In the first of a two-part series on hormone-replacement therapy, Dr Toni Hazell explains the importance of helping women to weigh up the risk–benefit ratio
Read this article to learn more about:
- the definition of the menopause, and how it should be diagnosed
- risks and benefits of hormone-replacement therapy (HRT)
- the role of the GP in helping women to make an informed decision about HRT use, and useful resources to signpost.
Read this article online at:GinP.co.uk/456887.article
Reflection is important for continuous learning and development, and a critical part of the revalidation process for healthcare professionals. Reflect on what you have learned after reading this article with our interactive template.
The menopause is defined as ‘a biological stage in a woman’s life when menstruation stops permanently due to the loss of ovarian follicular activity.’1 In the UK, the average age at which the menopause occurs is 51 years,1 and it is usually preceded by the perimenopause—a transitional period characterised by irregular ovulation and menstruation that is often accompanied by symptoms such as hot flushes and night sweats.2
The mainstay treatment for menopausal symptoms is hormone-replacement therapy (HRT),3 which replaces the oestrogen that is lost as ovarian function diminishes.4 The risks and benefits of HRT have been reported in the national press for many years; it is important that GPs are able to provide accurate information to allow a woman to make an informed decision about the risk–benefit ratio of taking HRT, taking into account the severity of her symptoms.
Diagnosis and treatment of menopausal symptoms
The menopause is usually diagnosed clinically; NICE advises that the following stages can be determined without laboratory tests in otherwise healthy women aged 45 years or older with menopausal symptoms:3
- perimenopause based on vasomotor symptoms and irregular periods
- menopause in women who have not had a period for at least 12 months and are not using hormonal contraception
- menopause based on symptoms in women without a uterus.
NICE states that clinicians should only consider using a test for follicle-stimulating hormone (FSH) to diagnose menopause in women:3
- aged 40–45 years with menopausal symptoms, including a change in their menstrual cycle
- aged less than 40 years in whom menopause is suspected.
NICE recommends HRT as the first-line treatment for menopausal symptoms (the second article in this series, in May 2022, will discuss HRT prescribing).3
For women with a uterus, unopposed oestrogen carries a risk of endometrial hyperplasia and malignancy;5 therefore, these women must be given combined HRT containing both oestrogen and a progestogen.3,6 If the woman’s last period was less than 12 months ago, she should start on sequential combined HRT (oestrogen daily, progesterone usually for 2 weeks per month), changing to continuous combined HRT (oestrogen and progesterone daily) 1 year after her last period.6 This reduces the risk of irregular bleeding in the first year, but means that the woman will still have a bleed each month.6 One way to avoid a monthly bleed is to use the Mirena® (Bayer plc) intrauterine system (IUS) as the progestogenic component of HRT (other brands are not licensed for this indication), which will often result in amenorrhoea and will also provide reliable contraception.6,7 A woman who does not want a Mirena IUS but still needs contraception can use any other non-oestrogen form of contraception (for example, an intrauterine device, implant, or progesterone-only pill) alongside her HRT.6
It is important to remember that HRT is not a contraceptive. In general, a woman needs contraception for 2 years after her last period if aged less than 50 years, and for 1 year after her last period if aged 50 years or older.8 Laboratory tests can be used to diagnose menopause in women who have not had a period for at least 12 months and who are using hormonal contraception. Thus, in women aged 50 years or older with amenorrhoea due to their method of contraception, an FSH level in the menopausal range can be considered analogous to the date of their last period; these women can stop using contraception 1 year after that date.8 Women who don’t want a blood test can continue using hormonal contraception until the age of 55 years, at which point spontaneous conception is ‘exceptionally uncommon even in women still experiencing some menstrual bleeding’, and contraception can be stopped.8
The constituents of HRT can be prescribed orally (for example, as tablets) or transdermally (for example, as patches or gels); these different routes of administration carry distinct risks and benefits.3,6
Risks and benefits associated with use of HRT
The risk of venous thromboembolism (VTE) associated with HRT use is more significant for oral than transdermal preparations.3,6 With oral HRT, the risk of VTE is doubled compared with baseline population risk.3,6 In contrast, there is no increased risk of VTE relative to baseline population risk with transdermal HRT.3,6 Therefore, transdermal HRT is recommended in menopausal women at increased risk of VTE (for example, those with a body mass index greater than 30 kg/m2).3,6 NICE also advises clinicians to consider referring menopausal women at a high risk of VTE (for example, those with a strong family history of VTE or a hereditary thrombophilia) to a haematologist for assessment before considering HRT;3 however, given the likely wait to be seen, the woman may choose to start a transdermal preparation in the meantime if she has severe symptoms.
Although the use of oestrogen-only HRT is associated with little or no change in the risk of breast cancer, the use of combined HRT can be associated with an increased risk of breast cancer.3,6 However, the baseline risk of breast cancer in women of menopausal age varies according to the presence of underlying risk factors.3,6 It is important to be aware that there is no evidence of any increase in mortality from breast cancer in women taking either oestrogen-only or combined HRT.6,9,10 This may be because the cancers detected in women taking HRT are less advanced and more amenable to treatment, or because they are detected earlier, before they have spread.10
The 2019 meta-analysis on HRT and breast cancer
In 2019, a meta-analysis on the association between HRT and breast cancer was published in The Lancet,11 prompting a Medicines and Healthcare products Regulatory Agency (MHRA) safety alert12 that made newspaper headlines and caused much confusion among women.13 The meta-analysis concluded that, for women of average weight, use of systemic HRT from the onset of menopause in their 40s or 50s and continuing for 5 years increases the number of cases of breast cancer by the age of 69 years by:11,12
- one cancer for every 50 users of continuous combined HRT
- one cancer for every 70 users of sequential combined HRT
- one cancer for every 200 users of oestrogen-only HRT.
In response to the MHRA safety alert,12 the 2015 NICE guideline Menopause: diagnosis and management was updated in 2019 to link to the MHRA risk table (bit.ly/3ItBFvJ),3 which states that, for every 1000 women treated with combined HRT up to the age of 69 years, there will be eight extra cases of breast cancer for 5 years’ HRT use, and 20 extra cases for 10 years’ HRT use.14 The numbers of extra cases of breast cancer are much lower among women using oestrogen-only HRT, at three and seven extra cases for 5 and 10 years’ HRT use, respectively.14
The meta-analysis was found to have some important limitations, including the fact that most of the women involved in the analysis were using conjugated oestrogens and medroxyprogesterone acetate with doses and routes of administration not comparable to current HRT regimens.6,11,13 Micronised progesterone is currently considered the progestogen of choice for HRT regimens, and micronised progesterone in combination with transdermal 17-beta-oestradiol is thought to be associated with a lower risk of breast cancer than the hormones used in the studies included in the meta-analysis.6,13 the British Menopause Society (BMS), the Royal College of Obstetricians & Gynaecologists (RCOG), and the International Menopause Society released a joint statement, in response to the meta-analysis and the MHRA safety alert.11,12 This is worth reading in full (see Box 1 for an extract).6,15
Box 1: PCWHF summary of the joint statement on HRT and breast cancer6,15
‘This meta-analysis[A] has revived concerns amongst healthcare professionals regarding the association between HRT and breast cancer. In response the BMS, IMS, and RCOG issued a joint statement:
“The meta-analysis[A]provides important additional information on the risks of breast cancer, but it needs to be considered in the context of the benefits of HRT in treating vasomotor symptoms, improving sleep and quality of life for symptomatic women, and the prevention of bone loss.
“The findings from the meta-analysis are in keeping with the NICE guidance observational data on breast cancer risk,[B]and discussions should also include findings from the WHI randomised trials and E3N observational studies which found no increased risk of breast cancer over five years with the use of oestradiol and micronised progesterone.
“An 18-year long-term follow-up study of the WHI randomised trials published in JAMAin 2020 [C] concluded that use of CEE alone was significantly associated with lower breast cancer incidence and mortality, whereas the use of CEE plus MPA was associated with a higher breast cancer incidence, but no significant difference in breast cancer mortality”.’
[A] Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019; 394 (10204): 1159–1168.
[B] NICE. Menopause: diagnosis and management. NICE Guideline 23. NICE, 2015 (last updated December 2019). Available at: www.nice.org.uk/ng23
[C] Chlebowski R, Anderson G, Aragaki A et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women’s Health Initiative randomized clinical trials. JAMA 2020; 324 (4): 369–380. jamanetwork.com/journals/jama/article-abstract/2768806
PCWHF=Primary Care Women’s Health Forum; HRT=hormone-replacement therapy; BMS=British Menopause Society; IMS=International Menopause Society; RCOG=Royal College of Obstetricians & Gynaecologists; WHI=Women’s Health Initiative; E3N=Etude Epidémiologique auprès de femmes de l’Education Nationale; JAMA=Journal of the American Medical Association; CEE=conjugated equine oestrogen; MPA=medroxyprogesterone acetate
© Primary Care Women’s Health Forum. Menopause—guidance on management and prescribing HRT for GPs. London: PCWHF, 2020. Available at: pcwhf.co.uk/wp-content/uploads/2021/12/Prescribing-HRT.pdf Reproduced with permission
Explaining breast cancer risk to patients
How can we explain this complex issue to patients? The BMS has produced a two-page Fast facts document,16 which patients may want to read when considering HRT. Its key messages are summarised in Box 2.16
Box 2: Key messages from the BMS Fast facts document16
- Use of combined HRT is not associated with an increased risk of breast cancer mortality, and the absolute excess risk of a breast cancer diagnosis with use of combined HRT is small
- this should be weighed against the reduced risk of endometrial cancer associated with long-term use of continuous-combined HRT
- Use of unopposed (oestrogen-only) HRT may be associated with a reduction in breast cancer mortality
- In women with a low background risk of breast cancer, the benefits of HRT use for up to 5 years will be greater than the potential harms
- There is no strong evidence that the use of HRT has an additive effect on risk in women who are already at high risk of breast cancer (e.g. due to a family history of the condition)
- women with menopausal symptoms and an elevated background risk of breast cancer should be referred to a menopause specialist for advice
- Use of vaginal oestrogen carries no increase in breast cancer risk.
BMS=British Menopause Society; HRT=hormone-replacement therapy
Patients may also find it useful to look at the BMS infographic Understanding the risks of breast cancer,17 which clearly sets out the risk of breast cancer associated with HRT use compared with baseline population risk, and the risk associated with smoking, alcohol use, weekly exercise, and obesity.
HRT initiated before the age of 60 years does not increase the risk of developing coronary artery disease or the risk of dying from cardiovascular disease, and the presence of cardiovascular risk factors are not a contraindication to HRT provided they are optimally managed.6 As with the risk of breast cancer, the baseline risk of coronary artery disease and stroke for women of menopausal age varies according to the presence of underlying risk factors.6 Oestrogen-only HRT is associated with no or reduced risk—and combined HRT with little or no increase in the risk—of coronary heart disease.6 There is a small increase in stroke risk with oral but not transdermal oestrogen; however, for the majority of women aged less than 60 years with a low background risk of stroke, this is unlikely to be significant.6
Other risks and benefits
In addition to the risks and benefits associated with HRT use already discussed:6
- the risk of fragility fracture is decreased while taking HRT6
- there is no increase in the risk of type 2 diabetes with HRT use, whether taken orally or transdermally, nor is there any association with worsening of blood glucose control in those who already have diabetes6
- limited data suggest an association between HRT use and the maintenance of muscle mass and strength after the menopause6
- there is a small increase in risk of ovarian cancer with use of either oestrogen-only or combined HRT, equating to one extra case per 1000 users and one extra death per 1700 users with 5 years’ HRT use6
- these figures are the same with 10 years’ HRT use.14
Managing premature ovarian insufficiency
The risks associated with HRT use do not increase until women reach the average age at which the menopause occurs (in the UK, this is 51 years of age3). Up to this age, HRT is replacing naturally occurring hormones and there is no effect on risk.18 This is a particularly important conversation to have with a woman with premature ovarian insufficiency (POI; menopause before the age of 40 years)—it is important that these women take either HRT or a combined hormonal contraceptive to reduce the sequelae of POI, which include dementia, cognitive decline, osteoporosis, and cardiovascular disease.6
Talking to patients about HRT is a complex issue, which may require a longer appointment, or even several appointments. Theoretical small increases in risk must be weighed against a woman’s experiences in the present—if she is about to lose her job because lack of sleep due to night sweats is making her unable to function during the day, or her relationship is at risk due to menopause-related mood changes, then the personal benefits of HRT are likely to outweigh the risks.
There are a variety of patient resources available from sources including the Rock My Menopause website,19 the RCOG’s Menopause and later life hub,20 the Patient website,21 and the Women’s Health Concern website.22
- The menopause is usually diagnosed clinically
- Women for whom less than 12 months have elapsed since their last period should be offered sequential rather than combined HRT to reduce the risk of irregular bleeding
- Combined HRT should be offered to menopausal women with a uterus to reduce the risk of endometrial hyperplasia and malignancy associated with unopposed oestrogen use
- Transdermal HRT is associated with a lower risk of stroke and VTE compared with oral HRT
- Although the use of oestrogen-only HRT is associated with little or no change in the risk of breast cancer, the use of combined HRT can be associated with an increased risk of breast cancer
- there is no excess mortality from breast cancer associated with use of HRT
- HRT is not a contraceptive, and some women aged more than 50 years will still need contraception
- the Mirena® (Bayer plc) IUS system is a useful device that can be used both as part of an HRT regimen and to provide contraception.
HRT=hormone-replacement therapy; VTE=venous thromboembolism; IUS=intrauterine system
Implementation actions for clinical pharmacists in general practice
written by Shivangee Maurya, Clinical Services Pharmacist, Soar Beyond Ltd
The i2i Network conducted a survey of clinical pharmacists in general practice in July 2021 to gain an insight into their role in managing the menopause, covering their current situation, future expectations, and views on the planned implementation of HRT clinics. Of the 82 pharmacists surveyed:
- 84% are dealing with supply issues
- 76% are giving advice on HRT; however, only 22% feel knowledgeable, and 61% lack the confidence to optimise HRT treatments
- 10% are currently running HRT clinics; however, 84% believe that they will in future
- 46% are currently optimising HRT treatment; however, 89% believe that they will in future
- 17% are currently initiating HRT; however, 76% believe that they will in the future
- 79% are extremely interested or interested in running HRT clinics rather than asthma or diabetes clinics
- 68% are very likely or likely to implement HRT clinics in future.
The survey results highlight that pharmacists are already instrumental in managing the menopause, and many would like to become more involved. Practically, they can do so by:
- ensuring that their knowledge is in line with current evidence, e.g.
- understanding the rationale for different management options―such as when a patient should receive sequential versus continuous HRT
- being aware of local menopause guidance, including treatment recommendations and cost-effective options
- understanding the risks and benefits of each treatment option
- being aware of red flags
- stratifying and prioritising key cohorts to review―e.g. women who have been on HRT for longer than 12 months without a review, or women who have had a hysterectomy but are not on oestrogen-only treatment[A]
- utilising existing or bespoke clinical system searches and templates to identify patients and conduct menopause reviews
- before creating searches and templates from scratch, pharmacists should check current searches on their clinical system and network with colleagues to understand which resources they may be using
- collaborating with their MDT and employing other resources―e.g., mobilising a pharmacy technician to run the searches to identify key patient cohorts, potentially freeing up pharmacist time to review patients
- agreeing KPIs and metrics to demonstrate the impact of a pharmacist-led menopause clinic
- working within their scope of competence, and understanding when to refer cases that are out of scope.
The i2i Network brings together clinical pharmacists from across the UK to help support, upskill, and equip pharmacists to manage long-term conditions.
To sign up for free or find out more, visit www.i2ipharmacists.co.uk/
[A] Derbyshire Joint Area Prescribing Committee. Menopause management guideline (based on NICE NG23/British Menopause Society guidance). Derbyshire: Derbyshire JPAC, 2020. Available at: www.derbyshiremedicinesmanagement.nhs.uk/assets/Clinical_Guidelines/Formulary_by_BNF_chapter_prescribing_guidelines/BNF_chapter_6/Menopause_Guideline.pdf
HRT=hormone-replacement therapy; MDT=multidisciplinary team; KPI=-key performance indicator
Dr Toni Hazell
Portfolio GP, Tottenham, London
Conflicts of interest
Dr Hazell is on the Executive Committee of the Primary Care Women’s Health Forum, a role that includes paid and unpaid work, and she also does paid work for the Patient website
A second article in this two-part series will be published in May 2022, and will focus on HRT prescribing
Reflection is important for continuous learning and development, and a critical part of the revalidation process for healthcare professionals. Reflect on what you have learned after reading this article with our interactive template.
- NICE. Menopause: what is it? NICE Clinical Knowledge Summary. Available at: cks.nice.org.uk/topics/menopause/background-information/definition/ (accessed 7 April 2022).
- NICE. Menopause: when should I suspect a diagnosis of menopause or perimenopause? NICE Clinical Knowledge Summary. Available at: cks.nice.org.uk/topics/menopause/diagnosis/diagnosis-of-menopause-perimenopause/ (accessed 7 April 2022).
- NICE. Menopause: diagnosis and management. NICE Guideline 23. NICE, 2015 (last updated 2019). Available at: www.nice.org.uk/ng23
- NICE. Menopause: what causes it? NICE Clinical Knowledge Summary. Available at: cks.nice.org.uk/topics/menopause/background-information/causes/ (accessed 7 April 2022).
- Royal College of Obstetricians & Gynaecologists. Management of endometrial hyperplasia. Green-top guideline no. 67. London: RCOG, 2016. Available at: www.rcog.org.uk/globalassets/documents/guidelines/green-top-guidelines/gtg_67_endometrial_hyperplasia.pdf
- Primary Care Women’s Health Forum. Menopause—guidance on management and prescribing HRT for GPs. London: PCWHF, 2020. Available at: pcwhf.co.uk/wp-content/uploads/2021/12/Prescribing-HRT.pdf
- Bayer plc. Mirena 20 micrograms/24 hours intrauterine delivery system—summary of product characteristics. www.medicines.org.uk/emc/product/1132 (accessed 7 April 2022).
- The Faculty of Sexual & Reproductive Healthcare. Contraception for women aged over 40 years. London: FSRH, 2017 (updated 2019). Available at: www.fsrh.org/documents/fsrh-guidance-contraception-for-women-aged-over-40-years-2017/fsrh-guideline-contraception-aged-over-40-sep-2019.pdf
- Chen W, Petitti D, Geiger A. Mortality following development of breast cancer while using oestrogen or oestrogen plus progestin: a computer record-linkage study. Br J Cancer 2005; 93 (4): 392–398.
- Jernström H, Frenander J, Fernö M, Olsson H. Hormone replacement therapy before breast cancer diagnosis significantly reduces the overall death rate compared with never-use among 984 breast cancer patients. Br J Cancer 1999; 80 (9): 1453–1458.
- Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019; 394 (10204): 1159–1168.
- GOV.UK website. Hormone replacement therapy (HRT): further information on the known increased risk of breast cancer with HRT and its persistence after stopping. www.gov.uk/drug-safety-update/hormone-replacement-therapy-hrt-further-information-on-the-known-increased-risk-of-breast-cancer-with-hrt-and-its-persistence-after-stopping (accessed 7 April 2022).
- Stevenson J, Farmer R. HRT and breast cancer: a million women ride again. Climacteric 2020; 23: 226–228.
- Medicines and Healthcare products Regulatory Agency. Table 1: summary of HRT risks and benefits during current use and current use plus post-treatment from age of menopause up to age 69 years, per 1000 women with 5 years or 10 years use of HRT. London: MHRA, 2019. Available at: assets.publishing.service.gov.uk/media/5d680409e5274a1711fbe65a/Table1.pdf
- British Menopause Society, International Menopause Society, European Menopause and Andropause Society, Royal College of Obstetricians & Gynaecologists, Australasian Menopause Society. BMS, IMS, EMAS, RCOG and AMS Joint Statement on menopausal hormone therapy (MHT) and breast cancer risk in response to EMA Pharmacovigilance Risk Assessment Committee recommendations in May 2020. BMS, IMS, EMAS, RCOG, AMS, 2020. Available at: www.imsociety.org/wp-content/uploads/2020/08/position-statement-hrt-breast-cancer-2020-08.pdf
- British Menopause Society. Fast facts: HRT and breast cancer risk. Marlow: BMS, 2020. Available at: thebms.org.uk/wp-content/uploads/2020/12/12-BMS-TfC-Fast-Facts-HRT-and-Breast-Cancer-Risk-01D.pdf
- British Menopause Society. Understanding the risks of breast cancer. Marlow: BMS, 2017. Available at: thebms.org.uk/wp-content/uploads/2016/04/WHC-UnderstandingRisksofBreastCancer-MARCH2017.pdf
- British Menopause Society website. Premature ovarian insufficiency.thebms.org.uk/publications/consensus-statements/premature-ovarian-insufficiency/ (accessed 7 April 2022).
- Rock My Menopause website. Rock my menopause. rockmymenopause.com/ (accessed 7 April 2022).
- Royal College of Obstetricians & Gynaecologists website. Menopause and later life. www.rcog.org.uk/for-the-public/menopause-and-later-life/ (accessed 7 April 2022).
- Patient website. Expert health articles, tips and information. patient.info/ (accessed 7 April 2022).
- Women’s Health Concern website. www.womens-health-concern.org/ (accessed 7 April 2022).
Lead image: RFBSIP/stock.adobe.com