Risks of Hormone Replacement Therapy (HRT)

Women need to be fully informed about the risks and benefits of HRT¹ .

Breast Cancer

Key points:Combined HRT increases the risk of breast cancer:¹

• The Million Women Study (MWS) ² found an increase in incidence of breast cancer within 1-2 years of starting treatment. Some have criticised the study suggesting that the apparent increase in the first year was actually due to observational bias.³
• The increased risk is proportional to the duration of HRT but not the age at which treatment is started.
• It appears to confer a comparable degree of risk to that associated with natural menopause (2.3% compared with 2.8% per year). ⁴ There will be an extra two cases of breast cancer per 1000 women using combined HRT from age 50 over 5 years.
• The excess risk subsides within 5 years of stopping.
• The additional breast cancer risk with HRT for an individual is small.
• The invasive breast tumours diagnosed in the combined HRT group of Women's Health Initiative (WHI) study⁵ were larger and more advanced than the placebo group. Previously it had been thought that breast tumours found in HRT users had a better prognosis.
• Tibilone increases the risk of breast cancer but to a lesser extent than combined HRT.

MWS² suggested a small increase in risk of breast cancer with oestrogen-only HRT compared to combined HRT. This was not found in WHI⁶ with unopposed oestrogen over 7 years.
It is possible to provide more quantified risks for women enquiring about their HRT use and breast cancer risk using the table below⁷. For example, your patient aged 50 has:

• A 6.1% baseline risk of getting breast cancer in the next 30 years.
• If she takes combined HRT for 3 years the risk rises to 6.41% (baseline risk plus additional risk)
• With HRT for 5 years, it rises to 6.7%.
• If she takes oestrogen only HRT for 5 years, the risk is 6.28%.

Cardiovascular Disease

Key points:¹

• HRT is not cardio-protective as originally thought and may increase the risk of coronary heart disease in the first year of treatment.
• No increased risk of heart disease was found in the oestrogen-only arm of WHI after 7 years.
• Risk of stroke is increased in those taking HRT.
• WHI suggests a small increase in overall rate of stroke in women taking combined HRT from 21 to 29 per 10,000 women-years.
• The risk of stroke with oestrogen-only HRT is higher accounting for an additional 12 strokes per 10,000 women-years.
• HRT does not appear to protect against cognitive decline. The WHI Memory Study trials suggest that HRT (pooled combined and oestrogen-only) increases the risk of dementia from 23 to 41 cases per 10,000 woman years.⁸

Venous thromboembolism (VTE)

Key points:¹

• HRT increases the risk of a DVT or PE especially in the first year of treatment.
• The baseline risk of VTE increases with age and use of HRT further adds to this risk.
• Women with additional risk factors for VTE should review the need for HRT as risks may outweigh potential benefit.

Gynaecological cancer

Key Points:¹

• Oestrogen only HRT and tibilone are associated with a small increase in endometrial cancer.
• The use of oestrogen-only HRT over 5 years would account for an extra 5 cases per 1000 (above the 3 per 1000 in women not using HRT in the same period).
  Combined HRT (with progestogen for at least 12 days per month) decreases the risk of endometrial cancer with HRT but because breast cancer is more common than endometrial cancer, there remains a higher risk of cancer using combined HRT compared to oestrogen-only HRT.
• There is a small increased risk of ovarian cancer developing in current users of HRT (but not past users), which increases with increasing duration of use, and is seen whichever preparation, constituents, or mode of administration is used.⁹ It amounts to one extra ovarian cancer for every 2500 users every five years.^9,10

The pendulum is beginning to swing back towards recognition of the valid therapeutic uses of HRT following the scare post-media reporting of the WHI and MWS. The British Menopause Society consensus statement (2006) stresses potential benefits can outweigh harms given appropriate dose, route and combination.⁴ WHI, on which many of our prescribing decisions are based, recruited post-menopausal women who were an average 63 years old (ie older than average UK HRT users) and thus may not necessarily be relevant to our younger postmenopausal patients.

Current indications

• To treat menopausal symptoms where the risk/benefit ratio is favourable, in fully informed women, in the lowest possible doses to control symptoms and for the shortest duration of treatment. ^11,12 This is in contrast to the International Menopause Society's guidelines (2004) which saw no new reasons to place mandatory limits on duration of use of HRT.³
• For women with premature ovarian failure (<45 years) until the average age of natural menopause (i.e. until aged 50). Since HRT only raises the risk of breast cancer in these women to that of their menstruating peers, they should not undergo early mammographic screening.^11,12

HRT does still have a clinical role in improving the quality of life in symptomatic menopausal women and many have opted to remain on HRT despite recent findings.¹¹

If long term HRT is needed:

• Long-term combined preparations are riskier than oestrogens alone.
• Consider using oestrogens alone with an IUS in women with a uterus.
• Consider tibilone (MWS showed a small increase in breast cancer but other studies have not shown this) and appears safer than combined HRT for relieving symptoms and bone protection.
• Use low dose topical oestrogens for uro-genital atrophy - no evidence of significant increased risk with long term use.
• Keep women on HRT under regular review. Assess the merits of long term use on an individual basis, possibly yearly.⁴

Do not use HRT

• In women with a history of breast cancer.
• In healthy women without menopausal symptoms (as risks outweigh benefits).