Medical history and medications

An example of a medical condition associated with an increased risk of endometrial cancer is diabetes.

Results are inconclusive for conditions such as endometriosis, polycystic ovary syndrome, high blood pressure and stress.

Examples of medications associated with an increased risk of endometrial cancer include use of oestrogen-only menopausal hormonal therapy (MHT) and the drug tamoxifen. Use of certain intrauterine devices (IUDs) may also be associated with a decreased risk of endometrial cancer.

Medications associated with a decreased risk of endometrial cancer include oral contraceptives and may include use of oral bisphosphonates and use of continuous combined menopausal hormonal therapy (MHT). Aspirin and other related medicines may be associated with a decreased risk of endometrial cancer in women who are obese.

A number of other medications have been examined to look for a possible association with endometrial cancer, but results are inconclusive. This includes use of metformin, statins and fertility drugs. There is no association between taking paracetamol and risk of endometrial cancer.   

Aspirin and related medicines

Regular use of non-steroidal anti-inflammatory drugs (NSAIDs)*, such as aspirin, may be associated with a decreased risk of endometrial cancer in women who are obese (women with a body mass index (BMI) of 30 kg/m² or higher).

There is some evidence that NSAIDs may also be associated with a decreased risk of endometrial cancer in women who are overweight (women with a BMI between 25 and 30 kg/m²). There is no evidence of an association between taking an NSAID and risk of endometrial cancer in women in the healthy weight range.

The risk of endometrial cancer has been shown to be up to 16% lower in obese or overweight women who take aspirin or another NSAID at least once a week compared to women who do not take one of these medicines. However, no decrease in risk is seen in obese or overweight women who take aspirin every day. This is probably because aspirin taken every day is usually a much lower dose used to help prevent heart attacks.

The protective effects of NSAIDs in obese and overweight women may be due to the anti-inflammatory effects of these medicines. Women who are obese or overweight have certain proteins and other factors in their blood caused by inflammation. These factors may increase the risk of endometrial cancer. By reducing the inflammation seen in obese or overweight women, NSAIDs may help to reduce the risk of endometrial cancer.

*NSAIDs are anti-inflammatory medicines used to treat pain, fever and inflammation. Aspirin is an example of an NSAID that can also be used to prevent heart attacks in some people when used at a low dose.

Diabetes

Having diabetes is associated with an increased risk of endometrial cancer.

The risk of endometrial cancer increases by at least 30% in women who have diabetes compared with those who do not.

It has been estimated that almost 11% of cases worldwide of endometrial cancer are due to women having diabetes.

Most people with diabetes have 'type 2' diabetes, which is associated with higher body fatness. Being overweight or obese may contribute to the increased risk of endometrial cancer in women with diabetes.

The increased risk of endometrial cancer in women with diabetes is likely to be due to hormones. People with diabetes have lower levels of the hormone insulin. This can result in higher levels of the female hormone oestrogen which can increase the risk of endometrial cancer.

Further information can be found at:

• Cancer Australia Position Statement – Lifestyle risk factors and the primary prevention of cancer
• Healthy Weight Guide – Australian Government Department of Health

Endometrial hyperplasia and polyps

Atypical endometrial hyperplasia

Having atypical endometrial hyperplasia* is associated with an increased risk of endometrial cancer. Atypical endometrial hyperplasia may go on to develop into endometrial cancer. Studies show that 28% of women who have atypical endometrial hyperplasia go on to develop endometrial cancer. In some women, atypical endometrial hyperplasia may exist alongside endometrial cancer. Around 42% of women with atypical endometrial hyperplasia also have endometrial cancer at the time of hysterectomy.

Endometrial hyperplasia is thought to be caused by continuous exposure to the female hormone oestrogen. The hormonal risk factors that increase the risk of endometrial cancer are also thought to increase the risk of endometrial hyperplasia.

*Endometrial hyperplasia is a condition in which the cells in the lining of the uterus grow faster than normal. There are two types of endometrial hyperplasia: typical and atypical. Atypical endometrial hyperplasia is thought to be a precancerous condition that can develop into endometrial cancer. Typical endometrial hyperplasia is less likely to progress to endometrial cancer.

Endometrial polyps

There is convincing evidence of a small association between endometrial polyps* and risk of endometrial cancer. Studies suggest that around 2–3% of endometrial polyps can become malignant (develop into cancer). The risk of endometrial polyps becoming malignant is higher if the polyps are causing bleeding, and if polyps occur in women who have reached menopause. 

Endometrial polyps are thought to be caused by overstimulation of endometrial glands by the female hormone oestrogen (or chemicals with similar effects to oestrogen).

*Endometrial polyps are small growths or projections of endometrial tissue from the lining of the uterus. Polyps may cause bleeding or may exist without causing symptoms. Most polyps shrink over time. 

Endometriosis

There is no conclusive evidence that having endometriosis* is associated with risk of endometrial cancer.

Results from studies that have looked at endometriosis and risk of endometrial cancer are not consistent. Some studies have found an increased risk of endometrial cancer in women who have endometriosis, some have found a decreased risk, and some have found no association.

*Endometriosis is a condition in which the lining of the womb (the endometrium) grows outside the womb, causing pain and infertility.

High blood pressure

There is no conclusive evidence that having high blood pressure is associated with an increased risk of endometrial cancer.

Only a small number of studies have been conducted to date. Most studies looking at high blood pressure and risk of endometrial cancer have not taken into account other factors such as diabetes and obesity that increase the risk of endometrial cancer, so it is not possible to make any definite conclusions.

Hormonal treatment for infertility

There is no conclusive evidence that taking drugs to increase fertility* is associated with an increased risk of endometrial cancer. Studies have been of poor quality.

Any change seen in the risk of endometrial cancer in women who use fertility drugs is likely to be due to the underlying reasons for infertility, such as ovulatory disorders and obesity, rather than use of the drugs.

*Fertility drugs are drugs used to stimulate the activity of the ovaries. They include a group of drugs called ‘selective oestrogen receptor modulators’ as well as drugs used during in-vitro fertilisation (IVF).

Intrauterine device (IUD) contraception

Use of some contraceptive intrauterine devices (IUD)* may be associated with a decreased risk of endometrial cancer. This association has been suggested for IUDs that release hormones and inert IUDs. No association has been seen for copper IUDs. Results are not consistent across different studies.

There are several possible ways that IUDs may decrease the risk of endometrial cancer. These include the local effects of the IUD on the endometrium as well as hormonal effects.

*An IUD is a contraceptive device that is placed in the womb (uterus). Two types of IUD are available in Australia: the hormonal IUD (Mirena^TM) and the copper IUD. Inert IUDs are another form of device but are not available in Australia. 

Menopausal hormone therapy  (MHT) also known as hormone replacement therapy (HRT)

Oestrogen-only MHT

Oral or transdermal (patch)

There is convincing evidence that use of oral or transdermal oestrogen-only menopausal hormone therapy (MHT)* is associated with an increased risk of endometrial cancer. The risk increases the longer a woman uses oral or transdermal oestrogen-only MHT. The increased risk continues for at least 10 years after stopping use.

Women who use oral or transdermal oestrogen-only MHT are twice as likely to develop endometrial cancer as women who never use MHT. For this reason, oestrogen-only MHT is usually only recommended for women who have had a hysterectomy.

It is estimated that about 3% of cases of endometrial cancer in Australia are due to women using oestrogen-only MHT.

Oestrogen is one of two important female hormones. It affects how endometrial cells grow and divide and can increase the risk of endometrial cancer. The effects of oestrogen on endometrial cells are balanced by the effects of the female hormone progestogen. When a woman uses oestrogen-only MHT, her levels of oestrogen are higher than her levels of progestogen. It is this increased level of ‘unopposed’ oestrogen that can increase the risk of endometrial cancer.

Vaginal

There is no conclusive evidence that vaginal oestrogen-only MHT affects the risk of endometrial cancer. Only a small number of studies have been conducted and the small amount of evidence suggests no association.

 *Oestrogen-only MHT is a form of hormone replacement therapy that doesn’t include a progestogen. It may be given as a pill (oral), via a patch (transdermal) or in the form or a cream, ring or pessary placed in the vagina.

Combined oestrogen–progestogen MHT 

Continuous combined 

Using continuous oestrogen-progestogen MHT* may be associated with a decreased risk of endometrial cancer. However studies have given inconsistent results.

Cyclical (progestogen at least 10 days/month)

There is no conclusive evidence that using cyclical oestrogen–progestogen MHT in which progestogen is given for 10 or more days per month is associated with an increased or decreased risk of endometrial cancer. Results from studies are not consistent and studies are of limited quality.

*Oestrogen-progestogen MHT is a form of hormone replacement therapy that uses a combination of oestrogen and progestogen. The two hormones may be used on each day of the month (continuous), or progestogen may be given for only some days of the month (cyclical). Progestogens are added to oestrogen for at least 10 days per month to reduce the increased risk of endometrial cancer associated with oestrogen-only MHT.

Tibolone

Use of tibolone is probably associated with an increased risk of endometrial cancer.

The risk of endometrial cancer is estimated to be between 2 and 4 times higher in women who use tibolone compared to women who do not use MHT. One study suggests that the risk may increase with longer use.

Once in the body, it acts like oestrogen, progestogen, and testosterone. Studies suggest that tibolone acts more like oestrogen than progestogen on the womb. This oestrogen-like effect may be what leads to the increased risk of endometrial cancer.

* Tibolone is a synthetic form of hormone replacement therapy. 

Metformin

There is no conclusive evidence that taking metformin* is associated with a decreased risk of endometrial cancer. Only a small number of studies have been conducted and these have been of limited quality.

It has been suggested that metformin could lower the risk of endometrial cancer by lowering the level of insulin and other factors in the blood that may affect cancer cell growth. 

*Metformin is a drug used to treat type 2 diabetes.

Oral Bisphosphonates

Taking an oral bisphosphonate* is probably associated with a decreased risk of endometrial cancer. The protective effect has been seen in women who take an oral bisphosphonate for more than one year. Oral bisphosphonates are usually taken by older women. The protective effect of oral bisphosphonates has been reported mainly in studies involving women who have reached menopause, but the effect may also occur in younger women. 

The longer a woman uses an oral bisphosphonate, the lower her risk of endometrial cancer becomes. In women taking an oral bisphosphonate for between 1 and 3 years, the risk of endometrial cancer has been shown to be 42% lower than in women who have never used this type of medicine. The risk is 66% lower in women who have used an oral bisphosphonate for more than 3 years.

The protective effects of bisphosphonates may be due to their effects on how cells grow and divide and possible effects on the immune system.

*Oral bisphosphonates are medicines used to treat osteoporosis. 

Oral contraceptive pill

Using an oral contraceptive* is associated with a decreased risk of endometrial cancer. The longer a woman uses an oral contraceptive, the lower her risk of endometrial cancer becomes. This protective effect continues for several decades after a woman stops using an oral contraceptive.

The risk of endometrial cancer has been shown to be around 30% lower in women who use or have previously used an oral contraceptive compared with women who have never used one. An Australian study estimates that use of combined oral contraceptives prevented about 1038 cases of endometrial cancers in 2013.

However, taking combined oral contraceptives is associated with a small increased risk of breast cancer while a woman is currently using it.

The protective effect of oral contraceptives is likely to be due to their effects on female hormones. Increased activity of the hormone oestrogen is associated with an increased risk of endometrial cancer. By reducing the activity of oestrogen, oral contraceptives may reduce the risk of endometrial cancer. 

*Oral contraceptives are also known as birth control pills or ‘the Pill’. Most women use a ‘combined’ oral contraceptive that contains oestrogen and progestogen. Some women (for example women who are breast feeding) use a progestogen-only oral contraceptive.

Paracetamol

Taking paracetamol* is not associated with risk of endometrial cancer. This finding is supported by high-quality studies.

The way in which paracetamol works is not yet fully understood. However, what is known about the way it works is not related to the growth of cancer cells.

*Paracetamol is a drug used to treat pain and fever.

Polycystic ovarian syndrome (PCOS)

There is no conclusive evidence that having polycystic ovary syndrome (PCOS)* is associated with risk of endometrial cancer. Only a small number of studies have been done to date and these have been of poor quality.

PCOS is associated with known endometrial cancer risk factors, such as obesity, diabetes, and metabolic syndrome. It is possible that this association results in an increase in risk of endometrial cancer in women with PCOS. It is also possible that PCOS itself results in an increased risk of endometrial cancer due to effects on the body’s metabolism.

Other factors that are common in women with PCOS, such as not having children, age at first pregnancy, use and/or length of use of hormone replacement therapy or oral contraceptives, may also affect risk of endometrial cancer. This makes the results of studies difficult to interpret.

* Polycystic ovary syndrome is a condition that affects around 8–13% of women during their reproductive years. Symptoms include irregular or no menstrual periods, difficulty getting pregnant, pelvic pain, skin and hair changes, and cysts on the ovaries.

Selective oestrogen receptor modulators

Tamoxifen

Use of tamoxifen* is associated with an increased risk of endometrial cancer. This increase in risk is seen in:

• women with breast cancer who take tamoxifen as adjuvant treatment (to reduce the risk of breast cancer coming back) and
• women at high risk of breast cancer who take tamoxifen to reduce their risk of developing breast cancer.

The risk of endometrial cancer in women using tamoxifen as adjuvant treatment for breast cancer has been measured in different ways. Some studies have compared women taking tamoxifen with those who do not take tamoxifen. Other studies have compared women who take tamoxifen with those who take a different medicine to reduce their risk of breast cancer coming back (for example, an aromatase inhibitor^#). The risk of endometrial cancer was consistently higher in women taking tamoxifen. The risk of endometrial cancer increases with longer use of tamoxifen. In women who take tamoxifen for 10 years, the risk of endometrial cancer is twice as high as the risk in women who take tamoxifen for 5 years.

The risk of endometrial cancer is about 3 times higher in postmenopausal women who take tamoxifen compared with women taking aromatase inhibitors for breast cancer treatment. Changing to an aromatase inhibitor instead of continued treatment with tamoxifen is also associated with a lower risk of endometrial cancer compared with long-term tamoxifen treatment.

Taking tamoxifen is an important adjuvant therapy and women should balance the important benefits of reducing breast cancer recurrence with any rare side effects including the increased risk of endometrial cancer.

An increased risk of endometrial cancer has also been seen in women who take tamoxifen to reduce their risk of breast cancer. The risk of endometrial cancer doubles as a result of taking tamoxifen. These studies have only shown an increase in endometrial cancer risk in women older than 50 years of age.

The association between tamoxifen and increased risk of endometrial cancer is likely to be due to hormones. Although tamoxifen blocks the effects of the female hormone oestrogen in breast cells, it has effects that are similar to oestrogen in the uterus. This is likely to contribute to an increased risk of endometrial cancer.

Raloxifene

Taking raloxifene is not associated with risk of endometrial cancer.

In studies of women taking raloxifene to reduce the risk of breast cancer, no change in the risk of endometrial cancer has been seen.

Raloxifene works in a different way to tamoxifen. Unlike tamoxifen, it does not have effects on the uterus that are similar to oestrogen.

*Selective oestrogen receptor modulators (SERMs) are medicines used in the treatment and prevention of breast cancer.

• Tamoxifen is a type of SERM therapy that is used in addition to other treatments for breast cancer to reduce the risk of breast cancer coming back after treatment. It is also used to reduce the risk of breast cancer in women at high risk of breast cancer. Tamoxifen can be used regardless of whether women have reached menopause.
• Raloxifene is another type of SERM therapy that is used to reduce the risk of breast cancer in women at high risk. It is also used to prevent and treat osteoporosis. Raloxifene is only used by women who have reached menopause. 

^#Aromatase inhibitors such as anastrazole and letrozole are a different type of hormone therapy used in the treatment of oestrogen-receptor positive breast cancer in postmenopausal women, and are used as an alternative to tamoxifen or in sequence after tamoxifen.

Statins

There is no conclusive evidence that taking a statin is associated with a decreased risk of endometrial cancer. Although studies show no association, the quality of studies conducted to date is limited.

Statins are drugs used to treat high cholesterol. It has been suggested that statins may decrease the risk of certain types of cancer because of their effects on cell growth.

Stress

There is no conclusive evidence that stress is associated with increased risk of endometrial cancer. Only one study has been identified to date.

Stress is the mental or emotional strain that results from difficult circumstances. Life changes such as illness, bereavement, breakdown in a relationship or loss of a job can cause stress.

Stress might affect processes in the body, such as the immune system. It can also lead to lifestyle changes, which could affect the risk of certain types of cancer.