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HRT: the risks and benefits for patients

If a patient asks if she should stop her hormone replacement therapy, what would you advise? Dr Helen Crawley provides some of the answers

hould I stop my HRT, doctor? After reading a plethora of conflicting articles my patients want some solid advice. My approach is to summarise the most up-to-date evidence so that each patient can make an informed decision.

Definite benefits

lRelief of menopausal symptoms There is good evidence from several trials that oestrogen therapy improves hot flushes as well as urogenital symptoms such as vaginal dryness, dyspareunia and urinary tract infections. For many women a couple of years of HRT are sufficient to tide them over the worst of their menopausal symptoms. Other women revert to unacceptable vasomotor symptoms whenever they try to discontinue their HRT and would prefer to continue treatment.

lColorectal cancer The Women's Health Initiative (WHI) included 16,608 women randomised to either placebo or continuous combined therapy of equine oestrogen 0.625mg with medroxyprogesterone acetate 2.5mg. The patients were aged 50 to 79 and had an average age of 63 at baseline. After a mean of 5.2 years follow-up there were six fewer cases of colorectal cancer per 10,000 patient-years.

lOsteoporosis Although oestrogen increases bone density the benefits appear to be confined to current or recent users. In the WHI study there were five fewer hip fractures per 10,000 patient-years. Most previous studies have not found a significant reduction in the number of vertebral or non-vertebral fractures, probably because the participants were younger and had a lower background risk.

Definite risks

lVenous thromboembolism

HRT should be used with caution in patients with risk factors for venous thromboembolism (VTE) such as obesity, prolonged bedrest, severe varicose veins, surgery, trauma or a personal or family history of VTE. The WHI study found an excess risk of 18 cases of VTE per 10,000 patient-years. This risk was higher than in most previous studies because the patients were older with a higher background risk. Mortality from VTE is around

1-2 per cent.

lBreast cancer Using pooled data the CSM advises that in women aged 50 not using HRT, about 45 per 1,000 will be diagnosed with breast cancer over the next 20 years. This rises to 47 per 1,000 with five years of HRT use, 51 with 10 years of use and 57 with 15 years'

use. The WHI study confirmed an excess risk of an additional eight cases per 10,000 patient-years in this older

study group.

The excess risk of breast cancer seems to disappear within about five years of stopping HRT. In women on HRT, breast cancers are less likely to have spread beyond the breast at diagnosis.

The type of HRT seems to affect risks. HRT is known to increase breast nodularity with combined oestrogen and progestogen preparations changing the breast more than oestrogen alone and continuous combined preparations increasing breast density more than sequential use.

Evidence is emerging that combined preparations increase the risks of breast cancer more than oestrogen alone. It is possible the effects of progestogens on the breast could be overcome by using a Mirena interuterine device together with systemic oestrogen. Alternatively, tibolone is suitable for women 12 months after their last period. It appears to have no adverse effects on the breast.

Risks and probable benefits

lEndometrial cancer In women with a uterus unopposed oestrogen increases the risk of endometrial cancer substantially. There will be about 420 extra cases for every 10,000 women treated for 10 years. Sequential combined HRT reduces the risks to

200 cases per 10,000 women treated for 10 years.

But the use of continuous combined HRT does not increase the risk of endometrial cancer and may even be protective compared with non-use of HRT. In recent studies of continuous combined therapy using 2mg oestradiol and 1mg norethisterone all women who had developed complex hyperplasia on sequential HRT returned to normal on continuous combined therapy. Whether this reduction in the risk of endometrial cancer occurs only with norethisterone or applies to all continuous combined preparations is not known.

Long-term users of HRT should consider switching from sequential to continuous combined therapy once they are safely past their biological menopause (eg, aged 54). But the uncertainties on cardiovascular risks should be discussed.

Controversial evidence

lCardiovascular disease Although observational studies suggest oestrogens reduce the risk of coronary heart disease, the publication of HERS, HERSII and the WHI study have thrown these findings into dispute. Both these studies looked at the effects of continuous combined therapy of 0.625mg conjugated oestrogens and 2.5mg medroxyprogesterone acetate daily: the nearest British equivalent is Premique containing 5mg medroxyprogesterone acetate daily. In the HERS studies HRT did not provide protection against non-fatal myocardial infarction or cardiac death in women with established coronary heart disease. There was an excess of seven coronary heart disease events and eight strokes per 10,000 patient-years in the WHI study of women without previous cardiovascular disease.

The CSM has taken the cautious approach that HRT should not be used for prevention of coronary heart disease. Other experts have pointed out HRT containing only oestrogens or other progesterones may have different biological effects on the cardiovascular system.

lMemory It appears from observational studies that HRT users have a 34 per cent decreased risk of developing Alzheimer's, although the quality of evidence is poor. A well-designed trial has shown that HRT did not improve patients with established Alzheimer's.

lOvarian cancer Recent research indicates a small increased risk of ovarian cancer with long-term use of oestrogen-only HRT. The effects of combined HRT are not clear.

What this means for patients

HRT is only licensed for the control of vasomotor symptoms and treatment of osteoporosis. In the WHI study mortality did not differ significantly between those taking placebo and those on HRT. Overall, women are unlikely to suffer significant adverse effects from taking HRT for a couple of years around the menopause to control vasomotor symptoms.

Non-hysterectomised women who continue to take HRT long after their menopause should probably be on continuous combined HRT because of the better protection this gives to the endometrium. But the effects of continuous progestogen on the breast and heart compared with sequential progestogen are not fully understood. Delivering progestagen directly to the uterus rather than systemically may turn out to be the best solution.

What next?

The oestrogen-only arm of the WHI study continues and will hopefully provide useful data on the effects of unopposed oestrogen. The British WISDOM study has now been halted. It was due to report in 2012 and was looking at quality of life markers as well as cardiovascular disease and cancers. The study has been abandoned because it was so similar to the WHI study that significant new data was unlikely.

HRT: the risks and benefits for patients

Women's Health Initiative study results

Event Events per 10,000 Events per 10,000 Difference in events

patient-years patient-years per 10,000

for placebo for HRT patient-years

Coronary heart 30 37 7 more

disease (non-fatal MI

and cardiac death)

Stroke 21 29 8 more

Breast cancer 30 38 8 more

VTE 16 34 18 more

Hip fracture 15 10 5 less

Colorectal cancer 16 10 6 less

Total mortality 53 52 Not significant

Long-term users should consider switching to continuous combined therapy once they are past the menopause~

Key points

Definite benefit

lRelief of menopausal symptoms

lColorectal cancer


'Grey areas'

lEndometrial cancer

lCardiovascular disease


lOvarian cancer

Definite risk

lVenous thromboembolism

lBreast cancer

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