Authors reply: ‘Response to the British Menopause society,Royal College of Obstetricians and Gynaecologists and Society for Endocrinology position statement – Best practice recommendations for the care of women experiencing the menopause’

Duration dependent association between HRT use and the risk of breast cancer

The letter questioned the reference to a duration dependent association between HRT use and the risk of breast cancer and suggested that no studies have directly examined breast cancer risk in relation to the duration of treatment with HRT.

We would like to highlight that the NICE guidelines on the diagnosis and management of the menopause published in 2015 concluded, based on its literature review, that the increase in the risk of breast cancer associated with HRT is related to treatment duration. In addition, the meta-analysis by the Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) published in the Lancet in August 2019 noted a duration-dependent risk of increased breast cancer diagnosis with HRT. The recommendations in our joint statement were based on the conclusions of these literature reviews.^2–4

HRT and breast cancer mortality

There is limited evidence assessing the risk of mortality from breast cancer with HRT use. The NICE guidelines on the diagnosis and management of the menopause published in 2015 concluded there was insufficient evidence on the outcome of mortality from breast cancer to demonstrate whether there is any significant difference between women who had either ever used or currently use HRT compared with those who never used HRT. ²

The 2019 CGHFBC meta-analysis did not collect information on breast cancer mortality, although an accompanying research letter from the Million Women Study (MWS) investigators published at the same time as the meta-analysis reported on this as did the report on the long-term follow-up of the randomised WHI study 2020 and reported conflicting results.^5,6

The MWS investigators reported that current and previous HRT use for a duration of more than 5 years was associated with an increased risk of breast cancer death. ⁵

The WHI long-term randomised clinical trials, published in JAMA 2020, reported on the association of HRT with breast cancer incidence and mortality and reported a significant reduction in breast cancer mortality (HR 0.60; 95% CI 0.37–0.97; p = .04) with estrogen-only HRT but the total number of events was small. Women who took combined estrogen and progestogen HRT had an increased risk of breast cancer compared to placebo (HR 1.28; 95% CI 1.13–1.45; p < .001), in keeping with the NICE guideline conclusions, but had no significant difference in breast cancer mortality compared with placebo (HR 1.35; 95% CI 0.94–1.95; p = .11). ⁶

In addition, the Finnish registry data, which followed up 489,105 women from HRT initiation between 1994 and 2009, showed breast cancer mortality was significantly reduced in all HRT users. ⁷

All the above evidence, however, is open to scrutiny as collectively there is failure to provide adequate information about disease stage, treatment and mode of breast cancer diagnosis and whether screen-detected or symptomatic, all factors which may have a significant impact on prognosis. In addition, hormone-sensitive breast cancer promoted by HRT has a higher long-term relapse pattern compared with hormone-insensitive disease. Beyond 5 years from diagnosis, the risk of recurrence is greater, and beyond 14 years, overall survival is worse in estrogen receptor (ER)-positive cancer. ⁸

HRT in women with breast cancer

The letter also questioned the evidence that supported the recommendation to not offer HRT routinely to women with breast cancer.

The clinical evidence on the risk of recurrence of breast cancer with HRT is inconclusive due to the premature closure of all three randomised trials of HRT in breast cancer patients, when all were underpowered. All three randomised trials of systemic HRT in breast cancer survivors (HABITS, Stockholm and LIBERATE) were stopped after an increase in recurrence was reported at the first interim analysis of one.^9–11

Extended follow-up of the HABITS study reported a statistically significant increased risk of new breast cancer events in women who took HRT. In addition, long-term follow-up from the Stockholm study reported a significantly higher number of contralateral breast cancers in women with breast cancer who took HRT compared to the control group. Although there is high concordance in hormone-receptor status between first and second primary breast cancers in women who have had an ER-negative primary, the recurrence can change phenotypically to an ER-positive cancer and there is an increased risk of ER-positive contralateral cancer and ER-positive metastatic disease.^8–10

The recommendations in national guidance are that HRT use in this context should be on an exceptional basis rather than being standard practice. For each individual there needs to be a discussion of the risks and benefits of different management options. For some women whose quality of life is substantially impaired by menopausal symptoms, an informed decision to take HRT may be fully justified. However, this should be stipulated in advice on this matter and be done in discussion with the woman, her menopause specialist as well as her oncology/breast team. Making women aware of the limitations and potential concerns is important to help them make an informed decision, taking into consideration the pros and cons of their choices. Our role is to guide women and help them make evidence-based, unbiased, informed choices, as per GMC guidance, after discussing the potential benefits, risks of harm and uncertainties of each option.

The NICE menopause guidance concluded: Do not offer hormone replacement therapy (HRT) (including estrogen/progestogen combination) routinely to women with menopausal symptoms and a history of breast cancer. HRT may, in exceptional cases, be offered to women with severe menopausal symptoms and with whom the associated risks have been discussed." ²

In addition, the BMS guidance recommends the following: ‘Women with ongoing symptoms who fail to respond to non-hormonal management should be referred to discuss their options with a menopause specialist and their oncology team to allow an individualised plan based on the woman’s own circumstances’. ³

Further research in adequately powered studies is needed to assess the risk of recurrence of breast cancer with HRT. However, based on current evidence, national and international guidance recommends that HRT should not be routinely offered to women with breast cancer.^2,3,12

Whilst there is a lack of adequately powered randomised data, there is a significant body of evidence, which supports the recommendation that systemic HRT should generally be avoided in breast cancer survivors and its use in this context should be done on an individualised basis (i.e. this is done on an exceptional basis rather than as standard practice).

Our statement emphasised current guidance on the topic and recommended that a history of breast cancer should be considered a contraindication to HRT. However, HRT may, in exceptional cases, be offered to women with breast cancer with severe menopausal symptoms if lifestyle modifications and non-hormonal treatment options are not effective.

The main references supporting the recommendations in our statement were included in the Editorial that was published simultaneously with the statement. ¹³

HRT in women with estrogen receptor negative breast cancer

The letter also referred to the lack of conclusive evidence on the risk of recurrence of breast cancer with HRT in women with estrogen receptor negative breast cancer.

Whilst women with estrogen receptor negative breast cancer are likely to have a lower risk of breast cancer recurrence with HRT compared to women with estrogen receptor positive cancer, this should not be interpreted as being without risk. The RCT trials referred to above included women with both estrogen receptor positive and estrogen receptor negative disease and were not sufficiently powered to address the risk for each group separately. Although there is high concordance in hormone-receptor status between first and second primary breast cancers, a minority with an ER-negative primary may present with an ER-positive contralateral cancer (up to 30%) and approximately 8% may present with ER-positive metastatic disease.^8–10

Whilst further evidence is needed to assess this, absence of evidence should not be viewed as evidence of safety. Guidance is therefore to advise women with estrogen receptor negative breast cancer in the same way as women with estrogen receptor positive breast cancer.

Based on the recommendations in national and international guidance, prescribing HRT to women with a personal history of breast cancer should only be done after appropriate multi-disciplinary input and on an individualised basis and in discussion with the woman’s oncology and breast team and not as standard practice.^2,3,8–12

HRT and risk of dementia

The letter questioned the recommendation that, HRT should not be initiated for the purpose of reducing the risk of dementia and referred to the study by, Kim et al. ¹⁴ that reported a lower risk of neurodegenerative diseases, including Alzheimer’s, in women who started HRT within 10 years of the menopause.

Whilst the study suggested a reduction in risk it had a number of methodological limitations. ¹⁴ The age at initiation of HRT and type of menopause (natural, surgical, or pharmacological) were not included. The study was limited to a 10 year analysis and women may have used multiple HRT preparations. The potential cross-over effect of different HRT preparations was not considered in the analysis. In addition, the study did not include information on the APOE genotype or family history of neurodegenerative diseases nor on the presence or severity of certain menopausal symptoms. The latter is an association which may affect the onset of age-associated neurodegenerative disorders. ¹⁴

The effect of HRT on the risk of dementia remains unclear, with studies reporting conflicting results. The Women’s Health Initiative Memory Study (WHIMS) reported that women who commenced HRT at the age of 50–55 did not show any measurable differences in tests of cognitive function, while women who commenced combined HRT over the age of 65 reported an increased risk of all-cause dementia. ¹⁵

The KEEPS Cognitive and Affective Study included 693 women (220 women randomised to receive 0.45 mg/day oral conjugated equine estrogen with sequential micronised progesterone, 211 women randomised to receive 50 mgm/day of transdermal estradiol with sequential micronised progesterone, and 262 women randomised to receive placebo. The study noted no improvement or worsening in cognitive outcomes during the 4-year intervention period of the study. ¹⁶

Savolainen-Peltonen et al. (2019) reported on the risk of Alzheimer’s disease with HRT in a nationwide case–control study from Finland. The study included 84,739 postmenopausal Finnish women diagnosed with Alzheimer’s disease compared to 84,739 controls. The study concluded that systemic HRT increased the risk of developing Alzheimer’s disease with both estrogen-only and combined estrogen–progestogen and was not related to the type of progestogen used. Women under the age of 60 at the time of initiation of HRT had an increased risk of developing Alzheimer’s with exposure of more than 10 years, whilst women over the age of 60 had an increased risk of developing Alzheimer’s with any exposure. ¹⁷

Current evidence suggest that HRT is unlikely to increase the risk of dementia or to have a detrimental effect on cognitive function in women initiating HRT before the age of 60. Based on the collective evidence, national and international guidance recommend that HRT should not be initiated for the sole purpose of improving cognitive function or reducing the risk of dementia in postmenopausal women.

Testosterone supplementation

In the letter, Dr Glynne also questioned the reference in the statement regarding the lack of evidence to support testosterone supplementation for the purpose of prevention or improving cognitive function, musculoskeletal health, improving bone density or fracture prevention.

Whilst further research is needed to assess this, current evidence, as summarised in national and international guidance including the Global Consensus Position Statement on the Use of Testosterone ¹⁸ and the International Society for the Study of Women’s Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women ¹⁹ does not support prescribing testosterone for the purpose of prevention or improving cognitive function, musculoskeletal health, improving bone density or fracture prevention.

Routine early hormone replacement in naturally menopausal women – HRT for disease prevention

Dr Glynne also questioned why naturally menopausal women (average age 51 years) are counselled differently to women with POI regarding the long-term benefits of HRT and the letter appears to suggest the need for routine early hormone replacement in naturally menopausal women.

Women with POI represent a different cohort to women who have natural menopause beyond the age of 50. Large observational studies have shown that women with POI and early menopause are at increased risk of cardiovascular disease, osteoporosis and cognitive impairment. ²⁰ As a result, all national and international menopause guidance recommends hormone replacement in women with POI and early menopause until the natural age of the menopause to protect against the long-term risk of cardiovascular disease, prevent osteoporosis and offer a protective effect on cognitive function.^2–4,20

The balance of benefits and risks with HRT, however, in naturally menopausal women over the age of 50 does not support a role for HRT in the primary or secondary prevention of disease.^3,12

Whilst the balance of benefits and risks for most women taking HRT for symptom management is favourable, this should be differentiated from recommending HRT for disease prevention without a clear indication for prescribing it.

HRT has been shown to have a protective effect against osteoporosis and related fragility fractures in both spine and hip. The NICE menopause guideline review assessed 20 RCTs that included sample sizes from 36 to 16,608 cases and 21 comparative cohort studies which included sample sizes from 157 to 170,852 cases. The evidence from RCTs in current users of HRT showed a significant reduction in the risk of fractures compared with women not using HRT. The evidence from comparative cohort studies showed reduced risk of fractures with current HRT use compared with non-use of HRT, whether used previously or never. ²

Whilst the evidence shows that the protective effective effect against osteoporosis is maintained during HRT intake and some beneficial effect may be noted for a longer period of time after stopping it, the evidence also shows this beneficial effect decreases once treatment stops. ²

In addition, Cochrane analysis suggests that HRT started before the age of 60 or within 10 years of the menopause is associated with a reduction in cardiovascular morbidity and mortality. ²¹ These findings are reassuring and should be discussed when counselling women about the benefits and risks associated with HRT intake. However, it would also be relevant to state that we have limited evidence regarding the optimal duration of intake in this context and the effect on long-term cardiovascular risk in later life after discontinuing HRT. As a result, national and international guidelines do not recommend the use of HRT for the primary or secondary prevention of cardiovascular disease.^2,3,12

For most women taking HRT the benefits are likely to outweigh the risks. However, this should be differentiated from a role in disease prevention in the absence of a clear indication for prescribing. For an intervention to be considered for prevention, there needs to be a clear demonstration of benefits over risks over defined periods of time also taking into consideration the effect of discontinuation on long-term effects. Menopause is a life stage and for many women this may not require intervention unless experiencing problematic symptoms. Menopause should not be viewed as a deficiency state. Based on current evidence HRT should not be recommended for disease prevention without a clear indication for prescribing.

The decision whether to take HRT and the duration of its use should be made on an individualised basis after discussing the benefits and risks with each patient. This should be considered in the context of the overall benefits obtained from using HRT including symptom control and improving quality of life, as well as considering the bone and cardiovascular benefits and the risk of breast cancer associated with HRT use.