Risk factors for endometrial cancer

Summary

Endometrial cancer is the most common malignancy of women in developed countries, and its incidence is rising among pre- and postmenopausal women. In developed and numerous developing countries endometrial cancer, as well as other types of female cancers are an ever-increasing threat that may be explained, among other reasons, by increased life expectancy and changes in lifestyle factors. Endometrial cancer is more common in postmenopausal women than in premenopausal women. Through a review of the literature it was found that the risk of endometrial cancer is positively correlated with older age, early menarche & late menopause, obesity, family history of endometrial cancer (especially among close relatives), radiation exposure, and infertility particularly in the presence of Polycystic Ovarian Syndrome. Long-term use of unopposed oestrogens for hormone replacement therapy also increases the risk of endometrial cancer. Caucasians have a higher incidence of endometrial cancer than African or Asian women. Obese women were found to be at high risk for developing endometrial cancer, while diabetes, hypertension, and geographical and socioeconomic factors are still inconclusive. Finally, smoking is considered as a protective factor against endometrial cancer due to its anti- estrogenic effect. .

Keywords:
endometrial cancer – older age – race – early menarche – late menopause – obesity – null parity – tamoxifen

INTRODUCTION

Endometrial cancer is the fourth most common diagnosed cancer of the female genital tract in developed countries [1]. It mostly occurs in postmenopausal women affecting women in their sixth and seventh decades of life [2]. Although endometrial cancer occupies a high rank among the incident of cancers in western world’ women and the incidence rate is ever increasing, the death rate from endometrial cancer is low [3]. This is because it has a favourable prognosis as the majority of patients present at an early stage. Endometrial cancer represents over 95% of uterine cancer [4], thus it is the most common type of uterine cancer (figure 1). Endometrial cancer develops along two distinct pathways with defined molecular alterations and distinct histologic and clinical features [5].

The majority (80–90%) of endometrial cancers have endometrioid differentiation and are classified as Type I endometrial cancer. Type I endometrial cancer is usually detected at an early stage. Compared with women with type I, women with type II endometrial cancer tend to be older at diagnosis (figure 2) and their cancers detected at a more advanced stage [5]. Type I endometrial cancer is estrogen dependent and develop through the hyperplasia-carcinoma sequence, whereas type II cancers are not estrogen dependent and develop independently of the endometrial hyperplasia pathway [5]. The other forms of endometrial cancer which fall under subtypes of type II endometrial cancer include; papillary serous adenocarcinoma, and clear cell adenocarcinoma. Because the last two types are less common than endometriod adenocarcinoma, their risk factors are less well identified. They are often detected at advanced stages, and tend to be more aggressive than endometrioid adenocarcinomas. When endometrial cancer has features of more than one subtype it called mixed adenocarcinoma and it represents less than 10% of all endometrial cancers [5].

Epidemiological studies have highlighted many risk factors (table 1) associated with an increased endometrial cancer risk. However, the association with these risk factors is based on probabilities, and even woman without any of these risk factors may still get endometrial cancer. The incidence of endometrial cancer is about 10 times higher in developed countries than developing countries [6]. This could be due to an increased life expectancy, increased caloric intake, obesity, adjuvant Tamoxifen use for breast cancer, and a reduction in fertility rates. The risk of the disease has been shown to be increased in Asian and African emigrants to developed countries, possibly due to changes in environmental risk factors [6, 7]. The wide difference in the incidence of endometrial cancer across the world can be also explained by differences in the distribution of known risk factors of the disease. This review will focus on the most important risk factor for endometrial cancer.

OLDER AGE

Endometrial cancer risk is found to be positively correlated with increasing age [5, 8, 9]. As endometrial cancer is more common in post-menopausal women than in premenopausal women, over 90% of the cases are diagnosed after the age of 50 years [10]. Advanced age is also considered as a predictor of poor outcome in patients with endometrial cancer [11]. The incidence peaks can be differed by country, race, and the targeted study population, as different studies showed differences incidence peaks [5, 9, 10, 12, 13, 14]. The incidence of endometrial cancer is higher in developed countries than most developing countries, because of increased life expectancy and changes in lifestyle [5]. On the other hand, the incidence of endometrial cancer is expected to be low in many African countries, mostly due to the decline in life expectancy [15] because of the increased prevalence of HIV, TB, and other diseases.

RACE

Data from Western countries showed differences in the incidence of endometrial cancer and mortality rate among races. White women have a higher risk of developing endometrial cancer than women belonging to other ethnic groups [2]. Endometrial cancer has a higher incidence in White Americans when compared to African Americans, Native Hawaiians, Japanese Americans, and Latinas [16]. However, in comparison with other races the mortality rate in white women is the lowest. Different incidence rates of endometrial cancer among races could be due to differences in life-style, socioeconomic status, and genetic predisposition to developing cancers [17]. Although the incidence of endometrial cancer is 30% less in African American compared with white American, African women usually present with advanced stage tumours resulting in up to 4 times increase in mortality compared with their white counterpart [18]. The high risk of death in black women is attributed to poor access to health care centres, advanced stage at diagnosis, tumour characteristics and delay of treatment [18]. On the contrary, early stage of diagnosis in white women can partially explain their low mortality rate from endometrial cancer compared with the high mortality in black and other race [19]. Early stage of diagnosis could be a reflection of high economic status and high educational level which usually leads to increase awareness and  ultimately create the racial gap in life expectancy and survival rate [20].

EARLY MENARCHE & LATE MENOPAUSE

Early age at menarche and late age at menopause are positively associated with some female cancers. Breast-, endometrial- and ovarian cancer were all found to be affected by degree of exposure to oestrogen [21]. Early age at menarche [13, 22, 23] and late age at menopause [24, 25] are associated with increase risk of endometrial cancer and the opposite is true [25, 26]. This is because earlier menarche and the later menopause increased the number of menstrual cycles. Ultimately, the total exposure time to oestrogen will increase [23]. Earlier menarche increases the risk of developing endometrial cancer up to 9 fold compared with woman whose menarche occurred at or above the age of fifteen year [22]. Setiawan and colleagues found a 67 percent elevated risk of endometrial cancer among women whose menopause occurred between the ages of 50 and 54 years, compared with women whose menopause occurred prior to the age of 45 years. The risk increased by 79 percent when menopause occurred after the age of 55 years [16].

FAMILY HISTORY

About 5% of endometrial cancer cases have a family history of the disease among first degree relatives [27]. Family history of endometrial cancer is associated with increased disease risk from two [28] to three fold among premenopausal women [29]. In women less than 50 years old, about 9% of endometrial cancer is due to mutations in mismatch repair genes (MSH1, MSH2, MSH6), which result in Hereditary Non-Polyposis Colorectal Cancer (HNPCC) also known as Lynch II syndrome. These mutations lead to microsatellite instability in 75% of endometrial cancers and 90% of colon cancers [30, 31]. Endometrial cancer is considered to be the second most common cancer in HNPCC and the average age of diagnosis of endometrial cancer has been reported to be between 46 and 62 years old [32]. These mutations raise the lifetime risk of endometrial cancer risk up to 60% by the age of 70 years [33]. A family history of other cancers such as uterine and intestinal cancer is directly associated with an increase in the risk of endometrial cancer [28]. The high incidence of endometrial cancer among young women who have a family history of other cancers, suggests a genetic link [33].

HISTORY OF OTHER FEMALE CANCERS

A woman who has a history of other cancers has a 3 fold increase in the risk of developing endometrial cancer, compared with woman with no history of cancer [34]. Breast-, endometrial- and some ovarian cancers are considered to be oestrogen related cancers, because they share common risk factors such as early age at menarche, late age at menopause, nulliparity and other factors responsible for elevating oestrogen level [35]. Women who had breast or ovarian cancer are at increased risk of developing endometrial cancer [36]. Uterine cancer risk increases 2.7 fold among BRCA1 carriers, which is less than the effect on the risk of breast cancer [37], while no increase in risk is found in BRCA2 mutation carriers [38].

INFERTILITY

The effect of infertility on endometrial cancer is well documented, as it puts the patients at risk of developing endometrial cancer at a younger age [39]. The majority of young patients with endometrial cancer (<40 years) suffers from chronic anovulation [40, 41]. Elevated serum oestrogen levels is one of the main features associated with chronic anovulation, and this creates enough reason to increase the risk of developing endometrial cancer [42]. Thus, women with Polycystic Ovary Syndrome (PCOS) and women with oestrogen-secreting ovarian tumours are more prone to have endometrial cancer especially in their reproductive life [42, 43]. Anovulation or oligoovulation that is associated with PCOS in premenopausal women results in an endometrium that is chronically exposed to unopposed oestradiol. Ultimately this causes proliferation and possibly can lead to neoplastic changes [44]. Almost a third of the cases with endometrial cancer have PCOS [42, 45]. Insulin resistance and PCOS, which are both components of the metabolic syndrome, may play a pivotal role in the pathogenesis of endometrial cancer, likely through disruption of hormonal processes [46]. On the other hand, medication such as clomiphene which is used as an ovulation-stimulating drug in the treatment of infertile woman has recently been reported to be a risk factor for uterine cancer as it increases oestradiol levels [47].

NULLPARITY

Lower parity [22] and/or nullparity [24] were found to increase the risk of developing endometrial cancer up to four fold, while multiparity decreases the risk of endometrial cancer up to 70% [48, 49]. Furthermore, any additional birth among parous women (after the birth of the second child) decreased the risk of developing the disease by 10 % for every new child [48]. This is because parity causes an alteration in the hormonal balance towards increasing progesterone and decreasing oestrogen which suppresses endometrial mitotic activity [48, 50]. The protective effect of parity was found to be stronger in pre-menopausal compared with postmenopausal women [48]. Shedding of the endometrial tissue during delivery could be the reason behind elimination of initiated or precancerous cells [51].

POSTMENOPAUSAL HORMONE THERAPY

Oestrogen Therapy (ET) is the use of oestrogen alone to offset the symptoms of menopause. In the past oestrogen was used alone to treat symptoms of menopause such as hot flushes [52, 53, 54]. Endometrial cancer is associated with a high level of exposure to oestrogen, and the use of oestrogen alone increases the risk of endometrial cancer fivefold as it delays the age of menopause. Since the 1980s, this finding has resulted in a huge reduction in the use of unopposed oestrogen by postmenopausal women who has not undergone a hysterectomy [55]. Thus, also Hormone Replacement Therapy (HRT), also called Oestrogen and Progestin Therapy (EST), which is a diverse combination of oestrogen plus progestin regimens, soon, became available for women with an intact uterus [56]. Results regarding the use of the Oestrogen and Progestin Therapy (EST) and endometrial cancer risk still controversial as some studies have found an increased risk (although it is less than that reported) with the use of ET [6, 22, 57, 58, 59, 60, 61], some found a decreased risk [62], while others found no association [63, 64].

HIGH INTAKE OF FATTY DIET

Endometrial cancer risk is positively correlated with high-fat diet or high energy intake from animal sources [65, 66]. Vegetarian diet, fruits and nutrients such as fibres and vitamins are associated with a reduced risk of endometrial cancer [67, 68], while high energy intake increases the risk up to three fold [69]. This can be explained in two ways. Firstly, a high fat diet can lead to the development of obesity that in turn is considered to be a risk factor for endometrial cancer. Secondly, a fatty diet promotes oestrogen metabolism, which increases the risk of endometrial cancer [70]. Thus, differences among nations in diet contents may be another reason behind differing cancer incidence. African Americans, who usually eat a high-fat diet with less fruits and vegetable, are at high risk compared with white American [71, 72].

OBESITY

Obesity is a well identified risk factor for endometrial cancer (figure 3), both in pre-menopausal and post-menopausal women [73]. The risk of endometrial cancer becomes higher when obesity is associated with infertility or amenorrhoe [74, 75]. This is because obesity increases insulin resistance and oestrogen exposure, which is already high in infertile women and women with anovulation or amenorrhoe [76, 77]. An obese woman has a 2–22 fold increased of the risk of developing endometrial cancer compared to woman with a normal BMI [75, 78, 79, 80]. Endometrial cancer risk increases by 1.2 fold for each 5 kilograms weight gain [78]. Obese premenopausal women have a more than 7 fold increased risk of developing endometrial cancer compared to obese postmenopausal women [80]. Upper body fat is more strongly related with endometrial cancer risk than lower body fat [75, 78]. The positive relationship between obesity and endometrial cancer becomes weaker when obese woman uses Hormone Replacement Therapy (HRT). Compared with current HRT user obese women, who never used Hormone Replacement Therapy, have five fold increases in the risk of developing endometrial cancer [81]. Obesity is associated with a poorer prognosis and increased mortality for both premenopausal and postmenopausal women [82, 83]. Obesity elevates circulating endogenous oestrogens in premenopausal and postmenopausal women, probably due to the conversion of androgen to oestrogen in excess adipose tissue [84]. Thus, and because obesity is also associated with insulin resistance and hyperinsulinemia [85], the positive relationship with endometrial cancer risk becomes even stronger [86].

DIABETES

Previous [23, 87] and recent studies [22, 73, 88, 89] have shown a positive relationship between endometrial cancer risk and diabetes. In comparison with non-diabetic woman, a diabetic woman has a 2 to 3 fold increased risk of developing endometrial cancer [87, 89]. Obesity can exaggerate the effect of diabetes, as most patients with Type II diabetes are obese. Friberg and colleagues found a more than 6 fold increase in the risk of endometrial cancer when diabetes is associated with obesity [89]. The risk rose up to 10 times when obese diabetic women don’t exercise [89]. Women with type1 diabetes have an increased risk of endometrial cancer of up to 3 fold [89]. However, this could be due to effect of confounders, as women with type 1 diabetes have a higher incidence of nulliparity , irregular menstruation and fertility disorders, which are all probable risk factors for endometrial cancer [90].

HYPERTENSION

Hypertensive women have a 3 fold increased risk of developing endometrial cancer compared to healthy women [22, 84]. However, it is unclear whether this positive relationship is due to hypertension or due to the interaction with weight [91] as the relationship between hypertension and endometrial cancer risk usually vanishes after adjusting for body weight [23].

TAMOXIFEN

Tamoxifen is a selective oestrogen receptor modulator often used to treat women with an oestrogen receptor positive breast cancer [92]. Tamoxifen stimulates endometrial proliferation and as the duration of treatment increases the thickness of the endometrium increases [93]. Endometrial cancer risk increases with the duration of tamoxifen use with a relative risks of 2.0 for 2–5 years and 6.9 for at least 5 years when compared to non-users [94]. In addition, the elevated risk of endometrial cancer with long term Tamoxifen use is usually associated with a poor prognosis and poor survival rate [94, 95].

SMOKING

Although smoking is considered a risk factor for endometrial cancer in a limited numbers of studies [13, 77] the majority of studies have considered smoking as a protective factor against endometrial cancer [96, 97, 98, 99, 100]. After analysing 34 studies, Zhou and colleagues have concluded that smoking may decrease the risk of endometrial cancer by up to 30% [101]. Furthermore, the risk of endometrial cancer has declined dramatically with increased numbers of daily cigarettes smoking per day [102] and duration of smoking/years [96, 98]. However, this positive correlation between decreased endometrial risk and smoking was reported only in postmenopausal women [96, 97].

The protective effect of smoking may be attributed to its anti-oestrogenic effect [99, 100]. Smokers have lower endogenous oestrogen levels compared to none-smokers [103, 104]. Smoking also reduced the effect of oestrogen by reducing the age of menopause so that smokers have less menstrual cycles compared non-smokers [105].

RADIOTHERAPY

A percentage of patients with radiotherapy experience face severe complications including late toxicity in normal tissues and significant excess of radiation-induced malignancies [106, 107, 108]. Radiation associated endometrial cancer may develop directly after irradiation the uterus or indirectly after surrounded area like; cervix, rectum or the urinary system [106]. The majority if not all radiation-associated endometrial cancers are second cancers developing in the lining cells of the body and remote from the treatment site [107]. Radiation therapy which used commonly to treat patients from cancers can cause damage to the surrounding tissues’ DNA, which ultimately increases the chance of developing second type of cancer [108].

GEOGRAPHICAL AND SOCIOECONOMIC FACTORS

The incidence of endometrial cancer may fluctuate from country to country or from area to another area in the same country, state, or even within the same city. This could be due to differences in lifestyle and socioeconomic status which usually exist among population, not only in regard with endometrial cancer incidence rate but most kind of cancer [108, 109, 110]. The socioeconomic gradients in cancer risk generally tend to affect women in different ways. It found to be positive (richer women are more affected than their poorer counterpart) for skin melanoma and cancers of the colon, breast, and ovaries, whereas negative association has been observed (i.e., poorer women are more affected than their richer counterpart) for lung, stomach, esophagus, and cervical cancer [111].

Although the relationship between education and endometrial cancer is still controversial, studies found that educated women usually use oestrogen replacement, contraception, and tend have lower parity, compared to un-educated women. This may put educated women under some risk of developing endometrial cancer. On the contrarily, educated women are aware of symptoms of the disease and thus they early diagnosed, get better access to medical care and therefore have less mortality rate, while uneducated women, even though they get the disease, they may died without seeking medical care [112]. From epidemiological point of view, education is found to be inversely associated with the incidence of most cancers, especially those related to avoidable risk factors such as smoking [113, 114, 115, 116].

To conclude, the risk of endometrial cancer increases with increasing age, being Caucasian, early menarche & late menopause, a positive family history of endometrial cancer, a history of other cancers, infertility, long-term use of unopposed oestrogens for hormone replacement therapy, fatty diet, obesity, and long duration of Tamoxifen use. The relationship with other reported risk factors, such as diabetes and hypertension, are still controversial. Smoking was found to be protective against endometrial cancer in most studies. Having one or more of these risk factors does not guarantee the occurrence of the disease but rather increases the risk of developing the disease, and the opposite is also true.

Acknowledgement

I would like to thank Professor Bill Botha, from the Department of Obstetrics and Gynaecology, at Tygerberg Hospital and Stellenbosch Medical School, for his valuable suggestions.

Dr. Aus Tariq Ali, , BSC, MSC-Nutrition, MSC-Medicine, PhD-Chemical Pathology

Department of Chemical Pathology

Tygerberg Hospital 7505

Cape Town, South Africa

e-mail: atali@sun.ac.za