2024更新—2015 NICE指南：更年期的诊断和管理（NG.23）

指南内分泌与代谢· 其他内分泌疾病 · 2024

Menopause: identification and management

Your responsibility

Abstract

The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals and practitioners are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or the people using their service.

It is not mandatory to apply the recommendations, and the guideline does not override the responsibility to make decisions appropriate to the circumstances of the individual, in consultation with them and their families and carers or guardian.

All problems (adverse events) related to a medicine or medical device used for treatment or in a procedure should be reported to the Medicines and Healthcare products Regulatory Agency using the Yellow Card Scheme.

Local commissioners and providers of healthcare have a responsibility to enable the guideline to be applied when individual professionals and people using services wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with complying with those duties.

Commissioners and providers have a responsibility to promote an environmentally sustainable health and care system and should assess and reduce the environmental impact of implementing NICE recommendations wherever possible.

Menopause: identification and management (NG23)

Recommendations

People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.

NICE guidelines set out the care and services suitable for people with a specific condition or need, and people in particular circumstances or settings. We aim to improve quality by ensuring that people receive the best care and advice. Using inclusive language in healthcare is important for safety, and to promote equity, respect and effective communication with everyone. Some recommendations in this guideline do not use inclusive language because:

• the evidence has not been reviewed, and expert opinion is that groups covered by these recommendations cannot be extended or

• the evidence has been reviewed, but the information available for some groups was too limited to make specific recommendations.

Healthcare professionals should use their clinical judgement when implementing the recommendations, taking into account each person's circumstances, needs and preferences, and ensuring all people are treated with dignity and respect throughout their care.

Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. This guideline covers women, trans men and non-binary people registered female at birth, who currently have menopause-associated symptoms or who will experience menopause in the future. The guideline does not cover people who are currently having genderaffirming hormone therapy. For trans men and non-binary people who have taken such therapy in the past and are no longer taking it, only recommendations 1.5.34 and 1.5.35 in the section on gender affirming therapy and the recommendation for research on the Menopause: identification and management (NG23) impact of hormone replacement therapy (HRT) on health outcomes for these groups of people apply. All other recommendations apply to women, trans men and non-binary people registered female at birth who have never taken gender-affirming hormone therapy.

1.1 Individualised care 1.1.1 Tailor your approach to the person at all times when identifying, discussing, investigating and managing menopause, and adapt the approach if symptoms change over time. Follow the recommendations in NICE's guideline on patient experience in adult NHS services. [2015]

1.1.2

For general principles on how to discuss symptom management plans with people, including how to communicate risks, benefits and consequences, see NICE's guideline on shared decision making. Share information about menopause with people who have associated symptoms or are approaching menopause, and their family members or carers (as appropriate). This information should include all of the following:

• what menopause is, including that it is a life transition which:

usually takes place in mid-life and can also happen earlier because of surgery or medical treatment, an inherited condition, or an unknown cause

• commonly associated symptoms (see recommendation 1.2.2)

• interventions, or changes the person can make to support their health and wellbeing. [2015, amended 2024]

1.2.2

Explain that symptoms associated with menopause may vary from minor to severe and be experienced over short or long time periods. As well as changes in menstrual cycle, symptoms may include:

• vasomotor symptoms (hot flushes and sweats)

• genitourinary symptoms (for example, vaginal dryness)

• effects on mood (for example, depressive symptoms)

• musculoskeletal symptoms (for example, joint and muscle pain)

• sexual difficulties (for example, low sexual desire).

[2015]

1.2.3

Share information about contraception with people who have menopauseassociated symptoms. See, for example, the Faculty of Sexual and Reproductive Healthcare guidance on contraception for women aged over 40 years.

1.2.4

Give advice on bone health to people experiencing menopause and discuss bone health with them at review appointments (see NICE's guideline on assessing the risk of fragility fracture in people with osteoporosis). Psychological support for early menopause 1.2.7 Offer psychological support to people who are experiencing early menopause (that is, menopause between the ages of 40 and 44) and are distressed by their diagnosis or its consequences. If needed, refer them to psychology services.

[2024]

For a short explanation of why the committee made the 2024 recommendation and how it might affect practice, see rationale and impact section on psychological support for early menopause.

Full details of the evidence and the committee's discussion are in evidence review I:

early menopause.

1.3 Identifying perimenopause and menopause

1.3.1

Identify the following, without laboratory tests, in otherwise healthy women, trans men and non-binary people registered female at birth who are aged 45 or over and have menopause-associated symptoms:

• perimenopause, if they have vasomotor symptoms that have recently started and any changes in their menstrual cycle

• menopause, if they have not had a period for at least 12 months and are not using hormonal contraception

• menopause, in those who have had a hysterectomy, based on the type and combination of symptoms they have (for example, vasomotor symptoms).

1.3.2

Take into account that it can be difficult to identify menopause in people who are taking hormonal treatments, for example, for the treatment of heavy menstrual bleeding.

1. 3.3 Be aware that people from some ethnic minority backgrounds and people with some lifelong conditions may experience menopause at a younger age. Do not use a follicle-stimulating hormone (FSH) blood test to identify menopause in people using combined oestrogen and progestogen contraception or highdose progestogen.

1.3.6

Consider using the person's serum FSH level to confirm menopause only:

• in people aged 40 to 45 with menopause-associated symptoms, including a change in their menstrual cycle

• in people under 40 in whom menopause is suspected (see also diagnosing and managing premature ovarian insufficiency).

See also the recommendations on offering psychological support to:

• people experiencing early menopause (aged 40 to 44)and

• people with premature ovarian insufficiency.

For a short explanation of why the committee made the 2024 recommendation and how it might affect practice, see the rationale and impact section on identifying perimenopause and menopause.

Full details of the evidence and the committee's discussion are in evidence review I: early menopause.

1.4 Discussing management options with people aged 40 or over

diagnosing and managing premature ovarian insufficiency, including what to discuss with the person.

1.4.1

Discuss with the person the benefits and risks associated with each potential management option for menopause-associated symptoms.

Hormone replacement therapy

1.4.2

When discussing hormone replacement therapy (HRT) as a possible treatment for menopause-associated symptoms (in line with the recommendations on managing symptoms associated with menopause in people aged 40 and over), talk about the benefits and risks associated with:

• combined versus oestrogen-only HRT (see the recommendation and its rationale on indications for combined and oestrogen-only HRT, in the section on starting HRT about which of the 2 types of HRT the person would be offered, and why)

• transdermal versus oral HRT

• types of oestrogen and progestogen

• sequential versus continuous combined HRT

• dose and duration.

Tailor the information about benefits and risks to the person's age, individual circumstances and potential risk factors. Use the information in managing symptoms associated with menopause in people aged 40 or over, and in the effect of HRT on specific health outcomes in people aged 40 or over to support this discussion. 1.4.3 If a person chooses to take HRT:

• discuss the possible duration of treatment at the outset • at every review, rediscuss the benefits and risks of continuing treatment (see the section on reviewing treatment for anyone)

• explain that symptoms may return when HRT is stopped and discuss the option of restarting treatment if necessary.

Cognitive behavioural therapy 1.4.4 When discussing cognitive behavioural therapy (CBT) as a possible management option for symptoms associated with menopause, explain what CBT is (including menopause-specific CBT) and talk about the available options, taking into account the person's preferences and needs, for example:

• face-to-face or remote sessions

• individual or group sessions

• self-help options.

For a short explanation of why the committee made the 2024 recommendations and how they might affect practice, see the rationale and impact section on discussing management options with people aged 40 or over.

Full details of the evidence and the committee's discussion are in:

• evidence review A: cognitive behavioural therapy

• evidence review B1: managing genitourinary symptoms (network meta-analyses)

• evidence review D: breast cancer

• evidence review I: early menopause.

Complementary therapies and unregulated preparations

1.4.5

Explain to people with menopause-associated symptoms that the efficacy and safety of unregulated hormone preparations are unknown.

Page 12 of 105 1.4.6

Explain to people who wish to try complementary therapies for menopauseassociated symptoms, that the safety, quality and purity of constituents in unregulated preparations may be unknown.

1.4.7

Explain to people that there is some evidence that isoflavones or black cohosh may relieve vasomotor symptoms associated with menopause. However, explain that:

• multiple preparations are available, and their safety is uncertain

• different preparations may vary

• interactions with other medicines have been reported.

1.4.8

Advise people with a personal history of, or at high risk of, breast cancer that, although there is some evidence that St John's wort may help relieve vasomotor symptoms associated with menopause, there is uncertainty about:

• appropriate dosage

• persistence of effect

• variation in the nature and potency of preparations

• potential serious interactions with other medicines (including tamoxifen, anticoagulants and anticonvulsants).

1.5 Managing symptoms associated with menopause in people aged 40 or over

This section only covers people aged 40 or over. For younger (aged under 40) women, trans men, and non-binary people registered female at birth, see the recommendations on diagnosing and managing premature ovarian insufficiency.

For information about how comorbidities, contraindications and medical history might affect management choices, see taking medical history into account before offering treatment.

Page 13 of 105

The benefits and risks of hormone replacement therapy (HRT) described in this guideline only cover the use of HRT within the licensed dosages.

Making decisions using NICE guidelines has information about prescribing medicines.

Vasomotor symptoms

1.5.1

Offer HRT to people with vasomotor symptoms associated with menopause.

1.5.2

Consider menopause-specific cognitive behavioural therapy (CBT) as an option for vasomotor symptoms associated with menopause:

• in addition to HRT or

• for people for whom HRT is contraindicated or

• for those who prefer not to take HRT.

1.5.3

Do not routinely offer selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs) or clonidine as first-line treatment for vasomotor symptoms alone.

For a short explanation of why the committee made the 2024 recommendation on CBT and how it might affect practice, see the rationale and impact section on CBT for vasomotor symptoms.

Full details of the evidence and the committee's discussion are in evidence review A: cognitive behavioural therapy.

Genitourinary symptoms associated with menopause

People with no history of breast cancer

1.5.4

Offer vaginal oestrogen to people with genitourinary symptoms associated with Menopause: identification and management (NG23) menopause (including those using systemic HRT) and review regularly as per the recommendations on reviews in this guideline.

1.5.5

When discussing the option of vaginal oestrogen, explain that:

• serious adverse effects are very rare

• their treatment should be reviewed in line with recommendations 1.9.2 and 1.9.3 in the section on reviewing treatment

• symptoms often return when vaginal oestrogen is stopped but treatment can be restarted if necessary

• vaginal oestrogen is absorbed locally -a minimal amount is absorbed into the bloodstream (when compared with systemic HRT), but this is unlikely to have a significant effect throughout the body.

1.5.6

When someone chooses vaginal oestrogen, make a shared decision with the person about whether to use an oestrogen cream, gel, tablet, pessary or ring.

1.5.7

Advise people with genitourinary symptoms associated with menopause that vaginal oestrogen can be used on its own or in combination with non-hormonal moisturisers or lubricants.

1.5.8

For people with genitourinary symptoms in whom vaginal oestrogen preparations are contraindicated, or for people who would prefer not to use vaginal oestrogen, consider non-hormonal vaginal moisturisers or lubricants.

1.5.9

Consider vaginal prasterone for genitourinary symptoms if vaginal oestrogen, or non-hormonal moisturisers or lubricants have been ineffective or are not tolerated.

1.5.10

Consider ospemifene as an oral treatment for genitourinary symptoms, if the use of locally applied treatments is impractical, for example, because of disability.

1.5.11

For the use of vaginal oestrogen in people with genitourinary symptoms and an overactive bladder, see the section on choosing medicines for an overactive Menopause: identification and management (NG23) For the use of vaginal oestrogen in people with genitourinary symptoms and recurrent urinary tract infections, see the recommendations on oestrogen in NICE's guideline on recurrent urinary tract infection (UTI) and the patient decision aid on reducing the chance of recurrent UTI in postmenopausal women.

For anyone who has been given any treatment for genitourinary symptoms associated with menopause, see the recommendations on reviewing treatment.

For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on genitourinary symptoms associated with menopause in people with no personal history of breast cancer.

Full details of the evidence and the committee's discussion are in evidence review B1: managing genitourinary symptoms (network meta-analyses).

People with a personal history of breast cancer

1.5.13

Offer non-hormonal moisturisers or lubricants to people with a personal history of breast cancer and genitourinary symptoms associated with menopause.

1.5.14

Consider vaginal oestrogen for people with a personal history of breast cancer and genitourinary symptoms that have continued despite trying non-hormonal treatments (see also recommendation 1.5.15 for people receiving adjuvant aromatase inhibitor treatment for breast cancer). Vaginal oestrogen may be used in combination with a non-hormonal moisturiser or a lubricant.

In November 2024, this was an off-label use of vaginal oestrogen. See NICE's information on prescribing medicines.

[2024] When assessing the safety of vaginal oestrogens for someone in relation to breast cancer recurrence, take into account all of the following:

• the person's general risk factors for breast cancer recurrence (see recommendations 1.7.7 and 1.7.8 in NICE's guideline on early and locally advanced breast cancer for the definitions of medium or high risk and of low risk of recurrence)

• it is unknown whether vaginal oestrogen affects the risks of breast cancer recurrence

• vaginal oestrogen is absorbed locally, and some of it is absorbed into the bloodstream but compared with oestrogen from systemic HRT, the amount is minimal.

1.5.17

For people with a personal history of oestrogen receptor negative breast cancer, recognise that any oestrogen systemically absorbed from taking vaginal oestrogen is unlikely to increase the risk of breast cancer recurrence, and so it is likely to be safe.

1.5.18

For people with a personal history of oestrogen receptor positive breast cancer, recognise that:

• it is unknown whether any oestrogen systemically absorbed from taking vaginal oestrogen could increase the risk of breast cancer recurrence and

• adjuvants that block oestrogen receptors in cancer cells (for example, tamoxifen) would reduce any such potential impact.

Menopause: identification and management (NG23) For a short explanation of why the committee made the 2024 recommendations and how they might affect practice, see the rationale and impact section on genitourinary symptoms associated with menopause in people with a personal history of breast cancer.

Full details of the evidence and the committee's decision are in evidence review B2: managing genitourinary symptoms (breast cancer recurrence).

Vaginal laser treatment For a short explanation of why the committee made the 2024 recommendation and how it might affect practice, see the rationale and impact section on vaginal laser treatment.

Full details of the evidence and the committee's discussion are in evidence review B2: managing genitourinary symptoms (breast cancer recurrence). Consider CBT as an option for people who have depressive symptoms (not meeting the criteria for a diagnosis of depression) in association with vasomotor symptoms:

Depressive symptoms

• in addition to other management options or

• for people for whom other options are contraindicated or

• for those who prefer not to try other options.

1.5.22

For people experiencing menopause who are suspected to have or have been diagnosed with depression, follow the recommendations in this guideline alongside the recommendations in NICE's guideline on treating and managing depression in adults to achieve an optimal management plan.

For a short explanation of why the committee made the 2024 recommendations and how they might affect practice, see the rationale and impact section on management options for depressive symptoms or depression in people with menopause-associated symptoms.

Sleep

1.5.23

Consider menopause-specific CBT as an option for people who have sleep problems (such as night-time awakening) in association with vasomotor symptoms:

• in addition to other management options (including HRT) or

• for people who prefer not to try other options.

For a short explanation of why the committee made the 2024 recommendation and how it might affect practice, see the rationale and impact section on CBT for sleep problems associated with menopause.

Altered sexual function Taking medical history into account before offering treatment for menopause associated symptoms

In this guideline, medical history covers both personal history and family history (for example, of breast cancer).

1.5.25

Consider referring people to a healthcare professional with expertise in menopause if:

• they have symptoms associated with menopause and contraindications to HRT or

• there is uncertainty about the most suitable management options for their symptoms.

Type 2 diabetes In November 2024, use of combined or oestrogen-only HRT in people with active or recent arterial thromboembolic disease was off-label. See NICE's information on prescribing medicines.

For a short explanation of why the committee made the 2024 recommendation and how it might affect practice, see the rationale and impact section on taking coronary heart disease or stroke into account before offering treatment.

Full details of the evidence and the committee's discussion are in evidence review C: cardiovascular disease and stroke.

Personal history of breast cancer or high risk of breast cancer

1.5.30

Offer people with menopause-associated symptoms and who have a personal history, or are at high risk, of breast cancer:

• information on all management options available to them

• referral to a healthcare professional with expertise in menopause. [2015,

amended 2024]

1.5.31

For advice on the treatment of menopause-associated symptoms in people with a personal history of breast cancer or at high risk of breast cancer, see the section on menopause symptoms in NICE's guideline on early and locally advanced breast cancer and the section on risk reduction and treatment strategies in NICE's guideline on familial breast cancer.

Also see the section on complementary therapy and unregulated preparations in this guideline.

High familial risk of ovarian cancer

See the section on HRT after risk-reducing surgery in NICE's guideline on identifying and managing familial and genetic risk of ovarian cancer.

Planned medical or surgical treatment that is likely to result in menopause 1.5.32 Offer people who are likely to experience menopause as a result of medical or surgical treatment the opportunity to discuss fertility, both before and after they have their treatment, with a healthcare professional with expertise in fertility.

[2015, amended 2024]

1.5.33

Offer people who are likely to experience menopause as a result of medical or surgical treatment the opportunity to discuss menopause, both before and after they have their treatment, with a healthcare professional with expertise in menopause. [2015, amended 2024]

Gender-affirming hormone therapy: past use

1.5.34

Ensure that trans men or non-binary people registered female at birth who have taken gender-affirming hormone therapy in the past and have symptoms associated with menopause can discuss these with a healthcare professional with expertise in menopause.

1.5.35

Consider menopause-specific CBT for vasomotor symptoms, difficulties with sleep or depressive symptoms associated with menopause for trans men and non-binary people registered female at birth who have taken gender-affirming hormone therapy in the past. CBT could be used:

Menopause: identification and management (NG23) For a short explanation of why the committee made the 2024 recommendations and how they might affect practice, see the rationale and impact section on managing menopause in people who have taken gender-affirming hormone therapy in the past.

1.6 Effects of hormone replacement therapy on specific health outcomes in people aged 40 or over

See the recommendation for people in early menopause (ages 40 to 44), for information on the effect of either taking or not taking HRT in early menopause on specific health outcomes.

People aged 45 or over

1.6.1

When discussing HRT as a treatment option for menopause-associated symptoms, explain that, overall, taking either combined HRT or oestrogen-only HRT is unlikely to affect life expectancy.

For a short explanation of why the committee made the 2024 recommendation and how it might affect practice, see the rationale and impact section on effect of HRT on life expectancy in people aged 45 or over.

Full details of the evidence and the committee's discussion are in evidence review H: all-cause mortality.

Combined HRT

This recommendation is for people with a uterus (see recommendation 1.8.1 on what type of HRT to offer).

1.6.2

When talking about combined HRT as a treatment option:

• discuss different combined HRT options to identify the one that best balances benefits and risks for the person

• share information from table 1: effect of combined HRT versus no HRT on specific health outcomes

• refer to the discussion aid on HRT and the likelihood of some medical conditions to provide information on the extent of benefits and risks associated with HRT.

Oestrogen-only HRT

This recommendation is for people who have had a total hysterectomy (see recommendation 1.8.1 on what type of HRT to offer).

1.6.3

When talking about oestrogen-only HRT as a treatment option:

• discuss different oestrogen-only HRT options to identify the one that best balances benefits and risks for the person

• share information from table 2: effect of oestrogen-only HRT versus no HRT on specific health outcomes

• recommendation on discussing benefits and risks of HRT, including the need to tailor the treatment to the person's age, personal circumstances and potential risk factors and

• section on communicating risks, benefits and consequences (including how to discuss numerical information) in NICE's guideline on shared decision making. people over a 5-year period).

Type 2 diabetes -

The risk of developing type 2 diabetes does not increase with HRT.

Generally, no adverse effect on blood glucose control is reported when taking HRT.

The risk is not affected whether HRT is taken orally or transdermally.

Venous thromboembolism (VTE)

-VTE risk is not increased with transdermal HRT.

VTE risk is increased with oral HRT.

VTE risk is greater with oral than transdermal

HRT. [2015]

-Table 2 lists the differences in specific health outcomes between people who are taking or have taken oestrogen-only HRT, and those who have never had HRT.

The statements from 2015 in tables 1 and 2 do not distinguish between combined and oestrogen-only HRT. These statements have been included in both tables to better support discussions.

Page 41 of 105

For a short explanation of why the committee made the 2024 recommendation and how it might affect practice, see the rationale and impact section on effect of oestrogen-only HRT on specific health outcomes in people aged 45 or over.

Cardiovascular disease prevention

1.6.4

Do not offer combined or oestrogen-only HRT for primary or secondary prevention of cardiovascular disease. For guidance on ways to reduce the risk of cardiovascular disease (for example, lifestyle changes), refer to NICE's guideline on cardiovascular disease: risk assessment and reduction, including lipid modification.

For a short explanation of why the committee made the 2024 recommendation and how it might affect practice, see the rationale and impact section on cardiovascular disease prevention.

Dementia prevention

1.6.5

Do not offer combined or oestrogen-only HRT for the purpose of dementia and frailty in later life -mid-life approaches to delay or prevent onset.

For a short explanation of why the committee made the 2024 recommendation and how it might affect practice, see the rationale and impact section on dementia prevention.

People in early menopause (ages 40 to 44)

1.6.6

When discussing HRT as a treatment option, explain to people experiencing early menopause that, for them, the benefits and risks of either taking or not taking HRT are likely to lie between those for people with premature ovarian insufficiency and those for people aged 45 or over.

See also the recommendations on discussing benefits and risks in the section on HRT and managing symptoms associated with menopause for people aged 40 and over, including the need to tailor the treatment to the person's age, personal circumstances and potential risk factors.

For a short explanation of why the committee made the 2024 recommendation and how it might affect practice, see the rationale and impact section on effects of HRT in early menopause on specific health outcomes.

1.7 Diagnosing and managing premature ovarian insufficiency in people under 40

Diagnosing premature ovarian insufficiency

1.7.1

Take into account the person's clinical history (for example, previous medical or surgical treatment) and family history when diagnosing premature ovarian insufficiency.

1.7.2

Diagnose premature ovarian insufficiency in women, trans men and non-binary people registered female at birth who are under 40 based on:

• menopause-associated symptoms, including no or infrequent periods (taking into account whether the person has had a hysterectomy) and

• elevated follicle stimulating hormone (FSH) levels on 2 blood samples taken 4 to 6 weeks apart. If there is doubt about the diagnosis of premature ovarian insufficiency, refer the person to a specialist with expertise in menopause or reproductive medicine.

Managing premature ovarian insufficiency

1.7.6

Offer sex steroid replacement with a choice of hormone replacement therapy (HRT) or a combined hormonal contraceptive to people with premature ovarian insufficiency, unless contraindicated (for example, in people with hormonesensitive cancer).

1.7.7

Explain to people with premature ovarian insufficiency:

Menopause: identification and management (NG23) Consider referring people with premature ovarian insufficiency to healthcare professionals with the relevant experience to help them manage all aspects of physical and psychosocial health related to their condition.

1.8 Starting and stopping hormone replacement therapy for anyone

Starting HRT

1.8.1

For people who wish to take hormone replacement therapy (HRT) for symptoms associated with menopause:

• offer combined HRT to people with a uterus Explain to people with a uterus that vaginal bleeding is a common side effect of systemic HRT within the first 3 months of treatment, and they will be asked about this during their 3-month review. Advise them to seek medical help promptly if they experience vaginal bleeding after 3 months.

Stopping HRT

1.8.5

Offer people who are stopping HRT a choice of gradually reducing or immediately stopping treatment.

1.8.6

Explain to people that:

• gradually reducing HRT may limit recurrence of symptoms in the short term

• gradually reducing or immediately stopping HRT makes no difference to their symptoms in the longer term.

1.8.7

Stop systemic HRT in people who are diagnosed with breast cancer in line with the recommendations on menopause symptoms in NICE's guideline on early and locally advanced breast cancer.

For a short explanation of why the committee made the 2024 recommendation and how it might affect practice, see the rationale and impact section on starting and stopping HRT for anyone.

• evidence review D: breast cancer risk

• evidence review E: endometrial cancer risk.

Menopause: identification and management (NG23) Review each treatment for symptoms associated with menopause:

• at 3 months to assess efficacy and tolerability

• annually thereafter, unless there are clinical indications for an earlier review (such as treatment ineffectiveness, side effects or adverse events).

1.9.3

Refer people to a healthcare professional with expertise in menopause if treatments do not improve their menopause-associated symptoms or they have ongoing side effects.

Terms used in this guideline

This section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.

Hormone replacement therapy (HRT) with oestrogen and progestogen.

Continuous combined HRT

HRT in which oestrogen and progestogen are taken together, daily.

For the purposes of this guideline, depressive symptoms are any symptoms included in the • depression, as defined by ICD-11 or DSM-5 or

• chronic depressive symptoms, as defined in NICE's guideline on managing and treating depression in adults.

Genitourinary symptoms associated with menopause include vulvovaginal dryness, pain with sex, vulvovaginal discomfort or irritation, and discomfort or pain when urinating.

Healthcare professional with expertise in menopause

Healthcare professionals with specialist knowledge, skills and training who can (in collaboration with the relevant specialists) manage, or advise colleagues in managing, complex menopause-related needs and risk factors affecting decision making, including:

• complex medical problems that potentially affect use of treatments for menopause associated symptoms

• menopause associated symptoms for those at elevated risk of breast or ovarian cancer, or with a personal history of hormone dependent cancer.

Their training should be recognised by a professional body such as the British Menopause Society, the Faculty of Sexual and Reproductive Healthcare or the Royal College of Obstetricians and Gynaecologists.

Sequential combined HRT

Sometimes also referred to as combined cyclical HRT. A form of HRT in which oestrogen is taken every day, and the progestogen is taken for usually half of the month.

Systemic HRT

HRT in which the hormones are absorbed into the bloodstream and have an effect throughout the body. As part of systemic HRT:

• oestrogen can be taken orally, or transdermally, as a patch, gel or spray that delivers the hormone through the skin Menopause: identification and management (NG23) • progestogen can be taken orally, transdermally as a patch, or be delivered through an intrauterine system.

Recommendations for research

The guideline committee has made the following recommendations for research.

Key recommendations for research 1 Impact of HRT on health outcomes in early menopause

What is the effect of either taking or not taking hormone replacement therapy (HRT) on health outcomes for people experiencing early menopause (aged 40 to 44)? [2024]

For a short explanation of why the committee made this recommendation for research, see the rationale section on effects of HRT use in early menopause on specific health outcomes.

Full details of the evidence and the committee's discussion are in evidence review I: early menopause. For a short explanation of why the committee made this recommendation for research, see the rationale section on effect of combined HRT on specific health outcomes in people aged 45 or over.

• evidence review E: endometrial cancer. For a short explanation of why the committee made this recommendation for research, see the rationale section on effect of combined HRT on specific health outcomes in people aged 45 or over.

3 Mode of administration of HRT

• evidence review E: endometrial cancer. For a short explanation of why the committee made this recommendation for research, see the rationale section on effect of oestrogen-only HRT on specific health outcomes in people aged 45 or over.

Oestrogen-only HRT

• evidence review E: endometrial cancer.

4 Safety of vaginal oestrogen use for longer than 12 months

What is the safety of vaginal oestrogen use for longer than 12 months? [2024]

For a short explanation of why the committee made this recommendation for research, see the rationale section on genitourinary symptoms associated with menopause in people with no personal history of breast cancer.

Full details of the evidence and the committee's discussion are in evidence review B1:

managing genitourinary symptoms (network meta-analyses).

5 Safety of vaginal oestrogen in terms of breast cancer recurrence

For people with a personal history of breast cancer, or at high familial or genetic risk of breast cancer, does vaginal oestrogen for genitourinary symptoms associated with menopause increase the risk of recurrence or incidence of breast cancer? [2024]

Menopause: identification and management (NG23) For a short explanation of why the committee made this recommendation for research, see the rationale section on genitourinary symptoms associated with menopause in people with a personal history of breast cancer.

Full details of the evidence and the committee's discussion are in in evidence review B2: managing genitourinary symptoms (breast cancer recurrence).

6 Impact of timing of HRT for menopause-associated symptoms on risk of coronary heart disease

Combined HRT

Does the person's age at menopause or the time between the person's menopause and their first use of HRT affect the long-term risk of coronary heart disease in people who take or have taken combined HRT? [2024]

For a short explanation of why the committee made this recommendation for research, see the rationale section on effect of combined HRT on specific health outcomes in people aged 45 or over.

Full details of the evidence and the committee's discussion are in evidence review C: cardiovascular disease and stroke. For a short explanation of why the committee made this recommendation for research, see the rationale section on effect of oestrogen-only HRT on specific health outcomes in people aged 45 or over.

7 Vaginal laser treatment for genitourinary symptoms associated with menopause

What is the safety and efficacy of vaginal laser treatment for genitourinary symptoms associated with menopause? [2024]

For a short explanation of why the committee made this recommendation for research, see the rationale section on vaginal laser treatment.

8 Impact of HRT on health outcomes for trans men and nonbinary people registered female at birth (who are not taking gender-affirming hormone therapy at the time of taking HRT or in the follow-up period)

What is the impact of HRT on health outcomes for trans men and non-binary people registered female at birth (who are not taking gender-affirming hormone therapy at the time of taking HRT or in the follow-up period) in relation to:

• cardiovascular disease For a short explanation of why the committee made this recommendation for research, see the rationale section on managing menopause in people who have taken gender-affirming hormone therapy in the past.

9 Impact of HRT on health outcomes for people from ethnic minority backgrounds

What is the impact of HRT on health outcomes for people from ethnic minority backgrounds in relation to:

• cardiovascular disease

• stroke

• breast, endometrial and ovarian cancer

• dementia

• all-cause mortality? [2024]

For a short explanation of why the committee made this recommendation for research, see the rationale section on effects of combined HRT on specific health outcomes in people aged 45 or over.

Full details of the evidence and the committee's discussion are in evidence review C: Menopause: identification and management (NG23)

Rationale and impact

These sections briefly explain why the committee made the recommendations and how they might affect practice.

Psychological support for early menopause

Recommendation 1.2.7

In the committee's experience, some people can be distressed by going through menopause at an earlier age than expected and earlier than their peers. If someone is experiencing emotional distress to a level that raises concerns, the committee agreed that they may need to be referred to psychology services.

How the recommendation might affect practice

It is common practice to provide psychological support to this group of people. While a potential referral will have a resource impact, support from psychology services will lead to improvements in quality of life and reduce future contacts with health services.

Return to recommendation

Identifying perimenopause and menopause

Recommendation 1.3.3

Evidence is lacking on the average age of menopause in people from ethnic minority backgrounds. However, the committee was aware, from experience, that people from some ethnic minority groups, and people with some lifelong conditions (for example, Down's syndrome), experience menopause at a younger age. The committee agreed it was important to raise awareness of this so that healthcare professionals can more easily Menopause: identification and management (NG23) identify symptoms of menopause in ethnic minority populations or in people with lifelong conditions.

The recommendation will raise awareness that people from some ethnic minority groups, and those with some lifelong conditions, experience menopause at a younger age. It is unclear whether this will change clinical practice, but it might lead to earlier identification of menopause and earlier management of menopause symptoms.

Discussing management options with people aged 40 or over

Recommendations 1.4.1 to 1.4.4

Why the committee made the recommendations

Based on experience, the committee agreed that these basic principles of care would allow people to make an informed choice about management options:

• using an individualised approach with discussions about benefits and risks of any management option and

• tailoring information to individual circumstances and potential risk factors.

Hormone replacement therapy

The committee noted there are different ways of prescribing hormone replacement therapy (HRT) in terms of mode of administration, types of hormones, schedule, and individualised dose and duration. All these options influence benefits and risks so the best combination of them differs from one person to another and should be carefully chosen with, and for, each person. The committee agreed that clinicians should provide and discuss information about all this so that the person can take an active part in shared decision making.

Managing menopause-associated symptoms in people who have taken gender-affirming hormone therapy in the past

Recommendations 1.5.34 and 1.5.35

The committee noted a lack of evidence on HRT use in trans men and non-binary people registered female at birth who have taken gender-affirming hormone therapy in the past.

This uncertainty means that, for example, it is not known whether past hormone treatment could influence the choice of HRT, or whether giving HRT to someone who previously had hormone therapy would alter their health risks. For this reason, the committee agreed that trans men and non-binary people registered female at birth who have taken genderaffirming hormone therapy in the past should be able to discuss their menopauseassociated symptoms with a healthcare professional with expertise in menopause. They can then make a shared decision about any potential treatment the person may wish to have. Because of the lack of evidence, the committee also made a recommendation for research on the impact of HRT on health outcomes for trans men and non-binary people registered female at birth, which covers people who have never taken gender-affirming hormone therapy, or who have taken it in the past but are not currently taking it.

The committee discussed the evidence related to CBT. This did not include evidence related to trans men or non-binary people registered female at birth. However, the committee agreed that the use of CBT for menopause symptoms would be suitable for any person, regardless of whether they have taken gender-affirming hormone therapy in the past.

The committee decided to make a specific recommendation for trans men and non-binary people registered female at birth who have taken gender-affirming hormone therapy in the past to promote equality in access to CBT services for managing menopause-associated symptoms within these groups, acknowledging their unique experiences and needs.

Because, without further evidence, other recommendations in this guideline cannot be extended to these groups, the committee agreed that a separate recommendation would highlight CBT as a management option for these groups.

In the committee's experience, there is no clear current practice related to the treatment of menopause-associated symptoms in people who have taken gender-affirming hormone therapy in the past. The committee agreed that access to both advice from a healthcare professional with expertise in menopause and to CBT were a matter of equality and inclusivity.

Menopause: identification and management (NG23) The recommendations may increase the number of referrals both to healthcare professionals with expertise in menopause, and for CBT. The committee noted that there is pressure on services providing CBT. However, the recommendations should also lead to more appropriate care and improved outcomes for people who have had gender-affirming hormone therapy in the past.

Effect of HRT on life expectancy in people aged 45 and over

Recommendation 1.6.1

The committee discussed the evidence on the impact of HRT on all-cause mortality (life expectancy). The multitude of confounding factors that may affect life expectancy meant that evidence had to be restricted to randomised controlled trials (RCTs). This is because, in RCTs, participants are randomly assigned to different treatment groups, which helps control known and unknown confounders.

The committee noted that high-quality evidence showed no difference in mortality with either oestrogen-only or combined HRT compared with not taking HRT. They agreed that this was an important finding and therefore emphasised the need to tell people thinking about either treatment option that taking combined or oestrogen-only HRT is unlikely to affect life expectancy.

The committee looked at the analysis for groups of women starting HRT at different ages.

They noted that, for most age groups, there was no difference in mortality between those who are taking or have taken HRT compared with placebo. There was also no significant variation in this difference depending on the age of starting HRT.

A decrease in all-cause mortality was reported for 1 isolated subgroup (women starting oestrogen-only HRT aged between 50 and 59). In isolation, this was a statistically significant figure. But in a wider context, it cannot be interpreted as good evidence of a different effect in this group. This is because:

• there was no identifiable pattern of change in risk as people aged and

• the statistical analysis showed that any differences observed between age groups could be down to random chance and therefore did not represent a real difference between age groups.

As a result, the committee did not refer to this decrease in all-cause mortality in the recommendation.

It is current practice to discuss benefits and risks with people when treatment options are being considered. The effect of treatment on life expectancy is an important part of these discussions and was not covered in the previous version of this guideline. The recommendations will standardise the information that will be given. But it is unclear how this will change the treatment choices made and how this will impact on practice.

Effect of combined HRT on specific health outcomes in people aged 45 or over

Recommendation 1.6.2 and table 1

What this rationale covers

The committee highlighted the importance of presenting people with a complete picture of benefits and risks associated with HRT to enable shared and informed decision making.

This rationale briefly describes the available evidence on combined HRT and how it affects risks related to:

• cancer: breast • stroke

• dementia.

It also covers other considerations related to cardiovascular disease, and the need for further research in this area.

There was no evidence available for trans men and non-binary people registered female at birth. The committee agreed that their conclusion from the available evidence could be extended to those who have never taken gender-affirming hormone therapy. But they did not think it could be extended to those who have taken this type of therapy in the past, because it is not known whether such therapy would alter the benefits and risks of any treatment (especially hormonal treatments), or which treatment option might be best for the person. So, they made a recommendation for research on the impact of HRT on health outcomes for these groups. Combined and oestrogen-only HRT are prescribed to different groups of people, and so the committee looked separately at the benefits and risks associated with the 2 types of HRT.

Why the committee made this recommendation

Cancer: breast

In line with other NICE guidance, the committee agreed that advice needs to be tailored to the person according to their individual risk factors, such as having a family history of breast cancer, living with overweight, or drinking alcohol. The committee acknowledged that people also need to be made aware that these factors will affect absolute risks of breast cancer both when not taking and when taking HRT.

The committee discussed evidence on the effect of taking HRT on breast cancer incidence and breast cancer-related mortality that came from:

• randomised controlled trials (RCTs) and

• a meta-analysis of individual patient data from observational studies.

Overall, it showed the risk of breast cancer incidence was consistently greater with combined HRT than with oestrogen-only HRT. The committee therefore looked in more detail at how combined HRT or oestrogen-only HRT each might affect the risk of breast cancer.

RCT evidence

Evidence from RCTs showed an increased risk of breast cancer incidence for women who are taking or have taken combined HRT compared with women taking placebo. The group included in the trial took combined HRT for approximately 6 years and was followed up for breast cancer for about 7 years after the trial ended.

The evidence showed that, with combined HRT, breast cancer risk was increased regardless of ethnicity or whether there was a family history of breast cancer.

Observational study evidence

Evidence from observational studies was consistent with evidence from the RCTs but provided further information on the duration and recency of use. It showed that, for women who were taking combined HRT, the risk of breast cancer incidence:

• was higher than in those who did not take HRT

• started increasing in the first year of use

• increased with duration of use.

For women who had taken combined HRT in the past, it showed that the risk of breast cancer incidence:

• remained higher than for women who did not take HRT

• was greater the longer women had used combined HRT

• reduced after stopping HRT but was still increased for as long as at least 10 years after stopping use.

The evidence showed that breast cancer risk with sequential combined HRT is lower than with continuous combined HRT but is higher than without HRT. The committee therefore decided that this should be discussed as part of shared decision making so that people can make an informed choice.

All types of progestogen were associated with an increased risk of breast cancer incidence, although there was limited evidence on the risk of breast cancer incidence with micronised progesterone or dydrogesterone. Overall, there was insufficient evidence to Menopause: identification and management (NG23)

Page 77 of 105 say whether micronised progesterone or dydrogesterone may lead to a different risk of breast cancer incidence and therefore the committee made a recommendation for research on whether different types of progestogen in HRT alter breast cancer risk.

It was unclear from the evidence whether, for people who take HRT, the risk of breast cancer changes with the mode of administration. The committee therefore made a recommendation for research on modes of administration for systemic HRT.

Mortality related to breast cancer

Both RCT and observational evidence showed that mortality from breast cancer was slightly higher in women who have taken combined HRT than in those who have not taken HRT. The committee agreed that a difference in breast cancer mortality would be consistent with an increase in breast cancer incidence and agreed that this should be explained to people. However, they also emphasised that the difference in risk:

• is very small between those who have taken HRT and those who have not and

• should be thought about within the wider context, in that there is no overall change in life expectancy with HRT.

Cancer: endometrial

The committee discussed evidence from RCTs and observational studies.

Some of the RCT evidence showed that using continuous combined HRT decreased the risk of endometrial cancer for women taking combined HRT, compared with women not taking HRT.

For women currently taking continuous combined HRT, with any duration of use, some observational studies showed a reduced risk of endometrial cancer while others showed that there was no difference in risk of endometrial cancer compared with women not taking HRT.

The committee discussed the well-established association between oestrogen-only HRT and the risk of endometrial cancer. They agreed it was important to explain to people with a uterus that:

• this is why they would be offered combined HRT as per recommendation 1.8.1 in the section on starting HRT but

• although oestrogen has an adverse effect on the endometrium when used on its own, progestogens counteract this in a dose-dependent manner.

They concluded that continuous combined HRT, where progestogen is taken every day with oestrogen, decreases the risk of endometrial cancer.

Evidence from another observational study showed that sequential combined HRT, when used for 10 years or more, increases the risk of endometrial cancer, but not when it is used for less than 10 years. Based on their own knowledge and experience, the committee agreed that the risk is likely to increase slowly over time. They agreed that, with sequential combined HRT, the protective effect of progestogen increases with the number of days on which progestogen is taken every month.

Because the way sequential HRT is taken may vary in duration of use, days of progestogen per cycle, and oestrogen dose, the committee decided to highlight how different sequential HRT regimens and duration of use affect the risk of endometrial cancer.

However, they recognised that, overall, this corresponded to a very slight increase in the absolute risk of endometrial cancer.

Cancer: ovarian

The committee discussed the evidence from RCTs as well as from observational studies.

Overall, evidence from an RCT showed that there were more ovarian cancer cases in people taking combined HRT than in people not taking HRT, but the difference was not statistically significant. The committee noted that the number of people diagnosed with ovarian cancer was very small in both groups and this made the evidence less robust.

The observational evidence showed that the risk of ovarian cancer increased with HRT use. The committee noted that both the number of participants and the number of diagnosed cases of ovarian cancer were far larger in the observational evidence than in the RCT, which made the findings more robust.

However, the committee agreed that, although the risk was increased overall, the risk was small in absolute terms, especially with the low baseline risk of ovarian cancer. Overall, there was an increase in ovarian cancer incidence by 1 in 1,000. The committee agreed that all of this should be explained when HRT is being considered.

Coronary heart disease

The committee based their recommendations on evidence from RCTs and observational studies.

The majority of the RCT and observational evidence both showed that the risk of coronary heart disease did not increase when taking HRT. The committee agreed this information should be shared with people to allow them to make an informed decision.

The committee also discussed the evidence on the possible impact of 2 factors:

• the length of time between menopause and first use of HRT

• duration of HRT use.

They looked at coronary heart disease risk for different subgroups, and at the statistical significance of any differences observed between these subgroups. As a result, they agreed they could not make any recommendations about the impact of either of these factors on coronary heart disease risk in people taking HRT. This is because there were:

• no statistically significant subgroup differences in the RCT evidence and

• inconsistent results between different observational studies.

Findings from the RCT evidence did not all lead to the same conclusions.

For coronary heart disease and cardiac event composite scores, most RCT evidence showed no difference between combined HRT and placebo. This was shown for both continuous and sequential HRT.

However, some isolated results were not in line with this overall trend, but for most of them:

• the isolated results were not statistically significant or

Page 80 of 105

• the difference between the group in which these results were obtained and other subgroups was not statistically significant.

See evidence review C: cardiovascular disease and stroke for further discussion of this.

Mortality related to coronary heart disease

The committee looked at RCT and observational study evidence which showed that, for women with no history of coronary heart disease, there was no increase in mortality from cardiovascular disease from taking HRT. They agreed that it was important for people to know this so they could make an informed choice.

Stroke

The committee based their recommendations on RCTs and observational studies.

Evidence showed a significant difference in risk depending on the mode of administration.

The use of combined HRT does not increase the risk of stroke when the oestrogen component is taken transdermally, but it does increase the risk if it is taken orally. These findings were supported by observational evidence. The committee decided that it was important to share this information so that it could be taken into consideration.

However, national statistics show that the baseline risk for stroke in women aged under 60 is very low. The committee agreed that this should be explained to anyone thinking about HRT because the risk may remain small despite any change in risk reported in the RCT and observational study findings.

The RCTs showed that, overall, there is an increased risk of stroke in women currently taking combined HRT with oral oestrogen.

Evidence on duration of use showed that risk of stroke:

• did not increase when combined HRT was used for up to 4 years but

• increased when combined HRT was taken for 5 to 9 years.

Page 81 of 105

Evidence related to age at starting combined HRT containing oral oestrogen also showed a greater risk of stroke in women currently taking HRT. This risk increased with age at starting HRT (that is, the older people were when they started taking HRT). This was when HRT was taken for 5 to 9 years.

Evidence also showed significant differences in the risk of stroke depending on ethnicity.

Among those taking combined HRT, the risk of stroke was greater in women of Black ethnicity compared with people from other backgrounds, though numbers of people affected by stroke in all ethnic minority groups were small. Because of the small size of the population taking part in the trials, the evidence was not very robust, so the committee reflected this uncertainty by explaining that the risk 'may' be greater for Black people. The committee agreed that all of this should be explained to people from ethnic minority backgrounds to help them reach a decision.

However, the committee did comment on whether the conclusions made in NICE's 2024 evidence review aligned with the findings of these 3 systematic reviews. Although there were differences observed in certain areas, none of them challenged the overall conclusion that HRT does not increase coronary heart disease risk.

Dementia

The committee noted that there was relatively little evidence on dementia compared with other health outcomes, with only 7 studies identified. They acknowledged that most of the evidence was from observational studies and so they very carefully looked at how various confounders had been adjusted for.

The committee agreed that some of the evidence did not make the necessary adjustments for confounding factors, such as socioeconomic status, or did not reliably ascertain incidence of dementia.

To guide their discussions and support the recommendations, the committee agreed to focus on 2 observational studies, 1 from the UK and the other from Denmark (which both made the most appropriate adjustments for confounders). They also focused on the Women's Health Initiative Memory Study (WHIMS) of women starting HRT over the age of 65, which is based on data from an RCT from the Women's Health Initiative (WHI).

Currently, the treatment recommended for vasomotor symptoms associated with menopause is HRT. Access to CBT may address some health inequalities, providing other effective options for those who cannot or do not wish to use pharmacological treatments for menopause symptoms.

Genitourinary symptoms associated with menopause in people with no personal history of breast cancer

Recommendations 1.5.4 to 1.5.12 Menopause: identification and management (NG23)

The committee discussed evidence from network meta-analyses (NMA) which looked at a number of management options for specific subtypes of genitourinary symptoms associated with menopause such as vaginal dryness, pain with sex, and vulvovaginal discomfort or irritation. They also took into account evidence from the health economic model developed for the 2024 update of this guideline.

Evidence showed that vaginal oestrogen (particularly estriol but also oestradiol) was effective in reducing vaginal dryness and pain with sex. Estriol also showed effectiveness in reducing vulvovaginal discomfort or irritation. The economic model conducted for this review showed that vaginal oestrogen was cost-effective.

There was limited evidence on long-term use of vaginal oestrogen preparations. However, the committee acknowledged that efficacy and tolerability would be assessed regularly, as per the recommendations on reviewing treatment.

To gain a better understanding of it, the committee made a recommendation for research on the safety of vaginal oestrogen when used for more than 12 months.

Based on their expertise, the committee agreed that what is known about the safety of long-term use should be taken into account and discussed with the person before offering vaginal oestrogen. They agreed that the following points should also be brought up:

• Serious adverse effects from vaginal oestrogen are rare. For example, the committee was aware of the 2019 Medicines and Healthcare products Regulatory Agency drug safety update on HRT safety advice, which states that there is no evidence of an effect of vaginal oestrogen on breast cancer risk. This was consistent with the findings from the NMA, which showed that discontinuation due to adverse events was relatively low.

• In the committee's experience, people are not always aware that symptoms often return when vaginal oestrogen is stopped.

• Because absorption into the bloodstream is minimal, there is no need to combine vaginal oestrogens with systemic progestogen treatment to protect the person against endometrial hyperplasia and cancer (whereas, with systemic HRT, people with a uterus need progestogen treatment for protection -see the rationale section on starting and stopping HRT).

Preparations were not all shown to be equally effective. However, there were also uncertainties around the differences observed. So, the committee agreed that, overall, it was unlikely that 1 type of vaginal oestrogen preparation would be more effective than another. They concluded that people with genitourinary symptoms associated with menopause should be given different options for vaginal oestrogen preparations so they could choose the 1 they prefer.

The committee thought that people did not always realise that moisturisers or lubricants can be used alone or in addition to vaginal oestrogen and, therefore, thought that this information should be included in discussions about management options.

The NMA suggested that non-hormonal vaginal moisturisers and lubricants were less effective than vaginal oestrogen, but a smaller proportion of people stopped using their treatment when using non-hormonal vaginal moisturisers or lubricants than when using other types of treatments. This may suggest that, when non-hormonal vaginal moisturisers and lubricants worked for a person, the person felt comfortable to keep using them (for example, because these are readily available over the counter options). While the evidence highlighted uncertainty around the effectiveness of non-hormonal moisturisers and lubricants, based on their experience, the committee decided that moisturisers and lubricants could be tried when vaginal oestrogen is contraindicated or not preferred.

The committee discussed the role of vaginal prasterone and oral ospemifene in the management of genitourinary symptoms associated with menopause. They noted that both these medicines are more expensive than vaginal oestrogen, moisturisers or lubricants. However, the NMA showed them to be effective in reducing vaginal dryness and pain with sex but not vulvovaginal discomfort or irritation. They were also seldom discontinued because of adverse events.

The economic model showed vaginal prasterone was not cost-effective as a first-line option. However, given its clinical effectiveness, the committee agreed that it could be Menopause: identification and management (NG23) offered as a second-line management option when other options (vaginal oestrogen, or non-hormonal moisturisers or lubricants) are ineffective for persisting genitourinary symptoms or are not tolerated.

Evidence showed that ospemifene was not cost-effective and could therefore not be recommended as a first-line treatment option for all people with genitourinary symptoms associated with menopause. However, the committee noted that, for some people, local application of vaginal oestrogen may be impractical. For example, people with physical or intellectual disabilities may find it difficult to use local vaginal oestrogen. Ospemifene is an oral tablet and should therefore be considered as an option in such specific circumstances.

The committee was aware that the symptoms of overactive bladder can occur alongside genitourinary symptoms associated with menopause and that vaginal oestrogen can be given in these circumstances. They decided not to include people with a personal history of breast cancer in the recommendation on this because vaginal oestrogen is not the firstline treatment for genitourinary symptoms associated with menopause in this population.

The evidence showed that the most cost-effective option for the treatment of genitourinary symptoms associated with menopause is vaginal oestrogen, which is routinely offered in current practice. The recommendations will standardise practice rather than change it.

Genitourinary symptoms associated with menopause in people with a personal history of breast cancer

Recommendations 1.5.13 to 1.5.18

The committee acknowledged that evidence was sparse, with only 4 studies providing information on breast cancer recurrence in people with a personal history of breast cancer Menopause: identification and management (NG23) taking vaginal hormone treatment for genitourinary symptoms associated with menopause. The committee also had methodological concerns about some of the studies, particularly about:

• how they accounted for confounding factors (including how many factors, which factors and how they accounted for these factors in their analysis of data) and

• duration of follow-up, which was not long enough to capture breast cancer recurrence.

The committee discussed the evidence comparing vaginal oestrogen to no treatment in women with a personal history of breast cancer. Most of the evidence included all women together and so did not distinguish between those who used adjuvant treatment for breast cancer and those who did not. Based on this evidence, it is not possible to say with certainty whether vaginal oestrogen, when used for genitourinary symptoms associated with menopause, leads to any change in breast cancer recurrence or not.

The uncertainties around the evidence also led the committee to agree that:

• The first choice for people with a personal history of breast cancer and genitourinary symptoms associated with menopause should be non-hormonal moisturisers and lubricants.

• Vaginal oestrogen should only be considered as a second-line option, when nonhormonal treatment has not been effective, and symptoms continue to impact negatively on the person's quality of life. The committee noted that people may not realise that non-hormonal moisturisers and lubricants could also be used in combination with vaginal oestrogen, so they agreed to highlight this.

For this reason, the committee agreed that, if vaginal oestrogen is considered for people on aromatase inhibitors as an adjuvant treatment, treatment options should be discussed with a breast cancer specialist (for example, this may include switching to tamoxifen).

The committee noted that treatment decisions would need to be tailored to each person because:

• Some people have a lower risk of breast cancer recurrence than others (as covered by NICE's guideline on early and locally advanced breast cancer). The committee decided that this was an important factor because it is worse to potentially add to the risk of those who already have a high risk than those who have a low risk of recurrence.

• Vaginal oestrogen is absorbed locally. Some of it is absorbed systemically, that is, further into the body, but, compared with systemic HRT, the amount is minimal, and so it may or may not be a sufficient amount to affect breast cancer recurrence. This makes it difficult to assess the safety of vaginal oestrogen with respect to breast cancer recurrence.

There was relatively little evidence for the use of vaginal oestrogen to manage genitourinary symptoms associated with menopause after breast cancer, particularly related to long-term use and use in conjunction with adjuvant therapy. Therefore, the committee made a recommendation for research on the safety of vaginal oestrogen in terms of breast cancer recurrence.

People who carry genetic variants that increase the risk of breast cancer

No evidence on the use of vaginal oestrogen was identified for people who carry genetic variants that increase the risk of breast cancer. The committee therefore decided that it could not make a recommendation but made a recommendation for research on the safety of vaginal oestrogens for people who have a high genetic risk of breast cancer.

The recommendation about the use of non-hormonal treatment options as first-line treatment for people with a personal history of breast cancer and genitourinary symptoms associated with menopause is in line with current practice. There is variation in:

• the clinical factors taken into account when considering local vaginal oestrogens after an ineffective first-line treatment

• when to seek specialist oncology advice

• what is discussed with people, particularly around the uncertainty of the evidence.

The recommendations will standardise practice.

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Vaginal laser treatment

Recommendation 1.5.19

The committee made a recommendation on vaginal laser treatment that applies to people with genitourinary symptoms associated with menopause, regardless of whether they have a personal history of breast cancer.

The evidence showed that laser treatment was effective for all outcomes. However, the committee agreed that, despite some promising results, the evidence base was too small.

In addition, laser treatment has a potential for harm (for example, scarring) and evidence showed it was not cost-effective. As a result, it should only be offered in the context of research. The committee also made a recommendation for research on vaginal laser treatment to address this.

Laser treatment was not included in the previous version of this guideline, but the recommendation to only consider it in the context of research will not affect practice.

Management options for depressive symptoms or depression in people with menopause-associated symptoms

Recommendations 1.5.21 and 1.5.22

The committee made recommendations based on the evidence which looked at CBT compared with no treatment or to treatment as usual, in the context of menopause. The common criteria used in all studies to show that women had experienced or were approaching menopause was the presence of vasomotor symptoms.

There was no evidence available for trans men and non-binary people registered female at birth. However, the committee agreed that the use of CBT for menopause symptoms would be suitable for anyone, regardless of whether they have taken gender-affirming hormone therapy in the past. (For more details, see the rationale on managing symptoms associated with menopause in people who have taken gender-affirming hormone therapy in the past.)

Observational evidence

Observational evidence on oral oestrogen doses as part of combined HRT, when compared with not taking HRT, showed:

• an increased risk of stroke in women taking continuous combined HRT when the oestrogen dose was high and

• no difference in risk when the oestrogen dose was lower.

Impact of timing of HRT for menopause symptoms on risk of coronary heart disease

There was not a lot of data to check whether the following factors impact on risk of coronary heart disease:

• the age of the person when they start HRT and

• the time between a person's menopause and when they start HRT.

This resulted in what is called 'lack of statistical power'. In other words, the lack of data means that statistical test could show a difference where there is none.

Menopause: identification and management (NG23)

In what little data was available, the risk did not have a clear tendency to decrease or increase with either of the above 2 factors (that is, with the age of the person when they start HRT or the time between a person's menopause and when they start HRT).

As a result, the committee decided to make a recommendation for research on the impact of timing of HRT on risk of coronary heart disease.

Impact of the type of progestogen in combined HRT on cardiovascular disease risk

There was insufficient evidence to conclude whether, as part of HRT, different progestogens had different impact on risk of cardiovascular disease. The committee made a key recommendation for research on different types of progestogen.

Impact of mode of administration of combined HRT on coronary heart disease

There was insufficient evidence on whether 1 mode of administration of combined HRT differed to another in its impact on risk of coronary heart disease. The committee therefore made a key recommendation for research on different modes of administration.

Risk of cardiovascular disease with HRT in people from ethnic minority backgrounds

The committee noted that there was little evidence on how HRT affects people from ethnic minority backgrounds in terms of cardiovascular health and stroke (as well as all other health outcomes), so they made a recommendation for research on the impact of HRT on health outcomes for these groups of people.

Other considerations relating to cardiovascular disease

The committee were aware of systematic reviews by Boardman et al. (2015) , Kim et al. • they combined data for participants who received combined HRT and oestrogen-only HRT (Boardman et al. 2015) or

• some individual studies included within a review did not match NICE's 2024 criteria and therefore the entire systematic review could not be included (Kim et al. 2020 and Salpeter et al. 2006) .

The studies included in these systematic reviews were checked and any that matched the relevant criteria were included in NICE's 2024 evidence review.

These recommendations are a change to clinical practice. While wider use of CBT as an additional option could increase costs and add pressure to already limited services, especially in the short-term, it also gives people more choices for managing symptoms, including the option to have both CBT and HRT. This may lead to better outcomes.

The committee noted that there are long waiting times for CBT. They also noted that people currently trained in providing this kind of therapy may not be familiar with menopause-specific CBT, so training on this may incur costs and increase waiting times in the short term. However, online and group CBT may be easier and less costly to adapt to be menopause specific. There are also resources available to train people in providing menopause-specific CBT (that could also inform the adaptation of online CBT), which could facilitate implementation.

The committee agreed that the evidence from the 2 observational studies was inconsistent:

• One study showed no difference in risk of dementia between combined HRT use and no HRT, with different durations of use.

• The other study showed an increase in incidence of dementia with combined HRT use when compared with no HRT, and the risk increased with duration of use.

The committee agreed that, although both studies adjusted for many relevant Menopause: identification and management (NG23) confounders, neither adjusted for all. They concluded that the evidence might be at risk of bias from confounding.

They noted that the evidence was for all types of dementia. The risk for some types of dementia may be different to others, and the proportion of each type identified at followup may differ for each study. The committee thought this may explain some of the differences in risk.

Evidence from the WHIMS study on combined HRT compared with placebo was inconsistent with the observational evidence from the UK, but in line with that from Denmark (showing an increased risk in dementia in the HRT group). They also noted that the population was different from a typical group of people taking HRT, in that they first started taking HRT at age 65 or over.

The committee were not unanimous in their interpretation of the evidence and how to formulate a recommendation best reflecting the evidence base. Some members of the committee had concerns about highlighting a risk of dementia when evidence from a UK setting showed no difference in risk.

The committee made these recommendations because:

• non-hormonal treatment may be less effective than local hormonal treatment but

• although it is important to treat menopause-associated symptoms, the risk of breast cancer recurrence is a greater concern.

The committee advised that the mechanism of action of aromatase inhibitors makes genitourinary symptoms likely. However, the mechanism of action of tamoxifen is less likely to cause genitourinary symptoms and may even alleviate some of them. Vaginal oestrogen may also lessen the efficacy of aromatase inhibitors.

The committee agreed it could not be confident about the evidence on the safety of local vaginal oestrogens in those taking either tamoxifen or aromatase inhibitors. This was because of:

• concerns about the quality of the evidence and

• lack of data comparing the risk of breast cancer recurrence in people taking aromatase inhibitors alone with the same risk in people taking vaginal oestrogen (the comparison was aromatase inhibitor versus aromatase inhibitor plus vaginal oestrogen).

In someone with an oestrogen receptor negative breast cancer, oestrogen does not affect the growth of cancer cells, but in someone with an oestrogen receptor positive breast cancer, it increases the risk of recurrence.

In someone with an oestrogen receptor positive breast cancer taking adjuvant treatment:

• if this treatment inhibits the production of oestrogen (in the ovaries or in fat or muscle tissues), it will have no effect on any oestrogen coming from a source outside the body, and this oestrogen would then be able to bind to cancer cells and stimulate their growth but

• if this treatment stops oestrogen from binding to oestrogen receptors (regardless of whether the oestrogen is produced by the body or absorbed from some treatment), it will stop oestrogen, regardless of source, from binding to receptors on cancer cells and so their growth will not be stimulated.

There were many different scales and measurements for mental health-related symptoms, and, in the context of menopause:

• most of the evidence on depressive symptoms showed no difference between CBT and the comparison groups (no treatment or treatment as usual)

• some evidence showed that CBT improved mood in women with depressive symptoms

• no evidence showed that CBT might make depressive symptoms any more severe.

There were some concerns about the evidence. These related to study design and to biases in the way studies were carried out. There were also uncertainties around:

• the outcomes, with different results being obtained for different outcome measurement scales and subgroups and

• how large the effect of CBT was, even when it was found to be effective.

However, the committee acknowledged that the overall effectiveness of CBT for depressive symptoms is established (see NICE's guideline on depression in adults). For this reason, they agreed that CBT should be a management option for depressive symptoms associated with vasomotor symptoms.

If depression is suspected or diagnosed, the committee noted that the optimal treatment plan can only be achieved by following both this menopause guideline and NICE's guideline on depression in adults.

These recommendations could lead to a change to clinical practice. Wider use of CBT could increase costs and add pressure onto already limited services, especially in the short term. However, it also gives people more management choices, including the option to have both CBT and HRT. Having more options may result in better outcomes.

There are currently long waiting times for CBT. However, the use of online and group CBT may make it easier and less costly to introduce CBT for depressive symptoms associated with menopause, where this option is not already in place.

Cognitive behavioural therapy for sleep problems associated with menopause

Recommendation 1.5.23

The committee based the recommendation on the evidence on CBT compared with no treatment or compared with treatment as usual.

Evidence showed CBT improved sleep quality, but this varied depending on the scale used to measure sleep disturbances. The committee agreed it was difficult to define difficulties with sleep, but the evidence showed that CBT was beneficial for various aspects of sleep, Menopause: identification and management (NG23) as defined by each scale (for example, the measures contributing to scales included the number of hours of sleep per night, how long it takes to fall asleep and the number and duration of night-time awakenings; there were also some specific scales for insomnia). The committee acknowledged there may be other options to manage difficulties with sleep associated with menopause. NICE will monitor evidence on these for a future update.

While not all the CBT approaches used in the evidence were specifically developed for menopause-associated symptoms, the committee agreed that this kind of CBT would be more effective given that the evidence showed that:

• the women with sleep problems also had vasomotor symptoms which can negatively impact sleep and

• menopause-specific CBT was also beneficial for the management of vasomotor symptoms.

The committee agreed that the evidence had some limitations, including uncertainties around:

• outcomes, with different results being obtained for different outcome measurement scales and subgroups

• how large the effect of CBT was, even when it was shown to be effective.

The committee also had concerns around study design and biases around how studies were carried out.

As a result, they recommended CBT as an option rather than as routine management for sleep problems associated with menopause.

These recommendations could lead to a change to clinical practice. Although increased use of CBT could have a resource impact and add pressure to already limited services, especially in the short term, it also provides more management choices, including the option to have both CBT and other treatments (including HRT). This may lead to better outcomes.

There CBT. However, the use of online or group CBT may make it easier and less costly to adapt as menopause-specific CBT. The committee was aware of existing resources that can be used to train people in providing menopause-specific CBT (including adapting online CBT).

They agreed that this would facilitate implementation.

Taking medical history of coronary heart disease or stroke into account before offering treatment

Recommendation 1.5.29

For people with a history of coronary heart disease or stroke, the committee agreed that different risk factors mean that people have different baseline levels of risk. They concluded that decisions on HRT use for menopause-associated symptoms would need to be tailored to the person and their particular risk factors and risk levels and that, therefore, these decisions should be made with a healthcare professional with expertise in menopause.

It is current practice that people with pre-existing conditions get expert advice on HRT as a treatment option for menopause-associated symptoms. However, there is variation in which expert would be consulted on this. This recommendation will standardise practice.

• no statistically significant subgroup differences in the RCT evidence

• inconsistent results between different observational studies and

• inconsistency between the conclusions of the RCT evidence and observational studies.

• One study showed a reduced risk of coronary heart disease when HRT was started within 4 years of menopause, while the other study showed no difference in risk when HRT was started between the ages of 45 to 54 (which is likely to be within 4 years of menopause).

Menopause: identification and management (NG23) However, the committee did comment on whether the conclusions made in NICE's 2024 evidence review aligned with the findings of these 3 systematic reviews. Although there were differences observed in certain areas, none of them challenged the overall conclusion that HRT does not increase coronary heart disease risk.

To guide their discussions and support the recommendations, the committee agreed to focus on 2 observational studies, 1 from the UK and 1 from Denmark (which both made the most appropriate adjustments for confounders). They also focused on the Women's Health

Initiative Memory Study (WHIMS) of women starting HRT over the age of 65, which is based on data from a randomised controlled trial (RCT) from the Women's Health Initiative (WHI).

The observational evidence showed no significant differences in dementia risk when comparing oestrogen-only HRT with no HRT use. The evidence from the WHIMS study also showed no significant differences in incidence of dementia, between those who are taking or have taken oestrogen-only HRT and those taking placebo.

The committee discussed some of the limitations in the WHIMS study, such as the low incidence of dementia in the placebo arm, which was lower than the incidence of dementia in the UK. They also noted that the population was different from a typical group of people taking HRT, in that they first started taking HRT at the age of 65 or over.

Recommendations for research

The committee recognised that there are still uncertainties around the current evidence base and that further research is needed. They noted that the previous version of the guideline included a recommendation for research related to dementia and decided to Menopause: identification and management (NG23) keep this.

The evidence was unclear about the impact of mode of administration on risk of dementia.

The committee therefore prioritised a recommendation for research on mode of administration for systemic HRT.

It is current practice to discuss benefits and risks with people when considering treatment options. The recommendation will standardise the information that will be shared. While the 2024 version of this guideline includes some new or updated information to share, it is unclear how this will change the treatment choices made and how this will impact on practice.

It is possible that the recommendation may increase the use of transdermal HRT since it was not associated with an increased risk of stroke (and, according to 2015 recommendations that were not reviewed in 2024, it is also associated with a lower risk of venous thromboembolism than oral preparations).

Cardiovascular disease prevention

Recommendation 1.6.4

Given the findings about the effect of HRT on coronary heart disease and stroke (as covered in the rationales on the effect of combined and of oestrogen-only HRT) the committee agreed that the evidence did not support the use of combined or oestrogenonly HRT for primary or secondary prevention of cardiovascular disease.

It is unclear whether it is current practice to use HRT for the specific purpose of primary or Menopause: identification and management (NG23)

Dementia prevention

Recommendation 1.6.5

The committee noted the scope of this guideline and agreed that the indication for HRT prescriptions in the UK was menopause symptoms. Therefore, the aim of the included studies was not dementia prevention. They agreed it was important to highlight that the evidence did not support this indication.

It is unclear whether it is current practice to use HRT for the specific purpose of dementia prevention. So, the recommendation is likely to standardise practice.

Effects of HRT use in early menopause on specific health outcomes

Recommendation 1.6.6

No evidence was identified on the benefits and risks of either taking or not taking HRT relating to osteoporosis, risk of fractures or cardiovascular outcomes, or endometrial or ovarian cancer in people experiencing early menopause (people aged 40 to 44). Some evidence was identified on the effect of taking or not taking HRT on breast cancer risk in this age group.

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The committee did not look at evidence on whether early menopause itself may have an impact on health outcomes, and how to manage any impact it might have. Therefore, they could not make any recommendations on the benefits and risks of HRT to manage any differences in risk that may result from early menopause.

The committee agreed it was important to take a person's age at the onset of menopauseassociated symptoms into account during discussions about HRT (in line with the section on discussing management options). They agreed that the age cut-offs defining premature ovarian insufficiency (POI), early menopause and typical menopause were a little arbitrary.

They also agreed it is clinically plausible that the benefits and risks evolve gradually from what they are for people with premature ovarian insufficiency to what they are for people aged 45 or over. As a result, it is likely that, for people with early menopause, the benefits and risks of either taking or not taking HRT lie somewhere between those for people with premature ovarian insufficiency and those for people aged 45 or over, for whom there is more evidence about these benefits and risks.

The committee discussed the similarities between early menopause and POI. Although there is little evidence of the impact of HRT on health outcomes in people with POI, it is current practice for this group to take HRT routinely. HRT is offered to them to lower the risk of some health outcomes, for example, osteoporosis. The situation may be similar for early menopause, for which routine HRT is also current practice.

Evidence showed that, as for people aged 45 or over, the risk of breast cancer in early menopause is increased when taking HRT compared with not taking HRT. However, the committee agreed that taking HRT in early menopause may affect the risk of different health outcome in different ways (that is, it may decrease some risks and increase others), as it does for people with POI and for people experiencing menopause at 45 or over.

As a result, the lack of evidence on outcomes other than breast cancer meant that it was not possible to make recommendations about the overall balance of benefits and risks of taking or not taking HRT in early menopause.

The committee agreed that it was important to highlight this lack of evidence and made a key recommendation for research on the impact of HRT in early menopause on specific health outcomes to address it.

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The recommendations reflect current practice in choice of HRT prescribing for people with a uterus or for people who have had a total hysterectomy.

It is common practice to seek advice from a healthcare professional with expertise in a Menopause: identification and management (NG23)

Page 100 of 105 condition when the clinical situation is complex, such as identifying the most suitable type of HRT for someone whose condition may be affected by it. This would usually be an informal process, so it is unlikely to have a significant impact on practice.

Stopping HRT if a person is diagnosed with breast cancer is also current practice.

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Implementation

Through engagement with stakeholders and with the help of the guideline committee, NICE has identified areas of its guideline on menopause that (at the time of the 2024 update) may be a significant change to practice or challenging to implement. These are:

• access to healthcare professionals with expertise in menopause

• communicating the benefits and risks of hormone replacement therapy (HRT)

• access to menopause specific cognitive behavioural therapy (CBT)

• equity of services.

For further information and support, see tools and resources.

||||Page 24 of 105|

|Menopause: identification and management (NG23)|||| |---|---|---|---|

||Breast cancer|||

||risk increases|||

||with combined|||

||HRT and the|||

||increase:|||

||• rises with|||

||duration of use|||

|||||Page 29 of 105|

||There is limited|||

||evidence|||

|-|suggesting that HRT may improve|-|-|

||muscle mass and|||

||strength. [2015]|||

||||Page 30 of 105|

|The baseline||||

|population risk||||

|of fragility||||

|fracture:||||

|• is low in the UK for women, trans men|Fragility fracture risk is decreased while taking HRT and this benefit:|||

|and non-|• is maintained|||

|binary|during|||

|people|treatment but|||

|registered|decreases|||

|female at|once|||

|birth who|treatment|||

|are around|stops|||

|the age of and menopause,|people who for longer in • may continue|-|-|

|• varies from|take HRT for|||

|one person|longer. [2015]|||

|to another. [2015]|(Use the discussion aid on|||

|(Use the|HRT for the|||

|discussion aid|incidence of|||

|on HRT for the|fragility fractures|||

|incidence of|in women taking|||

|fragility|HRT.) [2015]|||

|fractures in||||

|women not||||

|taking HRT.)||||

|[2015]||||

||||Page 31 of 105|

|||Stroke risk is||

|||unlikely to||

|||increase with||

|||the use of||

|||combined HRT||

|||that includes||

|||transdermal||

|||oestrogen (see||

|||the discussion||

|||aid on HRT, for||

|||the number of||

|||stroke cases per||

|||1,000 people||

|||over a 5-year||

|The baseline||period). [2024]||

|population risk||Stroke risk||

|of stroke in||increases with||

|women aged|-|combined HRT|-|

|under 60 is||containing oral||

|very low.||oestrogen and||

|[2024]||the increase:||

|||• rises with||

|||higher||

|||oestrogen||

|||dosage and||

|||longer||

|||duration of||

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|||years||

|||• is greater||

||||Page 32 of 105|

es with both HRT. [2024] oestrogen-only and oral transdermal|-|

|||Does the type of hormone taken affect these risks?| |---|---|---|

|||Coronary heart disease|

|||risk does not increase|

|||with oestrogen-only HRT|

|||(use the discussion aid|

|Coronary heart disease (Information in this table applies to people with no personal history of coronary heart disease)|-|on HRT for the number of coronary heart disease cases per 1,000 people over a 5-year period). [2024] Mortality from|

|||cardiovascular disease|

|||does not increase with|

|||oestrogen-only HRT.|

References

However, the committee reached a majority decision. Taking all evidence into account, they decided the evidence pointed towards a possible increased risk in dementia incidence if HRT is started at a later age. They agreed it was important that people thinking about HRT for menopause-associated symptoms should be made aware of this, so that they could make an informed decision.

As part of this, the committee:

• chose to use the word 'might' to express uncertainty, given the differences between study results

• agreed that it was important to highlight, based on the WHIMS evidence, the increase in risk that was noted when HRT was started over 65 years of age.

It is current practice to discuss benefits and risks with people when thinking about treatment options. The recommendation will standardise and update the information that will be shared. While the 2024 version of this guideline includes some new or updated information to share, it is unclear how this will affect treatment choices and impact on practice.

It is possible that the recommendation may increase the use of transdermal HRT, given that it was not associated with an increased risk of stroke (and, according to 2015 recommendations that were not reviewed in 2024, it is also associated with a lower risk of venous thromboembolism than oral preparations).

Effect of oestrogen-only HRT on specific health outcomes in people aged 45 or over

The committee agreed that people should be presented with a complete picture of benefits and risks associated with HRT to enable shared, and informed, decision making.

This rationale briefly describes the available evidence on oestrogen-only HRT and how it affects risks related to:

• cancer: breast It also covers other considerations related to cardiovascular disease, and the need for further research in this area.

There was no evidence available for trans men and non-binary people registered female at birth. The committee agreed that their conclusion from the available evidence could be extended to those who have never taken gender-affirming hormone therapy. But they did not think it could be extended to those who have taken this type of therapy in the past, because it is not known whether such therapy would alter the benefits and risks of any management option (especially hormonal treatments), or which management option might be best for the person. So, they made a recommendation for research on the impact of HRT on health outcomes for these groups.

Combined and oestrogen-only HRT are prescribed to different groups of people, as per recommendation 1.8.1, and so the committee looked separately at the benefits and risks associated with the 2 types of HRT.

The committee discussed evidence on the effect of taking HRT on breast cancer incidence and breast cancer mortality that came from:

Overall, it showed the risk of breast cancer incidence was consistently greater with combined HRT than with oestrogen-only HRT. Only women, trans men and non-binary people who have had a hysterectomy are eligible to take oestrogen-only HRT, so most people taking HRT will take combined HRT.

The committee discussed the evidence from the analysis of different durations of use of oestrogen-only HRT versus no HRT or versus placebo.

RCT evidence showed a reduced risk in the incidence of breast cancer for women who are taking, or have taken, oestrogen-only HRT compared with women taking placebo. Women taking oestrogen-only HRT as part of the trial took it for approximately 6 years and were followed up for breast cancer for 7 years after the trial ended.

The evidence showed the risk was reduced regardless of ethnicity. There was insufficient data to detect whether having or not having a family history of breast cancer lead to a different level of breast cancer risk with oestrogen-only HRT.

Evidence from observational studies was not consistent with the RCT evidence but provided further information on the duration and recency of use. It showed that for women currently taking oestrogen-only HRT, the risk of breast cancer incidence:

• was higher in those who had been taking HRT for at least 1 year and

For women who had taken oestrogen-only HRT in the past, it showed the risk of breast cancer incidence:

• was not quite as high as in those currently taking it

• was greater the longer they had taken HRT

• remained higher than for women who had never taken HRT for up to at least 10 years after stopping use.

Interpretation of the evidence on breast cancer incidence with oestrogen-only HRT

The committee decided that the difference between RCT results and evidence from observational studies meant that it was not possible to be certain of the conclusions. They also agreed this should be highlighted in the wording of the recommendation, by explaining that there was little or no increase in the risk of breast cancer incidence.

The committee also looked at evidence that compared different types of oestrogens and different modes of administration. The evidence did not show any differences in risk of incidence of breast cancer for different types of oestrogen. There was some uncertainty in relation to mode of administration. The committee therefore made a recommendation for research on mode of administration for systemic HRT.

Mortality from breast cancer

Evidence from an RCT showed that there was a reduction in the risk of mortality from breast cancer in those using oestrogen-only HRT compared with placebo. The observational data was not in line with the RCT data, as it showed there was an increased risk of mortality from breast cancer in oestrogen-only HRT users. The committee agreed that, although the RCT evidence showed a reduced risk, there was also evidence showing an increased risk. Therefore, it was important to highlight in the recommendations that there is a possibility of a small increase in the risk of breast cancer mortality.

The committee discussed the evidence from RCTs and observational studies. The evidence from RCTs was unclear because there were only 2 studies with no, or few, cases of endometrial cancer.

The committee also discussed the evidence from observational studies on oestrogen-only HRT versus no HRT in women with a uterus. It showed that the risk of endometrial cancer is increased in those:

• currently taking oestrogen-only HRT and

• who have been taking HRT for over 10 years (and are still taking it) or have taken oestrogen-only HRT in the past for over 10 years.

This increase in risk was present regardless of whether the treatment was oral or transdermal.

The committee discussed the well-established association between oestrogen-only HRT and the risk of endometrial cancer. They agreed it was important to explain to people with a uterus that this is why they would be offered combined HRT as per recommendation 1.8.1 in the section on starting HRT.

The committee discussed the evidence from observational studies. No evidence from RCTs was identified. Overall, with oestrogen-only HRT, the evidence showed that the risk of ovarian cancer:

• was higher in those who had been taking HRT for at least 5 years

• increased with duration of HRT use.

However, the committee agreed that risk remained small in absolute terms, because the baseline risk of ovarian cancer is low. The risk increased by 1 in 1,000 women for oestrogen-only HRT, when currently taking it, having started at the age of 50. The committee agreed that all of this should be explained when HRT is being considered.

The majority of the RCT and observational evidence both showed the risk of coronary heart disease did not increase when taking HRT. The committee agreed this information should be shared with people to allow them to make an informed decision.

• the length of time between menopause and the first use of HRT • the person's age at first HRT use.

When looking at women of all ages at first HRT use together as 1 group, the evidence showed no difference in risk of coronary heart disease between women who had been taking oestrogen-only HRT for 5 to 9 years and were still taking it, and women who were not taking HRT and had never taken it.

Subgroup analysis that looked at whether coronary heart disease risk was affected differently (if at all) for people of different ages at first HRT use, showed:

• an isolated reduced risk in 1 subgroup (when people were 50 to 59 at first HRT use)

but

• no difference in risk for any of the other subgroups.

In addition, statistical testing showed that the difference between people aged 50 to 59 at first HRT use and other subgroups was not significant and so should not be included in information shared with people considering HRT.

The committee looked at observational evidence on whether the length of time between a person's menopause and the moment they start HRT affects their risk of coronary heart disease. For women currently taking oestrogen-only HRT, who had been taking it for an unknown duration, the 2 observational studies reported different conclusions on this:

Page 91 of 105

• One study showed no difference when HRT was started more than 10 years after menopause, while the other study showed a reduction in risk when HRT was started between the ages of 65 and 74 (which is likely to be 10 years or more after menopause).

The committee recognised that some observational studies may have been influenced by residual confounding factors such as socioeconomic status, smoking, medical history or other factors which may be related to HRT use and cardiovascular risk.

Differences in direction of effect across study types

When looking at the effect of age at first use of HRT on the risk of coronary heart disease, there was also some variation in results across different study types, for example:

• the RCT evidence showed no difference in risk when HRT was started between the ages of 60 and 69

• an observational study showed a reduction in risk when HRT was started between the ages of 65 and 74.

The age groups overlap between the RCT and observational study, but the results for these overlapping age groups are contradictory, making it difficult to reach a conclusion with regards to age trends.

The RCT and observational study evidence both showed that, for women with no history of coronary heart disease, there was no increase in mortality from cardiovascular disease from taking HRT. The committee agreed that it was important for people to know this so they could make an informed choice.

The RCTs showed that, overall, there is an increased risk of stroke in women currently taking oral oestrogen-only HRT. These findings were supported by observational evidence. National statistics also show that the baseline risk for stroke in women aged under 60 is very low. The committee agreed that this should be explained to anyone thinking about HRT because the risk may remain small despite any change in risk reported in the RCT and observational study findings.

Observational evidence showed that transdermal oestradiol did not increase the risk of stroke whereas oral oestradiol did. The committee noted that this was consistent with the pattern in combined HRT. They agreed that this should be explained so that people can factor this into their decision making.

The observational evidence showed an increased risk of stroke when oestrogen-only HRT was given at a high dose while, at low and medium doses, there was no increase in risk for oestrogen-only HRT compared with no HRT. Risk was also increased in women currently taking oestrogen-only HRT who had been taking it for 5 to 9 years when they had been aged 60 years or over at first HRT use. The committee decided that both these points should be covered when making shared decisions on treatment.

This resulted in what is called 'lack of statistical power'. In other words, the small amount of data means that statistical test could show a difference where there is none.

In what little data was available, the risk did not have a clear tendency to decrease or Menopause: identification and management (NG23) increase with either of the above 2 factors (that is, with the age of the person when they start HRT or the time between a person's menopause and when they start HRT).

Impact of mode of administration of oestrogen-only HRT on coronary heart disease

There was no evidence on whether 1 mode of administration of oestrogen-only HRT differed to another in its impact on risk of coronary heart disease. The committee therefore prioritised a recommendation for research on the mode of administration for systemic HRT.

The committee noted that there was little evidence for people from ethnic minority backgrounds for cardiovascular health and stroke (as well as all other health outcomes), so they made a recommendation for research on the impact of HRT on health outcomes for these groups of people.

The • some individual studies included within a review did not match NICE's 2024 criteria and therefore the entire systematic review could not be included (Kim et al. 2020 and Salpeter et al. 2006) .

The studies included in these systematic reviews were checked and any relevant ones were then included in NICE's 2024 evidence review if they matched its criteria.

While the recommendation may help people make decisions about treatment, it is unclear how it will change these decisions and how that will impact overall resource use. It would however be unethical to prevent such information being discussed with people experiencing early menopause even if it did lead to an increase in resource use.

Starting and stopping HRT for anyone

Recommendations 1.8.1 to 1.8.3 and 1.8.7

Starting HRT

When a person decides they want to take HRT for menopause-associated symptoms, the committee recommended, that, if the person has a uterus, they should be offered combined oestrogen and progestogen. Whereas, if the person has had a total hysterectomy, they should be offered oestrogen alone.

The main reason for this is the established knowledge that oestrogen alone, if given to people with an intact uterus, can stimulate the growth of the uterine lining (endometrium).

In turn, this oestrogen stimulation can lead to an increased risk of endometrial hyperplasia (overgrowth of the endometrium) and potentially, endometrial cancer. This is consistent with the evidence showing that oestrogen-only HRT increases the incidence of endometrial cancer in people with a uterus (see the section related to the effect of oestrogen-only HRT on endometrial cancer for people aged 45 and over).

However, because it is now considered unsafe to give oestrogen-only HRT to people with a uterus, no further research is being carried out, and the recommendation is based on established knowledge more than on the evidence identified for this guideline. Adding progestogen to the HRT regimen helps protect the endometrium by counteracting the stimulating effects of oestrogen, and so reduces the risk of endometrial hyperplasia and cancer.

Progestogen is given to protect the uterine lining, so it is not needed for people who have had a total hysterectomy. The committee discussed that this may be different for people with a subtotal hysterectomy. They decided that they could not be prescriptive about the type of HRT to be used for people who have had a subtotal hysterectomy because their condition is clinically complex, and they had not reviewed evidence about the effect of HRT on risk of endometrial cancer for this group. They acknowledged that people who were going to have, or had had, a subtotal hysterectomy would likely be under the care of a specialist (or a relevant member of the associated multidisciplinary team) who could discuss HRT options tailored to their needs.

Some people have a hysterectomy for a condition that may be affected by HRT, such as endometriosis. The committee did not review evidence related to such conditions.

However, they recognised that the decision about the type of HRT that best balances benefits and risks for a person who has had a hysterectomy may be affected by the condition that led to the hysterectomy. For this reason, advice from a healthcare professional with specialist knowledge of that condition may be needed.

The committee noted that it is common practice to prescribe the smallest effective dosage of a treatment to help balance its benefits and risks, so they recommended this for HRT too. Effectiveness of HRT can vary between people, so starting with the lowest effective dosage helps find the right balance between effectively treating symptoms and managing risks from the treatment, taking into account each person's specific needs.

Stopping HRT

A personal history of cancer is a contraindication to systemic HRT because it has been shown that systemic HRT can lead to cancer progression or recurrence. Therefore, the committee agreed that systemic HRT should be stopped in people who are diagnosed with breast cancer because this would be off-label use and therefore there would be safety concerns. However, they agreed that this is already covered in NICE's guideline on early and locally advanced breast cancer.

Finding more information and committee details

To find NICE guidance on related topics, including guidance in development, see the NICE topic page on menopause.

For full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.

NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice.

Page 104 of 105

Update information

We have reviewed the evidence and made new or updated recommendations on:

• cognitive behavioural therapy to manage symptoms associated with the menopause

• managing genitourinary symptoms associated with the menopause

• the effects of hormone replacement therapy (HRT) on specific health outcomes.

These recommendations are marked [2024].

We have also made some changes without an evidence review. These changes include clarifying:

• the information about menopause and fertility that should be shared and discussed We have also made some presentational changes without changing the meaning of the recommendations.

• Changes have been made to the wording to bring the language and style up to date.

• Information on the risk of the effects of hormone replacement therapy (HRT) on some health outcomes (muscle mass and strength, osteoporosis, type 2 diabetes and venous thromboembolism) has been clarified.

These recommendations are marked [2015].

ISBN: 978-1-4731-6125-429

|Menopause: identification and management (NG23)|Menopause: identification and management (NG23)| |---|---|

|Personal history of coronary heart disease or stroke|Personal history of coronary heart disease or stroke|

|1.5.29|For people with a personal history of coronary heart disease or stroke, ensure|

||that combined or oestrogen-only HRT is discussed with and offered, if|

||appropriate, by a healthcare professional with expertise in menopause. [2024]|

|1.5.27|Consider transdermal rather than oral HRT for people with menopause-|

||associated symptoms who are at increased risk of venous thromboembolism|

||(VTE), including those with a body mass index (BMI) over 30 kg/m 2 . [2015]|

|1.5.28|Consider referring people with menopause-associated symptoms who are at high|

||Overall, life|||

||expectancy is|||

|-|unlikely to change with the|-|-|

||use of combined|||

||HRT. [2024]|||

|Breast cancer risk varies depending on a person's modifiable and non-modifiable risk factors. [2024]|• is higher in people currently taking HRT than in those who have taken it in the past • declines after stopping HRT but persists at least 10 years after stopping use. There is a very small increase in risk of death from|Breast cancer risk with sequential combined HRT is: • lower than with continuous combined HRT but • higher than without HRT. [2024]|There is insufficient evidence to establish whether the increase in risk of breast cancer is different with preparations containing micronised progesterone or dydrogesterone from what it is with preparations containing other progestogens. [2024]|

||breast cancer|||

||HRT.|||

||Use the|||

||discussion aid on|||

||HRT for the|||

||number of breast|||

||cancer cases per|||

||||Page 25 of 105|

|Menopause: identification and management (NG23)| |---|

|1,000 people|

|taking combined|

|HRT over a 5-or|

|10-year period.|

|[2024]|

|Page 26 of 105|

|||Endometrial||

|||cancer risk||

|||decreases with||

|||continuous||

|||(use the||

|||discussion aid||

|||on HRT for the||

|||number of||

|||endometrial||

|||cancer cases||

|||per 1,000||

|||people taking||

|||period). [2024]||

|-|-|Endometrial cancer risk may|-|

|||slightly increase||

|||with sequential||

|||combined HRT,||

|||and the||

|||increase may be||

|||greater with:||

|||• longer||

|||use||

|||• fewer days of||

|||progestogen||

|||per cycle||

|||• increased||

|||dosage of||

||||Page 27 of 105|

||In people with|||

|The baseline|ovaries, there is a|||

|population risk|very slight|||

|of ovarian|increase in|||

|cancer in|ovarian cancer|||

|women aged|risk with|||

|under 60 is|combined HRT|||

|very low (use|(use the|||

|the discussion|discussion aid on|-|-|

|aid on HRT for|HRT for the|||

|the number of|number of|||

|ovarian cancer|ovarian cancer|||

|cases per|cases per 1,000|||

|1,000 people|people over a|||

|over a 5-year|5-year and a|||

|period). [2024]|10-year period).|||

||[2024]|||

||||Page 28 of 105|

|Menopause: identification and management (NG23)||||| |---|---|---|---|---|

|||Coronary heart|||

|||disease risk does|||

|||not increase with|||

|||combined HRT|||

|||(use the|||

|||discussion aid on|||

|||HRT for the|||

|||number of|||

|||coronary heart|||

||-|disease cases|-|-|

|||per 1,000 people|||

|||over a 5-year|||

|||period.) [2024]|||

|||Mortality from|||

|||cardiovascular|||

|||disease does not|||

|||increase with|||

|||combined HRT.|||

|||[2024]|||

|||Dementia risk|||

|||might increase|||

|||with combined|||

|||HRT if it is|||

|||started at 65 or|||

|||over (use the|||

|Dementia|-|discussion aid on|-|-|

|||dementia cases|||

|||over a 4-year|||

|||period). [2024]|||

||||with||

||||increasing||

||||age at first||

||||starting HRT||

||||• differs||

||||between||

||||ethnic groups||

||||and may be||

||||greater in||

||||Black people.||

||||(See the|(See the|

||||discussion aid||

||||on HRT, for the||

||||number of||

||||stroke cases per||

||||1,000 people||

||||over a 5-year||

||||period.) [2024]||

|||The risk of|||

|||developing type|||

|||2 diabetes does|||

|||not increase with|The risk is not||

|||HRT. [2015]|affected|affected|

|||blood glucose|transdermally.||

|||control is|[2015]|[2015]|

|||reported when|||

|||taking HRT.|||

|||[2015]|||

|||||Page 33 of 105|

||||VTE risk is|| |---|---|---|---|---|

||||increased with||

|||VTE risk is not|oral HRT. [2015]||

|||[2015]|than||

||||transdermal||

||||HRT. [2015]||

|Table 1 lists the differences in specific health outcomes between people who are taking or|||||

|have taken combined HRT, and those who have never had HRT.|||||

|||Overall, life expectancy||| |---|---|---|---|---|

|All-cause mortality (life expectancy)|-|is unlikely to change oestrogen-only HRT. with the use of|-|-|

|||||Does the type of hormone taken affect these risks?|

|||There is very little or no|||

|||increase in breast cancer|||

|||risk with oestrogen-only|||

|||HRT.||Breast|

||Breast cancer|There is little or no||cancer risk|

||risk varies|increase in the risk of||is similar|

|Cancer: breast (Information in this table applies to people with no personal history of breast cancer)|depending on a person's modifiable and non-modifiable risk factors. [2024]|breast cancer mortality with oestrogen-only HRT. Use the discussion aid on HRT for the number of breast cancer cases per 1,000 people taking|-|with oestradiol and with conjugated equine oestrogen. [2024]|

|||oestrogen-only HRT over|||

|||a 5-or 10-year period.|||

|||In people with a uterus,|||

|||endometrial cancer risk|||

|||increases with|||

|||oestrogen-only HRT (use|||

|||the discussion aid on|||

|||HRT for the number of|In people with||

|||endometrial cancer|a uterus,||

|Cancer: endometrial (Information in this table applies personal history cancer) of endometrial to people with no|-|cases per 1,000 people taking oestrogen-only See also period). [2024] HRT over a 5-year|endometrial cancer risk transdermal both oral and increases with|-|

|||recommendation 1.8.1 on|oestrogen-only||

|||which type of HRT to|HRT. [2024]||

|||offer depending on|||

|||whether people have a|||

|||uterus or not in the|||

|||section on starting HRT.|||

|Cancer: ovarian (Information in this table applies to people with no personal history of ovarian cancer)|The baseline population risk of ovarian cancer in women aged under 60 is very low. (Use the discussion aid on [2024] 5-year period). people over a cases per 1,000 ovarian cancer number of HRT for the|In people with ovaries, ovarian cancer risk increases very slightly after 5 years of using oestrogen-only HRT and this risk increases with period). [2024] 5-year and a 10-year 1,000 people over a ovarian cancer cases per for the number of discussion aid on HRT duration of use (use the|Ovarian cancer risk increases with both HRT. [2024] oestrogen-only and oral transdermal|-|

引用 / 出处

2024更新—2015 NICE指南：更年期的诊断和管理（NG.23）. 2024.