observed in the RCTs reviewed by NICE2.
Local reactions
Local reactions may occur with topical preparations, but there was no statistically significant difference in withdrawal from treatment in the oestrogen v placebo groups in the RCTs.
References
1)HRT guide for health professionals. British Menospase Society. Accessed online Jan 2023.
2)National Institute for Health and Care Excellence. Menopause: diagnosis and management [Internet]. [London]: NICE; 2015. (NICE Guideline [NG23])
Figures derived from the 2015 NICE evidence review1:
Reference
1)National Institute for Health and Care Excellence. Menopause: diagnosis and management [Internet]. [London]: NICE; 2015. (NICE Guideline [NG23])
| This research provides a good indication of the treatment effect.
There is a moderate possibility that the true effect is smaller or greater. |
NICE this evidence as MODERATE quality:
However,
Reference
1)National Institute for Health and Care Excellence. Menopause: diagnosis and management [Internet]. [London]: NICE; 2015. (NICE Guideline [NG23])
The characteristics of the patients in these studies were summarised by NICE as:
Reference
1)National Institute for Health and Care Excellence. Menopause: diagnosis and management [Internet]. [London]: NICE; 2015. (NICE Guidleine [NG23])
The 2015 NICE evidence evidence review found some evidence of benefit on reduction of hot flushes with:
The recommendations to consider these treatments comes with a caveat that there is variation/uncertainty in the composition of various products available, so any effect is uncertain.
Source: MHRA
No statistically significant evidence of benefit was found for:
Reference
1)National Institute for Health and Care Excellence. Menopause: diagnosis and management [Internet]. [London]: NICE; 2015 [updated 2019]. (NICE Guideline [NG23])
People who have an adverse event
People whose adverse event is prevented by treatment
People who were never going to have an adverse event anyway
Graphics and NNTs are rounded to the nearest integer
These three statistical terms offer three different ways of looking at the results of trial data.
Absolute Risk Reduction
This tells you how many people out of 100 who take a treatment have an adverse event prevented.
MoreThe value of the ARR changes with the baseline risk of the person (or population) taking the treatment. The higher the starting risk, the greater the absolute chance of benefit.
You need to think about over what time the trial data show this benefit, as it is usually assumed that more absolute risk reduction is gained over time.
Your patient might be taking the treatment for much longer than the length of a clinical trial (or, if life expectancy is limited, perhaps for less time).
Number Needed to Treat
This tells you how many people need to take the treatment in order for one person to avoid an adverse event.
The lower the number, the more effective the treatment.
MoreThe value of the NNT changes with the baseline risk of the person (or population) taking the treatment. The higher the starting risk, the smaller the NNT.
You need to think about over what time the trial data show benefit, as it is usually assumed that more benefit is gained over time and therefore the NNT will drop over time.
Your patient might be taking the treatment for much longer than the length of a clinical trial (or, if life expectancy is limited, perhaps for less time).
Relative Risk Reduction
This tells you the proportion of adverse events that are avoided if the entire population at risk is treated.
MoreThe value of the RRR is usually constant in people (or populations) at varying degrees of risk.
It is also usually assumed to stay constant over time.
This can be helpful, especially when thinking about population outcomes, but can be misleading for an individual person:
For example, a RRR of 25% in someone with a baseline risk of 40% would give them an ARR of 10% and an NNT of 10.
A RRR of 25% in someone with a baseline risk of 4% would give them an ARR or 1% and an NNT of 100.
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If you are a patient/member of the public, do feel free to look around, but please don’t make any changes to your treatments based on information here. If you find something which seems relevant to you, you could show this website to your healthcare professional to help a discussion.