Hormone-replacement Therapy: What Are the Risks and Benefits?

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

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

Diagnosis

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.

Treatment

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

Venous Thromboembolism

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.

Breast Cancer

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

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

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. 

Cardiovascular Disease

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

Summary

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

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