Uterine (womb) cancer risk factors

Most of the established risk factors for uterine cancer are the result of excess exposure to oestrogen unopposed by progestagens , a process that stimulates proliferation of the cells of the womb, increasing cancer risk.1 In addition, insulin and insulin-like growth factors may increase the effect of oestrogen on uterine tissue.2 As all oestrogen exposure is unopposed in postmenopausal women, high circulating levels of oestrogens and androgens in these women is known to increase risk.36 Being overweight increases oestrogen levels in postmenopausal women3 and can disrupt ovulation and progesterone production in premenopausal women, resulting in continuous exposure of the womb to unopposed oestrogen (see section on bodyweight below).4 However, women with the highest levels of sex hormone binding globulin (which governs the bioavailability of oestrogens and androgens) have a significantly reduced risk.2,5

Pregnancy and parity reduce risk of uterine cancer by 30% for a woman’s first birth and by 25% for each successive birth,1 and later maternal age at last birth has also been shown to reduce risk.1 Recent results from the European Prospective Investigation into Cancer and Nutrition (EPIC) show that risk reduces by 22% per cumulative year of full-term pregnancy.37 Pregnancy and childbirth are thought to offer reduced risk through the elimination of pre-malignant cells with the “sloughing-off” of cells during delivery, and/or the break in unopposed oestrogen exposure during pregnancy. Research seems to suggest a greater protective effect of parity on post-menopausal than pre-menopausal women6,7 but results have been inconsistent.8 Early menarche and late menopause significantly increase risk, because they prolong years of oestrogen exposure.1 EPIC showed a risk reduction of 7-8% per year less of menstrual life.37 Other factors associated with increased risk include lack of, infrequent or irregular periods, periods, annovulatory menstrual cycles.   and more days of menstruation4,7

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Evidence suggests that risk of uterine cancer is 2-3 times higher in overweight and obese women, respectively.9-13 A study published in December 2011 estimated that around 34% of cases of uterine cancer in the UK in 2010 were linked to excess bodyweight.39 Prospective studies, mainly among post-menopausal women, report a significant association with BMI at enrolment, but also suggest that women’s BMI in younger adulthood is significant and that the increase in risk begins at a relatively modest raised BMI.8,9 Some evidence suggests that waist circumference and waist-to-hip ratio may be more important than BMI, with significant increases in risk reported in women in the two lowest quartiles of BMI but the highest quartile of waist circumference.10 However, more studies are needed to clarify the effects of central and peripheral obesity and risk of uterine cancer in both premenopausal and postmenopausal women.

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Recent results from the UK Million Women study report an increased risk of 50% among current users of oestrogen-only  hormone replacement therapy (HRT) and 80% in those using tibolone preparations. A meta-analysis of published studies reported in the same paper found there was a non-significant reduced risk for ever versus never users of continuous combined therapy, and a small but significant increase in risk for cyclic combined.14 The study did not have enough past-users to calculate risk after stopping HRT, but a Swedish case-control study reported an ongoing significant increase in risk in women who had used oestrogen-only HRT but had stopped five or more years previously.15 Since that meta-analysis, a Finnish study showed that women taking continuous-combined HRT had a 76% reduction in endometrial cancer risk, while women taking sequential HRT for at least five years had a 70% risk increase if the progestin was added monthly and a 180% risk increase if it was added every three months.35

A study published in December 2011 estimated that, in 2010, around 1% of cases of uterine cancer in the UK were linked to HRT.40

It is probable that BMI modifies the effect of HRT; the effects of tibolone and oestrogen-only HRT in the Million Women Study were limited to women whose BMI was lower than 25, while there was little if any risk increase in obese women.14 Risk of developing endometrial hyperplasia increases with oestrogen dose; one study reported a 32-fold increase in risk among women taking 1.25mg/d of unopposed oestrogen supplements for two years compared with those taking a 0.3mg/d dose.16

Users of combined oral contraceptives have a lasting reduction in risk as they have fewer days of unopposed oestrogen exposure each month. The EPIC study reported a 6% reduction in risk for each year of use.37 The risk reduction has been reported to persist for as long as 20 years after stopping use,17 and it is estimated that there were around 1,700 fewer cases of uterine cancer in the UK in 2010 due to use of OCs.40

Tamoxifen, an oestrogen receptor modulating hormone used to treat and prevent breast cancer, has been shown to treble risk of uterine cancer.18 This relationship doesn’t appear to be dose dependant, although it has been suggested that risk increases with duration of therapy. Excess deaths from uterine cancer among women taking tamoxifen is estimated to be about 2 per 10,000 women each year.18

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A recent meta-analysis reported that women with diabetes have double the risk of uterine cancer.32 Although risks associated with diabetes are difficult to separate from those of excess bodyweight, there is evidence of an independent effect,19 and results of a recent serum study suggest that circulating insulin and free insulin-like growth factor 1 may play a role in uterine cancer.20 Other studies show a higher risk of uterine cancer in women with higher blood and dietary glucose.21-,23,33

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A meta-analysis of prospective studies reported that the most active women have a 23% reduction in risk of uterine cancer.34 A study published in December 2011 estimated that around 4% of uterine cancers in the UK in 2010 were linked to women doing less than 150 minutes of physical activity per week.41

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Smokers have a modest reduction in uterine cancer risk.27 This effect may be linked with the fact that smokers metabolise oestrogens into less active metabolites than non-smokers. Recent results from the US Nurses’ Health study show a significant risk reduction in past as well as continuing smokers.28

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Ultrasound scanning suggests one-quarter of women of reproductive age have polycystic ovaries,29 but only 10% of women have additional symptoms associated with polycystic ovarian syndrome (PCOS) (also called Stein-Leventhal syndrome). These can include prolonged anovulatory menstrual cycles, lack of, infrequent or irregular periods, infertility, obesity, diabetes and hypertension. The hormonal factors governing these symptoms are complicated but are likely to include hyperandrogenism, an increase in production of luteinising hormone, disruption to progesterone production, and insulin resistance. Most of these symptoms are known to increase risk of uterine cancer.30 Metformin, the combined contraceptive pill or cyclic progestagens are often prescribed to women with PCOS to help prevent endometrial hyperplasia.30

Some types of ovarian cancers (granulosa-cell and theca-cell tumours) can secrete hormones such as oestrogens or androgens. Women with such tumours have a 10-fold higher risk of uterine cancer.31

Recent large cohort studies and a meta-analysis have shown that coffee drinking may lower womb cancer risk. In women who drank three to four cups of coffee a day the risk of womb cancer dropped by 29% compared to women who drank little or no coffee. Some research suggests that coffee may lower circulating levels of C-peptide – a marker of insulin production – and oestrogen, which could provide a plausible explanation for the protective association.42-44

Aspirin may protect against endometrial cancer, with a meta-analysis reporting a 13% risk reduction for any aspirin use.45 The association is stronger for women who are obese (28% risk reduction), while aspirin may not benefit women who have a healthy weight.45 Aspirin has anti-inflammatory effects, and other possible anti-cancer effects. However, because of the known side-effects of regular aspirin consumption (gastro-intestinal haemorrhage) it is not currently recommended as a chemopreventive agent.

section reviewed 01/08/05
section updated 01/08/05