Published: July 1998

Hormone Replacement Therapy and Breast Cancer, Endometrial Cancer and Venous Thromboembolism

Information on this subject has been updated. Read the most recent information.

Prescriber Update 16:10–15
July 1998

Medsafe Editorial Team

Seven recent studies have examined risks associated with hormone replacement therapy (HRT), namely breast and endometrial cancer and venous thromboembolism. The studies have confirmed associations with each of these events and identified risk factors.

A major reanalysis of 90% of the worldwide data on breast cancer and HRT found that current and recent users had a small increase (2.3%) in relative risk associated with each year of use of HRT. There was no significant increase in risk among women who had last used HRT at least 5 years earlier. These findings translate into an increase in absolute risk of breast cancer in women aged 50-70 years from a baseline of 45 cases in 1000 to 47 in 1000 with 5 years use.

Two separate studies of around 830 cases each found that unopposed oestrogen therapy increased the risk of endometrial cancer by two- or four-fold. Protection against the effects of oestrogen was achieved by taking progestogen for ≥ 10 days per cycle, but one study found some risk persisted in long term users. The risk declined with time since last use. These results suggest a rise in the absolute risk of endometrial cancer for 50-year-old women taking unopposed oestrogen therapy from 2 to 4-8 cases per 1000 women in 5 years.

Four studies found that HRT increased the risk of venous thromboembolism by around 2 cases per 10,000 woman-years. The risk appeared to be increased by higher doses of oestrogen, but appeared to be independent of use of progestogen.

These risks, along with the individual woman’s risk factors for these conditions, need to be considered along with the benefits expected in the individual before prescribing HRT.

Women take oestrogen therapy for the relief of symptoms of the menopause, such as hot flushes, and for long term health advantages such as reducing the risk of osteoporosis and heart disease. However, there has been concern about possible risks in both the short and long term use of hormone replacement therapy (HRT). Recently several significant studies have evaluated the associated risks of breast cancer, endometrial cancer and venous thromboembolism.

Breast Cancer

Study included data on 22,189 postmenopausal women with breast cancer

The Collaborative Group on Hormonal Factors in Breast Cancer1 has conducted a major reanalysis of individual data on 52,705 (22,189 postmenopausal) women with breast cancer and 108,411 (45,181 postmenopausal) women without breast cancer in order to assess the additional risk of breast cancer from using HRT. The study included data from 51 epidemiological studies which included at least 100 cases and had information on each woman’s use of HRT, reproductive history and menopause (90% of worldwide data on this subject).

Risk of breast cancer increased with delayed menopause

The data for those who had never used HRT were first analysed for an association between age at menopause and risk of breast cancer. As expected the analysis found that postmenopausal women had a lower risk of breast cancer than premenopausal women of the same age and childbearing pattern. The relative risk of breast cancer increased by 2.8% for every year older at menopause. It also increased with body-mass index by 3.1% per kg/m².

Risk increases by a small amount (2.3%) for each year of use (current and recent users)

The analysis for risk of breast cancer with use of HRT included 17,949 cases and 35,916 controls. 30% of the cases and 34% of the controls had used HRT at some time. The median age at first use was 48 years and 96% of users commenced therapy before 60 years.

Current or recent (within the last 5 years) users were found to have a relative risk that increased with duration of use (2.3% per year; 95% CI 1.1-3.6%), but past users had no significant increase in the relative risk of breast cancer. For current or recent users who had used HRT for ≥ 5 years the relative risk of breast cancer was 1.35 (1.21-1.49); the average duration of use in this group was 11 years.

The data were used to estimate absolute risk. Between the ages of 50 and 70 years, about 45 in 1000 women who have never used HRT will be diagnosed with breast cancer. The figure increases to 47 with 5 years use of HRT, to 51 with 10 years use, and to 57 with 15 years use.

Low body-mass index was the only modifying factor identified

Further analysis looked for categories of women for which HRT use was associated with an additional relative risk of breast cancer, including family history, parity, alcohol consumption, type of menopause, and combined oral contraceptive use in the past 10 years. None of these significantly increased the effect of HRT. Nevertheless, some of these factors, e.g. family history, increase the baseline risk, and hence are associated with a higher absolute risk through the use of HRT.

However, further analysis found a significant increase in the relative risk of breast cancer for current and recent users of low weight or body-mass who had taken HRT for long periods. This group have a lower than average baseline risk of breast cancer.

Women who had used HRT were significantly less likely to have a tumour that had spread beyond the breast to axillary lymph nodes or more distant sites. Nevertheless, results from the US Nurses Health Study suggest that long term (≥ 10 years) users have an increased risk of death from breast cancer.2

Only 12% of the women who had used HRT in the Collaborative Group Study had used combination preparations containing progestogen. No significant difference in the risk of breast cancer was found for these women.

Increased risk may reflect effective delaying of menopause

The authors suggest that these results may simply reflect a delaying of the effect of menopause on the breast cancer risk by replacing the levels of circulating ovarian hormones. However, other factors such as earlier diagnosis among those who receive HRT may have influenced the results. The association with body-mass index may be because oestrogen is largely produced by adipose tissue in postmenopausal women.

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Endometrial Cancer

Lower risk of endometrial cancer with ≥ 10 days progestogen per month

Two studies have examined the risk of endometrial cancer in those taking HRT and the advantage of cyclical progestogen therapy in reducing the risk. Both studies found that the progestogen needs to be taken for at least 10 days per cycle for it to provide protection against the risk of endometrial cancer.

Even with ≥ 10 days progestogen per month risk may be elevated after 5 years

The first study3 included 832 cases identified from a cancer registry in Washington State, and 1114 controls selected by random telephone dialling. The study found that women who had used unopposed oestrogen had a relative risk of endometrial cancer of 4.0 (95% confidence interval 3.1-5.1) compared with non-users. For those who had added progestogen for < 10 days per month for 6-35 months the relative risk for endometrial cancer was 2.1 (0.9-4.7), but for those who had added progestogen for ≥ 10 days per month the relative risk compared with non-users was 0.8 (0.4-1.8). Even this second group had an increased risk of endometrial cancer above non-users if they had used HRT for more than 5 years (relative risk 2.5; CI 1.1-5.5). However, the effect of different strengths of progestogens was not investigated.

Risk declines with time since last use

Similar results were obtained by another study4 which included 833 women aged 50-74 years with a diagnosis of endometrial cancer and 791 matched controls from Los Angeles County. The relative risk per 5 years of use for endometrial cancer in those who had received hormone replacement with oestrogen alone was 2.17 (1.91-2.47), in those who had received progestogen for < 10 days per cycle it fell to 1.87 (1.32-2.65), in those who received progestogen for ≥ 10 days per cycle it was 1.07 (0.82-1.41), and for those on continuous combined oestrogen and progestogen it was 1.07 (0.80-1.43). The risk of endometrial cancer declined with time since last use, with a relative risk of 1.63 (1.04-2.53) associated with use of oestrogen replacement therapy ending ≥ 10 years previously. There was a non-significant trend to higher risk with treatment at higher oestrogen doses.

For postmenopausal New Zealand women around 50 years of age the absolute risk of developing endometrial cancer is about 2 in 1000 in 5 years. The results of these studies suggest that the absolute risk associated with the use of unopposed oestrogen is 4-8 cases per 1000 women in 5 years.

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Venous Thromboembolism

For some time there has been a suspicion that HRT may increase the risk of venous thromboembolism (VTE). Recently four well-designed epidemiological studies provided evidence of this association and found that the additional risk was similar to that for low dose oral contraceptives in younger women—around 2 cases per 10,000 woman-years.

Risk of VTE increases with HRT, particularly in the first year

The first study by Daly, et al5 was conducted in Oxford, England and included 103 cases of idiopathic VTE in women aged 45-64 years, and 178 age-matched controls admitted to hospital with unrelated disorders. Women with cancer or serious heart disease, and those using anticoagulants or oral contraceptives were excluded. The relative risk for VTE in current users of HRT compared to past or never users and adjusted for the independent risk factors of history of varicose veins, body-mass index and socioeconomic status was 3.5 (95% CI 1.8-7.0). Short term current use was associated with a higher risk of VTE with a relative risk of 6.7 (2.1-21.3) for a current duration of use of 1-12 months.

Risk increased with higher oestrogen doses

Jick, et al6 selected women aged 50-74 who were admitted to hospital with idiopathic VTE from the Group Health Co-operative of Puget Sound, Washington State. Cases with medical conditions predisposing to VTE were excluded from the analysis which included 42 cases and 168 matched controls. The relative risk of VTE with current use of HRT was 3.6 (1.6-7.8). Again short duration of current use was found to be a risk factor. Another factor found in this study was oestrogen dose, with daily doses ≥ 1.25mg of conjugated oestrogens associated with a relative risk of 6.9 (1.5-33.0).

Cigarette smoking does not appear to be a risk factor

The American Nurses’ Health Study cohort was used in a third study7 as the source for identifying 68 documented cases of primary pulmonary embolism (but not deep vein thrombosis) in postmenopausal women without medical risk factors. Women with cardiovascular disease or cancer were excluded. The adjusted relative risk of pulmonary embolism in current users of HRT was 2.1 (1.2-3.8). Short term use appeared to be associated with greater risk, but current dose was not found to change the risk. No additional risk was associated with cigarette smoking in this or the study by Jick, et al.

Use of progestogen did not appear to change the risk

A larger study by Gutthann, et al8 used the General Practice Research Database in the United Kingdom. The cases were 292 women aged 50-79 years admitted to hospital with a first episode of VTE. 10,000 controls in the same age range were selected from the same source. Women with a previous thromboembolic event or major risk factors for these events were excluded. The study confirmed that a history of varicose veins and body mass index > 25 kg/m² were risk factors for VTE. The relative risk for VTE in those using HRT was 2.1 (95% CI 1.4-3.2) after adjusting for age, history of varicose veins or superficial phlebitis, bilateral oophorectomy, body-mass index, smoking and calendar year. There was an inverse relationship between risk and duration of use with the highest risk occurring in the first 6 months: relative risk 4.6 (2.5-8.4). The dose of oestrogen, the use of progestogen and route of administration (oral or transdermal) did not significantly change the risk.

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Weigh benefits and risks when considering HRT

The study of breast cancer and HRT is a definitive work on this subject. The studies of endometrial cancer and venous thromboembolism are based on smaller numbers of patients, but all appear to have been well-conducted. Elevation in the risk of venous thromboembolism is theoretically likely and the consistency of the results of the recent studies suggests that the additional risk is real. The fact that oestrogen replacement therapy increases the risk of endometrial cancer has been known for some time. It is notable that two reasonably sizeable studies have found that ≥ 10 days of progestogen per month is necessary for protection against the effects of oestrogen on the uterus, and that one of these studies found that protection is not complete in long-term users.

When considering the need for HRT the woman’s risk factors for breast cancer and venous thromboembolism should be identified and the risk of these events and endometrial cancer weighed against the expected benefits, including relief of the symptoms of menopause, increased bone density and reduction in the risk of myocardial infarction.

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  1. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer. Lancet 1997;350:1047-59.
  2. Grodstein F, Stampfer MJ, Colditz GA, et al. Postmenopausal hormone therapy and mortality. New Eng J Med 1997;336:1769-75.
  3. Beresford SAA, Weiss NS, Voigt LF, McKnight B. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet 1997;349:458-61.
  4. Pike MC, Peters RK, Cozen W, et al. Estrogen-progestin replacement therapy and endometrial cancer. J Nat Can Inst 1997;89:1110-6.
  5. Daly E, Vessey MP, Hawkins MM, et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996;348:977-80.
  6. Jick H, Derby LE, Wald Myers M, et al. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet 1996;348:981-3.
  7. Grodstein F, Stampfer MJ, Goldhaber SZ, et al. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 1996;348:983-7.
  8. Gutthann SP, García Rodríguez LA, Castellsague J, Duque Oliart A. Hormone replacement therapy and risk of venous thromboembolism: population based case-control study. BMJ 1997;314:796-800.