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1994-96


Pilot studies involving 6,000 women found that the questionnaire was acceptable and that receiving the questionnaire did not affect whether or not women went to screening. The pilot studies also showed that around one third of women attending the NHS Breast Screening Programme were using hormone replacement therapy (HRT), and that if a large scale study of hormone replacement therapy and women’s health were to go ahead, the vast majority of those attending screening would take part.

1997


Launch of Million Women Study at 66 NHS Breast Screening Centres nationwide.
Around a third of women attending the NHS Breast Screening Programme were using hormone replacement therapy (HRT), and the majority of those attending breast screening said they would take part in a large scale study of hormone replacement therapy and women’s health.

2001


The Million Women Study finished recruiting - 1.3 million participants. Most women in the study were aged 50-64 at recruitment, with an average age of 56 years.  

2005


Collection of blood samples for genetic studies started via GP practices in England and Scotland and continues, along with follow-up of all women in the study through NHS medical record linkage and through follow-up questionnaires. Disease Susceptibility in Women 

The results from the study are published in peer-reviewed journals. (See Publications).

 

Analysis of responses to the recruitment questionnaire showed that among MWS participants:

  • 1 in 2 women had taken the oral contraceptive pill
  • 1 in 2 women had tried HRT
  • 1 in 3 women was currently using HRT
  • 1 in 4 had a hysterectomy
  • 1 in 11 had a close female relative with breast cancer
  • 1 in 70 had been diagnosed with breast cancer in the past

Use of HRT was strongly influenced by age and medical history – 48% of those who had a hysterectomy currently used HRT, but only 6% of women with a history of breast cancer used HRT.

HRT and breast cancer

  • Women currently using HRT are more likely to develop breast cancer than those who are not using HRT. Past users are not at increased risk.
  • Current users of oestrogen-progestagen HRT were at 2 fold increased risk of developing breast cancer, and current users of oestrogen-only HRT at 1.3 fold risk. 
  • The effects were similar for all specific types and doses of oestrogen and progestagen, (including pills skin patches, gels and HRT implants). 
  • Use of HRT by women aged 50-64 in the UK from 1993-2003 resulted in an estimated 20,000 extra breast cancers. 
  • Current users of hormone replacement therapy are more likely to be recalled for further assessment after mammography. (Banks et al, 2004 and 2005)
  • The effects of HRT on breast cancer risk vary depending on the histological (cell) type of tumour, with greater increases in risk for lobular and tubular than for ductal types. (Reeves et al, 2006)
  • Breast cancers in women with a family history of the disease are similar in size and type to those in women with no family history of breast cancer. (Couto et al, 2008)

HRT and endometrial cancer

  • Post-menopausal women who have not had a hysterectomy are at increased risk of cancer of the endometrium (the lining of the womb) if they take oestrogen-only HRT.
  • The risk of endometrial cancer is increased in women who take tibolone; but is not altered, or may be reduced, in women taking combined oestrogen-progestagen HRT (MWS 2005). The adverse effects of tibolone and oestrogen-only HRT are greatest in thinner women, and the beneficial effects of combined HRT are greatest in fatter women.

HRT and ovarian cancer

  • Women currently taking HRT have a 1.2 fold increase in risk of ovarian cancer. Past users are not at increased risk.
  • The risk is the same for oestrogen-only, combined oestrogen-progestagen and other types of HRT (including tibolone) and does not vary by type of oestrogen or progestagen, or between oral and patch administration.
  • The results are equivalent to one extra case of ovarian cancer for every 2500 women taking HRT, and one extra death from ovarian cancer per 3300 women taking HRT, over 5 years.

HRT and the overall risks of breast, endometrial and ovarian cancers

  • Breast cancer, endometrial cancer and ovarian cancer account for about 4 in 10 cancers in women in the UK.
  • In every 1000 women aged 50-69 who are not taking HRT, about 19 of these cancers will develop over 5 years. In those taking HRT this number is estimated to increase to about 31.
  • For women using combined oestrogen-progestagen HRT the increase is from 19 to 34 cancers over 5 years and in those using oestrogen-only HRT the increase is from 19 to 26 cancers over 5 years. This is because most of the overall increase is due to an increase in breast cancer, combined HRT has a higher risk of breast cancer than oestrogen-only HRT.
  • These results should be considered in the context of the other risks and benefits of HRT. Advice is to use HRT for as short a time as possible to treat menopausal symptoms.

HRT and rare cancers

  • For relatively rare cancers, any effect of HRT use on the risk of relatively rare cancer risk will not affect many people, but may help us to understand how cancers develop.
  • We found about 40% increased risk of brain tumours in women using HRT compared to women not using HRT but these cancers remain rare whether or not HRT is used. (Benson et al, 2010).

HRT and bones, joints, and gallbladder

  • HRT use reduces the risk of fractures, particularly those linked to osteoporosis. Risk of fracture in current users of HRT is about 40% lower than in non-users.
  • This protection increases the longer a woman uses HRT, but wears off rapidly after use ceases (Banks et al, 2004). 
  • Fractures are more common in older women so the number of fractures prevented by older women using HRT would be higher. However, women generally take HRT around the time of the menopause, when fracture risks are low, and the benefits for bone health do not persist after HRT use stops.
  • Overall, the increased risks of breast cancer and stroke associated with HRT use outweigh the reduced risks of fracture, and HRT is no longer recommended as a first-line treatment for osteoporosis.
  • HRT users are about 50% more likely than non-users to have joint replacements. The reasons for this association are not clear (Liu et al, 2008).
  • Gallbladder disease is common in postmenopausal women, and use of HRT increases the risk.
  • The increase in risk is much smaller in women using  patches and gels in which the hormones are absorbed through the skin, than in women using oral HRT.
  • This is thought to be because the hormones in oral HRT are processed by the liver and gallbladder before they circulate around the body whereas  transdermal HRT is absorbed directly into the blood stream and so hormone levels in the liver and gallbladder system are much lower.
  • Over a 5 year period 1.1 in 100 women who had never used HRT were admitted to hospital for removal of the gallbladder, compared with 1.3 per 100 tusing transdermal HRT and 2 per 100 taking oral HRT.

Other areas of study, including childbearing, smoking, alcohol, body size and diet

  • A woman’s reproductive history includes the age when her periods started (menarche), the number of children she has had, her age when they were born, whether she breastfed; and her age at menopause.
  • These factors are related to the natural levels of female hormones in the body, such as oestrogen and progesterone so are often linked to risk of breast cancer, which is also affected by use of female sex hormones for contraception or as HRT (Reeves et al, 2009),
  • Risk of gallbladder disease increases with the number of children a woman has; but there is a reduction in risk in women who breastfeed (Liu et al, 2008).
  • Risk of having hip or knee replacement surgery is higher in women with more children, taking into account related factors such as activity and body weight (Liu et al, 2008).
  • For women of similar age, postmenopausal women have twice the risk of hip fracture compared to women before the menopause, in older women it is age itself, and not age at or since menopause, which determines most of the fracture risk. (Banks et al, 2009).
  • Smoking increases the risk of pancreatic cancer (Stevens et al, 2008), but is not linked to risk of glioma or meningioma tumours of the brain (Benson et al, 2008).
  • There is no association between passive smoking and risk of breast cancer (Pirie et al, 2008),
  • Overall, cancer risk increases, the more alcohol is consumed, with a rise of 6% for every 10g of alcohol (about 1 unit) per day (Allen et al, 2009).
  • Risk is increased by 30-40% for cancers of the mouth and throat in women who also smoke, but because breast cancer is by far the most common cancer in middle aged women, the increase of about 12% per daily drink for breast cancer (regardless of smoking) makes the biggest contribution to the overall increased risk. Is this also Allen et al 2009?
  • For a few cancers, such as non-Hodgkin lymphoma, risk is lower in women who drink alcohol than in non-drinkers.
  • Smoking and alcohol affect the risks of cirrhosis of the liver and for gallbladder disease in different ways (Liu et al, 2009). For cirrhosis, alcohol and smoking separately increase risk, and their joint effects are particularly hazardous. For gallbladder disease, alcohol reduces risk and smoking results in a small risk increase.
  • The MWS collected detailed information on women’s body size throughout life, including birth weight, waist and hip measurements and weight and height at recruitment and at follow-up.  We also obtained height, weight, waist and hip measurements from a sample of women to compare with self-reported values and compare reported birth weights with those in medical records. 
  • Body size influences risk of many cancers and other conditions. 5% of all cancers in postmenopausal women in the UK, may be due to being overweight (BMI of 25-29) or obese (BMI of 30 or more) (Reeves et al, 2007).
  • Obesity is a major factor for endometrial cancer and for adenocarcinoma of the oesophagus.
  • The effects of HRT are greater in thinner women. This is thought to be because fatter women have higher levels of natural oestrogens, so the added hormones from HRT have less effect.
  • Risk of glioma and meningioma tumours of the brain is linked to height. The risk for the tallest women in the study is about 30% higher than for the shortest. (Benson et al, 2008).
  • We estimate that 17% of cases of cirrhosis in middle aged women in the UK may be due to overweight and obesity, compared with 42% due to drinking alcohol.
  • It is estimated that a quarter of hospital stays for gallbladder disease are related to obesity.

Genetic studies

  • Since 2006 we have collected more than 40,000 blood samples from women in the study [When was this written and what is the figure now?], The large size of the study, and information we have on environmental risk factors, enables us to examine how genetic and non-genetic factors act separately and together to affect disease risk.
  • The risk of breast cancer linked to several common genes which each carry a small increased risk of breast cancer was the same regardless of lifestyle factors such as childbearing, HRT use, obesity and alcohol consumption (Travis et a1 2010).
  • Both genes and lifestyle affect breast cancer risk independently.

Estimating the overall effects of common genes on breast cancer risk

  • We studied seven genes which increase breast cancer risk by about 10-20% and estimate that a woman who has several of these genes may have about twice the risk of developing breast cancer compared with a woman with no or very few such genes.
  • The risk associated with these genes is small compared with other known factors for breast cancer, such as use of HRT and childbearing and breastfeeding patterns. (Reeves et al, 2010). 
  • Genetic factors account for only about 20% of breast cancers, and about a quarter of these, 5% overall, are linked to the high risk genes BRCA1 and 2.
  • These genes have different effects on risk of different types of breast cancer. The main common low-penetrance genes are more strongly linked to risk of oestrogen-receptor (ER) positive than to ER negative breast cancers.

Validation and methodological studies

  • Throughout the study, we have conducted a number of  studies to compare the self reported information collected in questionnaires with similar information recorded elsewhere such as medical records and hospital admission data.

Collaborations

  • Data from the Million Women Study is included in several international collaborative studies. Data from many studies worldwide are re-analysed in a standard way so that the information can be pooled to give as complete and reliable a picture of disease risk as possible.

Public Health Implications: impact of the Million Women Study

  • Results from the Million Women Study, and from other studies such as the Women’s Health Initiative trial in the USA, have influenced national policy, including recommendations on the prescribing and use of hormone replacement therapy from the Royal College of Obstetricians and Gynaecologists and from the Commission on Human Medicines.
  • Because HRT use is linked to higher rates of breast and other cancers, and of stroke, it is recommended that it should generally only be used for a few years to relieve menopausal symptoms, although the balance of risks and benefits of HRT should be considered for each woman individually.
  • Use of HRT has fallen by about half in the UK and across the world.
  • Fewer breast cancers are now developing in women in their 50s and 60s, the age group most likely to use HRT.
  • While other factors need to be considered, it is thought that the fall in numbers of breast cancer cases and the reduction in use of HRT are linked.