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. Being overweight increases oestrogen levels in postmenopausal women 3 and can disrupt ovulation and progesterone production in premenopausal women, resulting in continuous exposure of the womb to unopposed oestrogen 4 (see section on bodyweight below). 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. 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 women 6,7, but results have been inconsistent 8. Early menarche and late menopause significantly increase risk, because they prolong years of oestrogen exposure 1. Other factors associated with increased risk include lack of, infrequent or irregular periods, periods, annovulatory menstrual cycles and more days of menstruation 4,7.

Evidence suggests that risk of uterine cancer is 2-3 times higher in overweight and obese women respectively and it is estimated that around 36% of cases of uterine cancer in the UK are caused by excess bodyweight 9-,13. 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.

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. 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 endometrialhyperplasia 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 risk reduction is about 10% for each year of use 1 and has been reported in some studies to persist for as long as 20 years after stopping use 17.

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.

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.

A meta-analysis of prospective studies reported that the most active women have a 23% reduction in risk of uterine cancer. 34

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.

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.