**2. Risk factors for endometrial cancer**

#### **2.1. Hormone replacement therapy**

The primary role of progestin in postmenopausal estrogen therapy is endometrial protection to prevent hyperplasia. [7] Prior to the widespread use of combined estrogen-progestin therapy (EPT), the risk of developing hyperplasia due to unopposed estrogen stimulation was substantial. Endometrial hyperplasia in postmenopausal women with an intact uterus, treated with unopposed oral estrogen, was found in 20% of women during the first year and in 62% after 3 years of estrogen therapy (ET). [8] In support of this finding, in the Postmenoapausal Estrogen/Progestin Intervention Trial, 62% of women who received only estrogen (0.625 mg of conjugated equine estrogen orally daily) developed endometrial hyperplasia. One third of these women had complex hyperplasia with or without atypia. [9] Hyperplasia is characterized by a proliferation of the endometrial glands. In non-atypical hyperplasia, the glands are outgrown yet normal, but in atypical hyperplasia glandular abnormality is already present both structurally and at cellular level. [10] Non-atypical hyperplasia rarely progresses to more severe conditions. Atypical adenomatous hyperplasia, on the other hand, has been observed to progress to adenocarcinoma of the uterus in 29% of cases. [11]

Progestins should, therefore, be added to ET in all postmenopausal women with an intact uterus. Since the mid-1980s, EPT has increasingly been prescribed. The North American Menopause Society reviewed the types of EPT regimen used in the USA and concluded that standard regimens provide adequate endometrial protection. [7] A Cochrane review devoted to this subject also came to the conclusion that the addition of an oral progestin to ET, admin‐ istered either continuous cyclic or continuous combined, is associated with reduced rates of hyperplasia. [12] An important drawback of postmenopausal EPT is the occurrence of withdrawal or breakthrough bleedings. Withdrawal uterine bleedings occur in 80% of women using cyclic EPT. Continuous combined regimens avoid withdrawal bleeding, but break‐ through bleeding has been observed in up to 40% of women during the first 6 months. Most postmenopausal women dislike breakthrough bleedings and this is the most common reason for discontinuation and non-adherence to the treatment regimen. With EPT, therefore, irregular bleeding should be kept to a minimum. Depending on the EPT type, dose and route of administration, progestins may have adverse effects on the cardiovascular system, coagu‐ lation and breast tissue. The Women's Health Initiative (WHI) reported an increased risk for heart disease, stroke and breast cancer. [13] Since these adverse effects were not observed with ET alone, it is speculated that adding progestins may diminish the beneficial effects on atherosclerosis, vasodilatation and plasma lipids and may contribute to the increased risk of breast cancer. Indeed, the WHI study suggests that EPT may stimulate breast cancer growth and hinder breast cancer diagnosis due to increased mammographic density when a progestin is added to ET. [14, 15] This was confirmed in the Million Women Study and other studies, in particular a Swedish cohort study. [16, 17, 18]

Intrauterine-administered progestin, such as levonorgestrel (LNG), delivered directly to the target cells of the endometrium, has a profound suppressive effect on endometrial growth rendering the endometrium inactive and simultaneously eliminating uterine bleeding. [19, 20] Pharmacokinetic studies with an intrauterine system (IUS) releasing 20 µg of LNG/day (Mirena®; Bayer AG, Germany) have shown substantially lower plasma LNG concentrations than those seen with a subdermal LNG implant (Norplant®; Pfizer Pharmaceuticals Inc, USA), the combined oral contraceptive pill and the mini-pill; moreover, unlike with oral contracep‐ tives, LNG levels with the Mirena LNG-IUS do not display peaks and troughs. [21] This is important because the low plasma levels may have a significantly lower impact on organs and tissues, such as the breast, coagulation system, and cardiovascular system.

Studies conducted by us and by others using continuous combined estrogen plus low-dose LNG-IUS after 5 years of use in postmenopausal women, provided data on the endometrial morphology to verify endometrial safety. The main objective of these studies was to evaluate an alternative route of progestin administration in postmenopausal women using ET. They suggest that continuous combined ET with intrauterine delivery of a progestin was highly accepted by the participating women. The rationale of the development of LNG-IUSs specifi‐ cally for postmenopausal women is to minimize the potential adverse systemic effects. As progestins are required only to oppose the stimulating effects of estrogens on the endometri‐ um, locally acting progestins, by definition, could avoid these unwanted metabolic effects. Intrauterine LNG delivery with low-dose systems, even though minimal absorption may occur, should be regarded as essentially locally acting. This regimen also offers important additional benefits that could be exploited, such as high adherence to treatment and a low discontinuation rate because of bleeding problems and progestin-like side effects. In addition, a LNG-IUS that adapts to the decreasing dimensions of the uterus gradually reduced in size due to the suppressive effect of LNG and the decreasing levels of endogenous estrogen, will be optimally tolerated by the women. [22, 23]

#### **2.2. Polycystic ovary syndrome**

**2. Risk factors for endometrial cancer**

to progress to adenocarcinoma of the uterus in 29% of cases. [11]

particular a Swedish cohort study. [16, 17, 18]

The primary role of progestin in postmenopausal estrogen therapy is endometrial protection to prevent hyperplasia. [7] Prior to the widespread use of combined estrogen-progestin therapy (EPT), the risk of developing hyperplasia due to unopposed estrogen stimulation was substantial. Endometrial hyperplasia in postmenopausal women with an intact uterus, treated with unopposed oral estrogen, was found in 20% of women during the first year and in 62% after 3 years of estrogen therapy (ET). [8] In support of this finding, in the Postmenoapausal Estrogen/Progestin Intervention Trial, 62% of women who received only estrogen (0.625 mg of conjugated equine estrogen orally daily) developed endometrial hyperplasia. One third of these women had complex hyperplasia with or without atypia. [9] Hyperplasia is characterized by a proliferation of the endometrial glands. In non-atypical hyperplasia, the glands are outgrown yet normal, but in atypical hyperplasia glandular abnormality is already present both structurally and at cellular level. [10] Non-atypical hyperplasia rarely progresses to more severe conditions. Atypical adenomatous hyperplasia, on the other hand, has been observed

Progestins should, therefore, be added to ET in all postmenopausal women with an intact uterus. Since the mid-1980s, EPT has increasingly been prescribed. The North American Menopause Society reviewed the types of EPT regimen used in the USA and concluded that standard regimens provide adequate endometrial protection. [7] A Cochrane review devoted to this subject also came to the conclusion that the addition of an oral progestin to ET, admin‐ istered either continuous cyclic or continuous combined, is associated with reduced rates of hyperplasia. [12] An important drawback of postmenopausal EPT is the occurrence of withdrawal or breakthrough bleedings. Withdrawal uterine bleedings occur in 80% of women using cyclic EPT. Continuous combined regimens avoid withdrawal bleeding, but break‐ through bleeding has been observed in up to 40% of women during the first 6 months. Most postmenopausal women dislike breakthrough bleedings and this is the most common reason for discontinuation and non-adherence to the treatment regimen. With EPT, therefore, irregular bleeding should be kept to a minimum. Depending on the EPT type, dose and route of administration, progestins may have adverse effects on the cardiovascular system, coagu‐ lation and breast tissue. The Women's Health Initiative (WHI) reported an increased risk for heart disease, stroke and breast cancer. [13] Since these adverse effects were not observed with ET alone, it is speculated that adding progestins may diminish the beneficial effects on atherosclerosis, vasodilatation and plasma lipids and may contribute to the increased risk of breast cancer. Indeed, the WHI study suggests that EPT may stimulate breast cancer growth and hinder breast cancer diagnosis due to increased mammographic density when a progestin is added to ET. [14, 15] This was confirmed in the Million Women Study and other studies, in

Intrauterine-administered progestin, such as levonorgestrel (LNG), delivered directly to the target cells of the endometrium, has a profound suppressive effect on endometrial growth rendering the endometrium inactive and simultaneously eliminating uterine bleeding. [19,

**2.1. Hormone replacement therapy**

184 Contemporary Gynecologic Practice

Women with polycystic ovary syndrome (PCOS) are about three times more likely to develop endometrial cancer compared with women without this condition. [24] PCOS affects approx‐ imately 5 to 10% of women of reproductive age. The disorder is characterized by a disruption of normal reproductive physiology and should be diagnosed in women with oligomenorrhea or amenoorrhea, hyperandrogenemia and polycystic ovaries defined by ultrasonography after exclusion of medical conditions that cause irregular menstrual cycles and androgen excess. [25] Women with PCOS have a higher prevalence of obesity, impaired glucose tolerance and type 2 diabetes. They are at risk of cardiovascular disease and often have features of metabolic syndrome, including hypertension, dyslipidemia, visceral obesity and insulin resistence. [26] Women with PCOS should, therefore, be screened for type 2 diabetes and for cardiovascular risk by fasting glucose followed by a glucose tolerance test, BMI, fasting lipid and lipoprotein levels, and other metabolic syndrome risk factors. The condition that makes PCOS patients vulnerable to endometrial cancer is chronic anovulation as prolonged exposure to unopposed estrogen can lead to endometrial hyperplasia and cancer. It is important to identify individuals at risk at an early stage.

From 2 to 14% of patients diagnosed with endometrial cancer are women younger than 40 and the diagnosis is typically associated with the detection of an accompanying hyperestrogenic state. [25] According to studies in the United States, an estimated prevalence in very young women is 0.8%. [27, 28] A comprehensive review of PCOS was published by the American College of Obstetricians and Gynecologists. [29] Of note, PCOS can occur both in normal weight and overweight women. Yet classically, the young woman with endometrial hyper‐ plasia or cancer is obese and nulliparous but, recently, several studies found up to 50% of women with endometrial cancer to be slender and with regular menstrual cycles. The pro‐ portion of estrogen and progesterone receptor positivity is similar in both obese and slim patients. Such women should be evaluated for concurrent ovarian malignancy (see Lynch syndrome below) which occurs in some studies in approximately 10% of cases. Therefore, 3- D ultrasound and magnetic resonance imaging (MRI) can be valuable additions in the diagnosis and staging of these patients.

## **2.3. Excessive body mass: Overweight and obesity**

Obesity has become a major public health problem on a global scale. Overweight and obesity are not only an established risk factor for cardiovascular disease and type 2 diabetes; they are also an important risk factor for the development of endometrial cancer. [30] Renehan at al. found that each increase in BMI of 5 kg/m2 significantly increased a woman's risk for the development of endometrial cancer. [31] Estrogen is a known endometrial growth factor in these women. The excess estrogens originate mostly from the conversion of androstenedione to estrone and testosterone to estradiol by peripheral adipose tissue. [32] Consequently, in obese postmenopausal women, adipose tissue becomes the primary source of circulating estrogen. Concentrations of estrogens in the adipose tissue have been measured at levels several-fold above that observed in plasma. Also, higher levels of insulin in obese women contribute to the increased risk for endometrial cancer as insulin demonstrates mitotic and antiapoptotic activity. Furthermore, serum sex hormone-binding globulin (SHBG) levels decrease with increasing adiposity, thus rising the fraction of circulating unbound estrogen.

The relationship between obesity and endometrial cancer has been well studied and has been acknowledged as a risk factor in women over 30 years of age. A strong association between early age at diagnosis and Type 1 endometrial cancer was found. The relationship was linear, suggesting that as obesity becomes more severe, the underlying carcinogenic mechanisms are more vividly activated. [4] There is limited public knowledge of the relationship between obesity and cancer risk. Making the data available to overweight and obese women could be useful to inform them about the risks which could affect their lives at an early age, and about the steps they could undertake to reduce or eliminate this risk, since prevention and other risk reduction strategies in the obese/overweight female population are possible with a high degree of success.

#### **2.4. Lynch syndrome**

Lynch syndrome is one of the most common cancer predisposition syndromes estimated to affect as many as 1 in 370 individuals. [33, 34] Often called hereditary nonpolyposis colorectal cancer it is an inherited disorder that increases the risk of many types of cancer, particularly cancers of the colon and rectum, which are collectively referred to as colorectal cancer. Individuals with Lynch syndrome also have an increased risk for cancers of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, and skin. Additionally, women with this disorder have a high risk for cancer of the ovaries and endometrium. Patients with Lynch syndrome may occasionally have noncancerous polyps in the colon. For many women with Lynch syndrome, the risk for endometrial cancer is comparable or even exceeds their risk for colorectal cancer. In the United States, about 140,000 new cases of colorectal cancer are diagnosed each year. Approximately 3 to 5 percent of these cancers are caused by Lynch syndrome. Estimates suggest that as many as 1 in 10 young age (< 50) endometrial cancers are associated with Lynch syndrome. Broader knowledge of population carrier frequency for DNA mismatch repair gene mutations could contribute to the understanding of the burden of cancer due to genetic susceptibility, but robust prevalence estimates are lacking. The lifetime endometrial cancer risk is between 27% and 71% which exceeds that of colorectal cancer. Mean age of occurrence is approximately 50 years (62 years in non-Lynch) and 18% are diagnosed under the age of 40 years. Practical guidelines for Lynch syndrome and early detection can be found via website: http://ghr.nlm.nih.gov/condition/lynch-syndrome. We are of opinion that women diagnosed with Lynch syndrome should be counseled on and consider the prophy‐ lactic long-term use of a LNG-IUS in relation to their increased endometrial cancer risk.

#### **2.5. Tamoxifen adjuvant treatment for breast cancer**

state. [25] According to studies in the United States, an estimated prevalence in very young women is 0.8%. [27, 28] A comprehensive review of PCOS was published by the American College of Obstetricians and Gynecologists. [29] Of note, PCOS can occur both in normal weight and overweight women. Yet classically, the young woman with endometrial hyper‐ plasia or cancer is obese and nulliparous but, recently, several studies found up to 50% of women with endometrial cancer to be slender and with regular menstrual cycles. The pro‐ portion of estrogen and progesterone receptor positivity is similar in both obese and slim patients. Such women should be evaluated for concurrent ovarian malignancy (see Lynch syndrome below) which occurs in some studies in approximately 10% of cases. Therefore, 3- D ultrasound and magnetic resonance imaging (MRI) can be valuable additions in the

Obesity has become a major public health problem on a global scale. Overweight and obesity are not only an established risk factor for cardiovascular disease and type 2 diabetes; they are also an important risk factor for the development of endometrial cancer. [30] Renehan at al.

development of endometrial cancer. [31] Estrogen is a known endometrial growth factor in these women. The excess estrogens originate mostly from the conversion of androstenedione to estrone and testosterone to estradiol by peripheral adipose tissue. [32] Consequently, in obese postmenopausal women, adipose tissue becomes the primary source of circulating estrogen. Concentrations of estrogens in the adipose tissue have been measured at levels several-fold above that observed in plasma. Also, higher levels of insulin in obese women contribute to the increased risk for endometrial cancer as insulin demonstrates mitotic and antiapoptotic activity. Furthermore, serum sex hormone-binding globulin (SHBG) levels decrease with increasing adiposity, thus rising the fraction of circulating unbound estrogen.

The relationship between obesity and endometrial cancer has been well studied and has been acknowledged as a risk factor in women over 30 years of age. A strong association between early age at diagnosis and Type 1 endometrial cancer was found. The relationship was linear, suggesting that as obesity becomes more severe, the underlying carcinogenic mechanisms are more vividly activated. [4] There is limited public knowledge of the relationship between obesity and cancer risk. Making the data available to overweight and obese women could be useful to inform them about the risks which could affect their lives at an early age, and about the steps they could undertake to reduce or eliminate this risk, since prevention and other risk reduction strategies in the obese/overweight female population are possible with a high degree

Lynch syndrome is one of the most common cancer predisposition syndromes estimated to affect as many as 1 in 370 individuals. [33, 34] Often called hereditary nonpolyposis colorectal cancer it is an inherited disorder that increases the risk of many types of cancer, particularly

significantly increased a woman's risk for the

diagnosis and staging of these patients.

186 Contemporary Gynecologic Practice

**2.3. Excessive body mass: Overweight and obesity**

found that each increase in BMI of 5 kg/m2

of success.

**2.4. Lynch syndrome**

The long-term recurrence and mortality rates of breast cancer have been substantially reduced due to adjuvant treatment with tamoxifen. Tamoxifen is a selective estrogen receptor modu‐ lator (see Table 1) which exerts an anti-estrogenic effect on mammary tissue. [35] However, it also induces endometrial proliferation and women using tamoxifen harbor significantly more endometrial polyps than other women of which up to 36% could have hyperplasia or cancer. [36] The prophylactic use of LNG-IUS in women with breast cancer treated with tamoxifen is still controversial as the effect of the progestin released from the device on breast cancer recurrence remains uncertain notwithstanding the significantly reduced incidence of endo‐ metrial polyps. [37] Nonetheless, in the future, this situation could be clarified by the advent of an intrauterine system impregnated with a selective progesterone receptor modulator (SPRM; see Table 2) that would demonstrate powerful progestin action on the endometrium without any stimulatory, if not purely inhibitory, properties with regards to hormonally sensitive breast glandular tissue.


**Table 1.** Examples of selective estrogen receptor modulators, or SERMs, for the use in the clinical setting.


**Table 2.** Examples of selective progesterone receptor modulators, or SPRMs, for the use in the clinical setting.
