Endometrial Cancer and Exogenous Hormones
        Estrogen replacement therapy
        Combination estrogen-progestin replacement therapy
        Oral contraceptives
Endometrial Cancer and Tamoxifen
Endometrial Cancer and Obesity and Body Mass Index
Endometrial Cancer and Physical Activity
Endometrial Cancer and Breastfeeding
Endometrial Cancer and Diet

Endometrial Cancer and Exogenous Hormones

Estrogen replacement therapy

The first report of an association between estrogen replacement therapy and endometrial cancer appeared at the end of 1975,[1] and the results were soon confirmed by two similar studies.[2,3] In these three studies, the overall risk ratio ranged from 4.5 to 8.0. A number of confirmatory studies indicated that the risk of developing endometrial cancer increased with duration of use (10-fold to 30-fold with 5 years or more of use),[4-7] and that once estrogen replacement had been used for at least a year, the risk might persist for more than 10 years after discontinuation.[8] With the publicity that attended these findings, there was a sharp fall in prescriptions for estrogen and an almost immediate decline in endometrial cancer incidence.[9]

For many years, it had been noted that postmenopausal women using estrogen were prone to develop adenomatous hyperplasia and that women with adenomatous hyperplasia were more likely to develop subsequent endometrial cancer.[10] There was also a history of using progestational agents to treat neoplastic lesions of the uterus.[11-13] Consequently, when the association between estrogen replacement therapy and endometrial cancer became known, clinical attention immediately focused on developing hormone replacement regimens that used both estrogen and a progestin.[14,15]

The Postmenopausal Estrogen Progestin Interventions (PEPI) Trial [16] provides some information on the impact of hormone therapy on the uterus. There were nearly 600 participants in PEPI who took part in a 3-year, multicenter, randomized trial that was double-masked and placebo-controlled. In addition to the placebo arm of the trial, one group received only conjugated equine estrogen (CEE) daily, while three other groups received CEE with progestin (medroxyprogesterone acetate [MPA] or micronized progesterone [MP] for the first 12 days of every 28-day cycle, or MP continuously). Endometrial biopsies were obtained at baseline and annually or at unscheduled visits when clinically indicated. For the women who received progestin with CEE, the occurrence of uterine hyperplasia was similar to that seen with placebo; however, women given estrogen alone had more endometrial tissue abnormalities than women taking placebo (simple hyperplasia: 27.7% vs. 0.8%, adenomatous hyperplasia: 22.7% vs. 0.8%, and atypical hyperplasia: 11.8% vs. 0%, respectively). These data showed that CEE at a dose of 0.625 mg daily was associated with the development of endometrial hyperplasia, which could be prevented by adding MPA or MP to the treatment regimen. A retrospective analysis of 170 women with endometrial hyperplasia who were followed for a mean of 13.4 years demonstrated that the risk of progression to endometrial carcinoma is dependent on the type of hyperplasia. Only 2% of women with endometrial hyperplasia without atypia developed carcinoma. By contrast, 23% of those with atypical hyperplasia developed carcinoma.[17] The vast majority of these tumors were low grade and minimally invasive. Therefore, endometrial hyperplasia with cytologic atypia is considered a precursor of certain types of well-differentiated endometrial carcinomas.[18]

More direct evidence regarding the impact of combining progestins with estrogens on endometrial cancer risk comes from the Women’s Health Initiative and the randomized trial component of combined hormone therapy (HT) (N = 16,609 women). This study found that, after an average follow-up of 5.6 years, women randomly assigned to combined HT had a hazard ratio for endometrial cancer of 0.81 (95% confidence interval [CI], 0.48–1.36) compared with women randomly assigned to placebo. This CI is wide, but is consistent with prior evidence showing no increased risk associated with combined HT use.[19]

A large population-based case-control study conducted in Los Angeles County concluded that administration of progestin in sequential estrogen-progestin replacement therapy should continue for at least 10 days per month in order to effectively nullify the increased risk of endometrial cancer associated with estrogen replacement therapy (ERT). For women who received ERT, the adjusted odds ratio (OR) was 2.17 (95% CI, 1.91–2.47) per 5 years of ERT use. Women who received sequential estrogen-progestin replacement therapy with progestin given less than 10 days per month had only a slightly lower risk, OR = 1.87 (95% CI, 1.32–2.65) per 5 years of use. In contrast, when progestin was given for more than 10 days per month, there was no associated increase in risk, OR = 1.07 (95% CI, 0.82–1.41) per 5 years of use.[20] Another population-based case-control study confirmed the decreased risk of endometrial cancer for women who received combination estrogen-progestin replacement therapy with progestin given for more than 10 days per month. However, the results suggest that this protective relationship is not sustained for long-term users. For women who received fewer than 10 days of progestin per month for 5 years or more, the risk was 3.7-fold higher (95% CI, 1.7–8.2). For women using progestin for more than 10 days per month for a period of 5 years or more, the risk was 2.5-fold higher (95% CI, 1.1–5.5).[21]

A prospective cohort study was conducted among Swedish women who had received prescriptions for replacement hormone therapies. For women who reported using medium-potency unopposed estrogens for 6 years or more, the relative risk (RR) of invasive endometrial cancer was 4.2 (95% CI, 2.5–8.4) while the risk for women using a progestin-combined treatment for the same length of time was not significantly elevated, RR = 1.4 (95% CI, 0.6–3.3).[22]

A protective effect on the endometrium of premenopausal women using combination oral contraceptives (COC) has been observed.[23] Estrogen and progestin COCs were used for 21 days of a 28-day cycle. On the days when the pill was not used, the endogenous estrogen levels remained low. With the use of COCs, the risk of developing endometrial cancer was decreased by approximately 40%, as demonstrated by case-control studies and supported by prospective cohort studies.[23-25] This decrease in risk was observed for at least 15 years after the women had ceased using COCs. Some of the evidence suggests that COCs must be used for up to a year before a decreased risk of endometrial cancer is observed.

A meta-analysis examining the risk of endometrial cancer in relation to COC use included ten case-control studies and one prospective study. Among the studies reporting duration of use (10 of 11), seven case-control studies demonstrated a decrease in risk estimates with increasing duration of COC use. Overall, 4 years of COC use was associated with a reduced risk of endometrial cancer of approximately 56%, 8 years with a reduced risk of 67%, and 12 years of use with a reduced risk of approximately 72%. Of note, the prospective study did not show a dose-response, however, the RR was consistently reduced by 80% after 9 years of follow-up.[26]

A population-based case-control study in Sweden reported a 30% decreased risk (OR = 0.7; 95% CI, 0.5–0.9) of endometrial cancer among women who had used any type of oral contraceptive; progestin-only pills were associated with a further reduction in risk by approximately 60% (OR = 0.4; 95% CI, 0.2–1.4). For women who reported 3 or more years of use of COCs, the OR was 0.5 (95% CI, 0.3–0.7) and continued to decline to OR = 0.2 (95% CI, 0.1–0.4) for women reporting 10 or more years of use. The risk of endometrial cancer decreased by 10% per year of COC utilization and was observed for atypical hyperplasias as well as for all grades of invasive tumors.[27]

Tamoxifen is a member of a group of drugs known as selective estrogen receptor modulators (SERMs) and recognized for divergent estrogen agonist and antagonist effects in different target organs. The association between endometrial cancer and tamoxifen was first recognized in 1985, when three cases of endometrial cancer were described in women who had been treated with tamoxifen for breast cancer.[28] Since then, confirmation of the association has been provided by results from randomized clinical trials using tamoxifen for breast cancer treatment and the Breast Cancer Prevention Trial.[29-31] The accumulating body of information about this association is further augmented by case-control,[32,33] observational, and laboratory studies.

A report was published in 1989 concerning second primary cancers observed in patients treated as part of a randomized Swedish study of adjuvant breast cancer treatment with 40 mg of tamoxifen daily for 2 or 5 years versus no endocrine treatment.[29] With a patient population of 1,846 and a median follow-up of 4.5 years, there was an increase in uterine cancer cases among the 931 tamoxifen-treated women, consistent with a RR of 6.4 (P < .01). In a Danish trial, women identified at greater risk of breast cancer recurrence on the basis of tumor-bearing axillary nodes or tumors greater than 5 cm were randomly assigned to be treated adjuvantly with either chest wall radiation or radiation and 48 weeks of tamoxifen at a dose of 30 mg daily after undergoing modified radical mastectomy.[31] Though the difference was not statistically significant, the cumulative incidence of endometrial cancer was 1% in the tamoxifen treated group compared to 0.3% among patients who did not receive tamoxifen. A meta-analysis of Scandinavian trials including the Swedish and Danish studies confirmed an RR of 4.1 for endometrial cancer at a median follow-up between 8 and 9 years for 4,914 patients.[30] The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial compared tamoxifen to placebo as adjuvant therapy for women with node-negative estrogen receptor-positive breast cancer, in the group of approximately 1,400 patients randomly assigned to receive tamoxifen, the hazard of developing endometrial cancer was 1.6 per 1,000 women per year.[34] The RR within the trial was 7.5, but the investigators were suspicious of an endometrial cancer detection bias since the rate of 0.2 per 1,000 women in the placebo group was much lower than expected on the basis of population-based data from the Surveillance, Epidemiology, and End Results program. The endometrial tumors observed in the B-14 study did not have a different distribution of histologies or prognoses compared with endometrial tumors in nontamoxifen-treated patients.

The NSABP Breast Cancer Prevention Trial P-1 Study confirmed an increased incidence of endometrial cancer in women at high risk of invasive breast cancer, who received tamoxifen, as compared with women who received placebo. The average annual rate of endometrial cancer was 2.3 per 1,000 among women who received tamoxifen and 0.91 per 1,000 in the placebo group: a 2.53 greater risk for women taking chemopreventive tamoxifen (95% CI, 1.35–4.97). The increase in risk differed according to menopausal status, for women aged 49 years or younger RR was 1.21 (95% CI, 0.41–3.60) compared with 4.01 (95% CI, 1.70–10.90) for women aged 50 years and older. All of the invasive endometrial cancer cases that occurred among women taking tamoxifen were International Federation of Gynecology and Obstetrics (FIGO) stage I. Similarly, 14 out of 15 (93%) of the invasive endometrial cancer cases diagnosed among women taking placebo were FIGO stage I.[35]

There have been several case-control studies looking at the level of risk for developing endometrial cancer after treatment with tamoxifen for breast cancer. One study looked at data for 98 patients who developed endometrial cancer subsequent to a diagnosis of breast cancer and reported that women who had used tamoxifen for more than 2 years had an RR of 2.3 (95% CI, 0.9–5.9).[32] In this study, there were statistically significant trends according to duration of use and cumulative tamoxifen dose. A population-based study of endometrial cancer subsequent to a diagnosis of breast cancer based on 42 such cases found no association between durations of tamoxifen use less than 2 years and endometrial cancer (OR = 0.6; 95% CI, 0.2–1.9).[33]

Whether tamoxifen is associated with a more aggressive histology than nontamoxifen-associated endometrial cancer is uncertain. The question was first raised by investigators at Yale University on the basis of a hospital-based case series of 53 breast cancer patients who subsequently developed endometrial cancer.[36] Of these 53 patients, 15 had received tamoxifen (40 mg per day). Of the women receiving tamoxifen, 67% had poorly differentiated endometrioid carcinomas or carcinomas associated with a poor outcome (papillary serous, clear cell, or mixed mullerian).

A Dutch study of 309 breast cancer patients who developed endometrial cancer compared with 860 age-matched and time-matched controls showed increased endometrial cancer risk associated with tamoxifen use and an increased risk for higher-stage cancers, poor-prognosis histology, and endometrial cancer-specific mortality.[37]

Similar to the histology results noted in the NSABP B-14 trial, a clinicopathologic description of 17 endometrial cancer cases in the Swedish trial indicated that most were not high grade, and the 10-year actuarial survival after post-tamoxifen endometrial cancer was 73%.[38] Of 16 tumors that were evaluable according to the WHO grading system, only one patient had advanced disease (stage IV).

Raloxifene is a second generation SERM approved for prophylaxis against postmenopausal osteoporosis. Unlike tamoxifen, it does not have an estrogenic effect on the uterus. Results from the Multiple Outcomes of Raloxifene (MORE) randomized trial, indicated that raloxifene reduced the risk of estrogen receptor-positive breast cancer, but was not associated with an increased risk of developing endometrial cancer (RR = 0.8; 95% CI, 0.2–2.7) after 40 months of follow-up.[39]

Elevated body mass index (BMI) and obesity have been associated in several studies with increased risk of endometrial cancer. Studies have measured body fat in a variety of ways including body weight, BMI, waist-to-thigh circumference ratio, and waist-to-hip circumference ratio.[40] One of the possible mechanisms for the observed association is an increased level of serum estrone in obese women as a result of aromatization of androstenedione in adipose tissue, which increases the production of estrogen, a well-known cause of endometrial cancer.[41] Alternatively, obesity has been associated with a reduction in levels of sex hormone-binding globulin (SHBG), which can increase bioavailable estrogen.[42] Obesity has been associated with several factors known to increase the risk of endometrial cancer, including upper-body or central adiposity, polycystic ovarian syndrome, physical inactivity, and a diet high in saturated fat.[43]

Presumably, body weight is a modifiable risk factor, which accounts for a substantial proportion of endometrial cases worldwide. A study conducted among European countries estimated that between 26% and 47% of endometrial cancer cases can be attributed to overweight and obesity. The same group conducted a meta-analysis of studies which examined the relationship between obesity and endometrial cancer. Eleven out of the 12 (five cohort and seven case-control) studies reviewed concluded that there is a positive association between endometrial cancer and excess weight.[44]

Relative risks associated with obesity range from two to ten.[40] Some studies have concluded that upper-body and central weight confer a higher risk than peripheral body weight, even after consideration of BMI.[40,45-47] However, other studies have failed to confirm such an association. Several studies have observed a stronger association between endometrial cancer and obesity close to the time of diagnosis compared to obesity earlier in life.[48-51] Although the role that obesity plays in the underlying etiology of endometrial cancer is not fully understood, several mechanisms have been proposed. According to the estrogen theory, postmenopausal women accumulate most of their plasma estrogen from the aromatization of androstenedione to estrone and estradiol, which occurs in adipose tissue.[41] This may explain the strength of the relationship observed between weight-gain late in life and endometrial cancer. Alternatively, the association between central adiposity and endometrial cancer may be due to underlying hyperinsulinemia; this would negate obesity as a causal factor in endometrial cancer.[52-54]

The first prospective investigation of endogenous estrogens and the risk of endometrial cancer was a case-control study nested within the New York University Women’s Health Study.[55] Results suggest an increased risk of endometrial cancer associated with postmenopausal levels of endogenous hormones including estradiol, percent free estradiol, and estrone. Conversely, risk was decreased with higher levels of percent SHBG-bound estradiol and SHBG. Analyses conducted prior to adjustment for hormone levels indicated a positive association with BMI. After adjustment for estrone level, the positive association of BMI with risk of endometrial cancer was attenuated, suggesting that hormone levels may be an intermediate effect of body weight.[56]

Given the observed association between obesity and endometrial cancer, it is important to understand how weight loss among overweight and obese women may impact their risk of developing endometrial cancer. To investigate this question, researchers examined intentional weight loss and cancer incidence among participants in the Iowa Women’s Health Study (N = 21,707 postmenopausal women).[57] Participants completed a self-report questionnaire in 1992, which retrospectively assessed weight loss during three age periods (18–39, 40–54, and 55 years ). The women were asked to report the number of times during the three age periods that they lost 5 to 9, 10 to 19, 20 to 49, or 50 or more pounds. Intentional weight loss was categorized separately from unintentional weight loss. Multivariate models adjusting for age, BMI, and BMI² found a nonsignificant decrease in endometrial cancer incidence for women who intentionally lost 20 pounds or more compared with women who had never lost 20 pounds or more (RR = 0.93; 95% CI, 0.60–1.44). Further adjustment of the model to include several covariates slightly attenuated the risk estimate (RR = 0.96; 95% CI, 0.61–1.52). Despite the advantage of studying this important question in a large, prospective cohort, this study does have limitations. The questionnaire data regarding weight loss is self-report and obtained retrospectively, which is potentially subject to recall bias (heavier people may be more likely to report any weight loss as intentional). The authors report that measures of intentionality of weight loss were not validated. Weight loss maintenance was not ascertained.[57]

Several studies including cohort [58,59] and case-control [60-68] designs have been conducted to investigate the relationship between physical activity and the risk of endometrial cancer. Results have demonstrated a weak to moderate inverse relationship; however, it is difficult to make comparisons between studies due to the varying methods of assessing physical activity levels. For postmenopausal women enrolled in The Netherlands Cohort Study on Diet and Cancer, a 46% reduction (RR = 0.54; 95% CI, 0.34–0.85, P trend = .002) in risk of endometrial cancer was reported in those women who were physically active 90 minutes or more per day compared with less than 30 minutes each day.[69] One case-control study was fairly large with 822 endometrial cancer cases and 1,111 population controls. When comparing women who exercised regularly with women who reported no exercise in the 2 years prior to diagnosis, the estimated risk of endometrial cancer was reduced by 38% (OR = 0.62; 95% CI, 0.51–0.76). The authors note, however, that there did not appear to be a trend in risk reduction with increasing duration or intensity of physical activity.[70] The Breast Cancer Detection Project Follow-up Study, a prospective cohort, found that recent physical activity levels do not appear to affect risk.[71] It has been hypothesized that physical activity modifies the risk of endometrial cancer by reducing obesity, a known risk factor for endometrial cancer or by reducing serum estrone levels.[72]

In addition to the decreased risk of endometrial cancer recognized among parous women, lactation also may reduce risk. It has been hypothesized that inhibited ovulation during breastfeeding may suppress the risk of endometrial cancer. A case-control study conducted in Mexico City, among low-risk women, indicates a 58% to 72% reduction in risk of endometrial cancer associated with increasing duration of lactation, with a statistically significant trend. A similar trend was reported for an increase in the number of children breastfed.[73] A population-based case-control study conducted among Wisconsin women reported a statistically nonsignificant reduction in risk for parous women who breastfed for at least 2 weeks compared with those who did not breastfeed, OR = 0.90 (95% CI, 0.72–1.13). Increasing duration of lactation was not associated with a decrease in disease risk. However, breastfeeding within the past three decades was associated with a reduced risk of disease, OR = 0.58 (95% CI, 0.36–0.96). The risk of endometrial cancer was reduced by 50% (95% CI, 0.28–0.90) for women who breastfed for the first time at age 30 years or older.[74]

A limited number of studies, mostly observational, have described the association between dietary factors and risk of endometrial cancer. However, findings are consistent that a diet low in saturated fats and high in fruit and vegetable intake is associated with reduced risk of developing endometrial cancer.[75-77] In contrast, a prospective cohort of postmenopausal Iowa women [78] and a case-cohort analysis using the National Breast Screening Study cohort in Canada [79] reported that energy intake was not strongly related to risk. There is case-control evidence suggesting that regular consumption of soy products reduces the risk of endometrial cancer.[80,81]

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