Abnormal uterine bleeding and uterine pathology in patients on tamoxifen therapy

INTRODUCTION — Tamoxifen is a nonsteroidal selective estrogen receptor modulator that is used primarily for adjuvant treatment of estrogen receptor-positive breast cancer in premenopausal patients and in some postmenopausal patients [1]. It is also used for chemoprevention in patients at increased risk for breast cancer.

Tamoxifen is associated with increased risks of uterine pathology, including endometrial polyps, endometrial carcinoma and hyperplasia, uterine sarcoma, and uterine carcinosarcoma.

Uterine pathology in patients on tamoxifen is reviewed here. Use of tamoxifen for breast cancer therapy or breast cancer prevention and management of other adverse effects associated with tamoxifen are reviewed separately. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer" and "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention" and "Managing the side effects of tamoxifen and aromatase inhibitors".)

PATHOPHYSIOLOGY

Mechanism of action — Tamoxifen is a competitive inhibitor of estrogen, binding to the estrogen receptor in the breast, which blocks tumor proliferation [2,3]. However, tamoxifen has a complex mechanism of action against tissues. While it is antiestrogenic in the breast, it can be either an estrogen antagonist or agonist at different sites of the female reproductive tract.

Endometrial and menstrual effects — Tamoxifen is a mixed estrogen antagonist and agonist (referred to as a selective estrogen receptor modulator [SERM]).

In premenopause, estrogen levels are >20 pg/mL, an estrogen-replete state. In the endometrium, the estrogen antagonist effect of tamoxifen predominates in premenopause because the endogenous estradiol stimulation is much greater than the estrogen agonist effect of tamoxifen. In postmenopause, estrogen levels are typically <20 pg/mL. In postmenopause, in the endometrium, the estrogen agonist effects of tamoxifen can predominate because endogenous estrogen levels are so low [4].

From a molecular standpoint, it is well recognized that KRAS mutations occur at a high rate (40 to 75 percent) in both premenopausal and postmenopausal endometria of patients on tamoxifen [5,6]. However, after cessation of tamoxifen, KRAS mutations appear to resolve and remain absent even in long-term follow-up [6].

Premenopausal patients — The effect of tamoxifen on hypothalamic-pituitary-ovarian axis in premenopausal patients is similar to clomiphene. Tamoxifen increases follicle-stimulating hormone (FSH) levels to a slight degree and estradiol levels to a large degree across the menstrual cycle. It is believed that SERMs like tamoxifen partially block estradiol's negative feedback loop and therefore up-regulate gonadotropin-releasing hormone agonist secretion from the hypothalamus; however, the mechanisms of action are complex and data in humans are limited [7].

Abnormal uterine bleeding (AUB) is common in premenopausal patients on tamoxifen [8,9]. Approximately half of premenopausal patients using tamoxifen will become oligomenorrheic or amenorrheic [4]. However, new-onset amenorrhea in the setting of tamoxifen does not correlate with low estradiol levels or a decrease in endometrial thickness [8].

Among premenopausal patients on tamoxifen who have AUB, up to 23 percent will be found to have underlying endometrial pathology, most often polyps and rarely hyperplasia. The risk of endometrial carcinoma (EC) even in symptomatic premenopausal patients on tamoxifen is exceedingly low [9,10]. (See 'Postmenopausal versus premenopausal patients' below.)

Postmenopausal patients — In postmenopausal patients, tamoxifen exerts an estrogenic effect that can stimulate endometrial proliferation. Tamoxifen appears to promote (1) cell proliferation through MAP kinase pathways, c-MYC, and insulin-like growth factor 1 (IGF1) pathways, (2) cell proliferation and invasion through alterations in estrogen receptor-alpha and the membrane-associated estrogen receptor G protein-coupled receptor 30 (GPR30), (3) cell migration through ERK and Src signaling, (4) DNA damage through DNA adduct formation, and (5) upregulation of the prosurvival unfolded protein response (UPR) pathway. However, the identification of all tamoxifen targets in the endometrium is likely incomplete and the effects of long-term tamoxifen exposure on molecular changes remain unclear [11].

Endometrial stimulation by tamoxifen in postmenopausal patients can lead to endometrial polyps, hyperplasia, or carcinoma. (See 'Risks and management of uterine pathology' below.)

CLINICAL PRESENTATION AND EVALUATION — Uterine pathology in patients on tamoxifen therapy usually presents in one of two ways: AUB or an incidental finding of uterine pathology on pelvic imaging.

Abnormal uterine bleeding — AUB during tamoxifen therapy occurs in over 50 percent of premenopausal patients [8,9] and up to 25 percent of postmenopausal patients [12]. AUB warrants further evaluation, and endometrial evaluation with endometrial sampling and/or pelvic ultrasound is required in patients if uterine pathology is suspected.

Evaluation — The unique aspects of evaluation of AUB in patients on tamoxifen are discussed here. The approach to AUB evaluation in the general population is discussed in detail separately. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis" and "Approach to the patient with postmenopausal uterine bleeding".)

Medical history — The medical history should include:

●Characteristics of the bleeding – Onset of AUB and timing, volume, and duration of bleeding over the past several months. For premenopausal patients, AUB includes many abnormal bleeding patterns, including intermenstrual bleeding, ovulatory dysfunction, or heavy menstrual bleeding (table 1). Patients may also develop amenorrhea or oligomenorrhea. For postmenopausal patients, any bleeding, spotting, or bloody vaginal discharge is abnormal. The American College of Obstetricians and Gynecologists (ACOG) advised that patients on tamoxifen should report any abnormal vaginal symptoms, including bloody discharge, spotting, staining, or leukorrhea [13].

●Menstrual and gynecologic history, including:

•A menstrual history should be taken, including the bleeding pattern before and after cancer treatment. Issues to determine include whether the patient had regular menses prior to starting tamoxifen therapy and whether the patient is postmenopausal. (See "Clinical manifestations and diagnosis of menopause".)

Some patients may have amenorrhea or irregular menses following chemotherapy. Alkylating agents (eg, cyclophosphamide) are often used in breast cancer, and these are potent causes of ovarian failure. The likelihood of ovarian insufficiency following chemotherapy depends upon the agent, dose, and patient age (table 2).

•Conditions associated with AUB (eg, uterine leiomyomas, adenomyosis, ovulatory dysfunction, von Willebrand disease) (table 3); these may be the etiology or contribute to current bleeding symptoms.

●Risk factors for endometrial carcinoma (EC), uterine sarcoma, and uterine carcinosarcoma:

•In particular, obesity or a long-term history of ovulatory dysfunction increase the risk of EC. Risk factors for EC are shown in the table (table 4). (See "Endometrial carcinoma: Epidemiology, risk factors, and prevention", section on 'Risk factors'.)

•Risk factors for uterine sarcoma include increasing age, Black race, tamoxifen, pelvic radiation, and some hereditary conditions.

•Risk factors for uterine carcinosarcoma include obesity, nulliparity, use of exogenous estrogen, tamoxifen, and pelvic radiation. (See "Clinical features, diagnosis, staging, and treatment of uterine carcinosarcoma", section on 'Epidemiology and risk factors'.)

Determining menopausal status — Determining menopausal status is of key importance in the evaluation of AUB, since the assessment of bleeding patterns and ultrasound findings differs for premenopausal and postmenopausal patients. If there is uncertainty about menopausal status, the patient should be evaluated as postmenopausal.

In the general population, the diagnosis of menopause is made based upon menstrual history and laboratory testing is typically not required. Menopause is defined as 12 months of amenorrhea and is due to a depletion of ovarian follicles. (See "Clinical manifestations and diagnosis of menopause".)

Based on the high prevalence of amenorrhea among patients on tamoxifen, menstrual history is not a reliable method of determining menopausal status [8]. Fifty percent of premenopausal patients treated with tamoxifen will have intermittent or long-term amenorrhea or irregular menses [4,8,9]. Patients may also have chemotherapy-induced amenorrhea, but menses may resume. In addition, approximately 20 percent of breast cancer cases in the United States are diagnosed between the ages of 45 to 54 years, and at these ages, many patients will be in the menopausal transition and have irregular menses (figure 1) [14].

For patients with estrogen receptor-positive breast cancer, choice of endocrine therapy depends upon menopausal status, since aromatase inhibitors are used only for postmenopausal patients. The approach to determining menopausal status prior to initiating endocrine therapy may differ somewhat from determining menopausal status in patients on tamoxifen with AUB because the threshold for clinical decision-making and the hormonal milieu are different. (See "Adjuvant endocrine therapy for premenopausal women with hormone receptor-positive breast cancer", section on 'Definition of menopause'.)

For patients on tamoxifen with AUB, our clinical approach to determining menopausal status is as follows (algorithm 1):

●For patients treated with tamoxifen who were already postmenopausal prior to cancer treatment, there is no ambiguity regarding menopausal status.

●Patients who are or who may be premenopausal require determination of menopausal status. It is important to note that the patient's status may have changed since treatment, either as a result of chemotherapy or because time has passed and the patient has entered menopause during the 5 to 10 years of tamoxifen therapy. Evaluation of menopausal status includes:

•The bleeding pattern before cancer treatment, after chemotherapy, and on tamoxifen should be determined. As noted above, approximately half of premenopausal patients using tamoxifen will become oligomenorrheic or amenorrheic [4]. However, new-onset amenorrhea in the setting of tamoxifen does not correlate with low estradiol levels or a decrease in endometrial thickness [8]. As such, amenorrhea is not reliable in diagnosing menopause in patients on tamoxifen. (See 'Medical history' above and 'Premenopausal patients' above.)

•Patients should be asked about whether the AUB has been accompanied by the onset of hot flashes, which may suggest menopause or premature ovarian insufficiency. However, there are many etiologies of heat intolerance or sweats that accompany cancer and cancer treatment.

•Menopausal status is further evaluated with serum hormone levels. For laboratory testing, we order serum estradiol (E2) and follicle-stimulating hormone (FSH) levels. These remain reliable endocrinologic markers in the setting of tamoxifen use [8]. Tamoxifen slightly raises FSH levels, but typically not to postmenopausal levels. Tamoxifen can raise estradiol levels across the menstrual cycle in premenopausal patients.

The results of hormonal testing for menopause should be interpreted with caution in all patients, since hormone levels in patients of reproductive age or in the menopausal transition may fluctuate dramatically in the same patient over a short period of time (figure 2). In addition, the range may vary by laboratory. Thus, if laboratory results are consistent with menopause, the evaluation of AUB should proceed as in a postmenopausal patient. However, the patient should be counseled that testing is not fully reliable and also that ovarian function may be present between tests or may return at varying intervals following chemotherapy. We interpret laboratory results as follows:

-In general, FSH of ≥70 to 100 IU/L is consistent with menopause.

-FSH of ≥25 to <70 IU/L is consistent with the late menopausal transition (figure 1) [15]. Based on this, if FSH is ≥25 international units/L, then an E2 <20 pg/mL is consistent with menopause. If E2 is ≥20 pg/mL, this is consistent with perimenopause.

-If FSH is <25 IU/L, an E2 ≥20 pg/mL is consistent with premenopause and an E2 <20 pg/mL is consistent with perimenopause.

Patients in perimenopause should be evaluated as premenopausal patients.

Additional laboratory testing for endocrine abnormalities or other etiologies of AUB should be performed as appropriate. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis".)

Pelvic ultrasound and endometrial sampling — Patients on tamoxifen therapy with AUB require evaluation for uterine pathology. The approach to evaluation differs between pre- and postmenopausal patients. The evaluation typically includes transvaginal ultrasound (TVUS) and/or endometrial sampling.

●Postmenopausal patients – Evaluation of the endometrium for EC is required for postmenopausal patients with vaginal bleeding; red, pink, or brown spotting or staining; or bloody vaginal discharge. We do an office endometrial biopsy and TVUS.

ACOG guidelines advise that the initial test used to evaluate postmenopausal bleeding in average-risk patients may be either endometrial sampling or TVUS [16]. Endometrial thickness ≤4 mm on TVUS in postmenopausal patients at average risk of endometrial cancer has been demonstrated to be an effective test to exclude EC. ACOG also advises that blind endometrial biopsy is most effective for detecting global (pathology occupies at least 50 percent of the surface area of the endometrial cavity), but may miss focal pathology [17-20]. If focal pathology is suspected, saline infusion sonogram or hysteroscopy should be performed.

For postmenopausal patients on tamoxifen, most experts advise endometrial biopsy rather than TVUS alone; however, some find expectant management in the setting of a thin endometrial echo (≤4 mm) to be acceptable. There are no high-quality data to evaluate the use of ultrasound measurement of the endometrial echo alone for exclusion of EC in patients on tamoxifen who have postmenopausal bleeding. As endometrial biopsy also has limitations (eg, it may miss focal pathology), we usually perform both endometrial biopsy and TVUS. (See "Overview of the evaluation of the endometrium for malignant or premalignant disease", section on 'Postmenopausal patients with bleeding'.)

Regarding method of endometrial sampling, office endometrial biopsy is typically the first-line test used for endometrial sampling, with dilation and curettage (D&C) used only if a follow-up evaluation is needed.

The goal of TVUS is to measure the endometrial echo, identify whether pathology is present, and identify whether it is global or focal. Also, TVUS may identify endometrial polyps or other uterine structural pathology (eg, leiomyomas, adenomyosis) that may contribute to AUB. Sonohysterogram or hysteroscopy (preferably in an office setting) may be required to differentiate a polyp from endometrial neoplasia or a submucosal leiomyoma [17]. (See "Endometrial polyps", section on 'Pelvic imaging'.)

Our approach to the evaluation of patients on tamoxifen with postmenopausal bleeding is as follows:

•In general, we perform both office endometrial biopsy and TVUS. However, in postmenopausal patients without other risk factors for EC (table 4) and no persistent bleeding, we manage expectantly if the endometrial echo is thin (≤4 mm) and an endometrial biopsy cannot be performed (eg, cervical stenosis). In postmenopausal patients with other EC risk factors (table 4) or persistent bleeding, endometrial sampling is warranted even if there is a thin endometrial echo on TVUS. (See "Endometrial carcinoma: Epidemiology, risk factors, and prevention", section on 'Risk factors'.)

•If the biopsy is positive for EC or atypical endometrial hyperplasia, manage as appropriate. (See "Endometrial carcinoma: Staging and surgical treatment" and "Endometrial hyperplasia: Management and prognosis".)

•If the biopsy is benign:

-For patients with a thin endometrial echo (≤4 mm) on TVUS, manage expectantly.

-For patients with a thick endometrial echo (>4 mm) or if adequate endometrial echo is not seen, perform either saline infusion sonohysterography or office hysteroscopy to triage such patients to global or focal findings. For patients with global pathology, the endometrial biopsy should be effective as a diagnostic method and the patient may be managed expectantly. For patients with focal abnormalities, proceed with direct visualization with hysteroscopy for biopsy and, if indicated, removal of pathology.

•If bleeding symptoms persist or recur, we evaluate with hysteroscopy and D&C. (See "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening", section on 'Approach to patients with nondiagnostic histopathology'.)

●Premenopausal patients – The evaluation for premenopausal patients depends on the bleeding pattern, since AUB is defined broadly and patient may also have amenorrhea. Menstrual irregularities and amenorrhea are common among premenopausal patients on tamoxifen, and endometrial sampling should be guided by risk factors other than tamoxifen use (table 4). This is consistent with advice from ACOG that states: "Premenopausal women treated with tamoxifen have no known increased risk of uterine cancer and as such require no additional monitoring beyond routine gynecologic care" [13]. (See 'Postmenopausal versus premenopausal patients' below.)

•For patients on tamoxifen with a new onset of amenorrhea or oligomenorrhea, menopausal status should be evaluated. Oligomenorrhea and amenorrhea are common in this patient population and may be secondary to tamoxifen or chemotherapy [7]. If testing shows that the patient is premenopausal or perimenopausal, we do not perform an endometrial biopsy unless there are other risk factors for endometrial cancer (eg, chronic ovulatory dysfunction). (See 'Determining menopausal status' above.)

•For patients with a new onset of heavy menstrual bleeding, intermenstrual bleeding, or irregular bleeding (more frequent than every 28 days), we do an office endometrial biopsy.

We also do a TVUS, if structural uterine pathology is suspected. TVUS measurement of endometrial thickness is not a reliable test for evaluating for endometrial hyperplasia or carcinoma in premenopausal patients since in this population the endometrial thickness varies with normal hormonal fluctuations. (See "Overview of the evaluation of the endometrium for malignant or premalignant disease", section on 'Premenopausal patients with abnormal bleeding'.)

Indications for evaluation for endometrial neoplasia are listed in the table and discussed in detail separately (table 5). (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis", section on 'Endometrial sampling: Choice of modality'.)

Our clinical approach for patients on tamoxifen with premenopausal heavy menstrual bleeding, intermenstrual bleeding, or frequent irregular menses is as follows:

-We perform an office endometrial biopsy. If the endometrial biopsy result is malignant or complex hyperplasia, we manage as appropriate. If the biopsy is benign and there is endometrial pathology on ultrasound, either saline infusion sonohysterography or office hysteroscopy may be used to distinguish global from focal findings.

-If the AUB persists or recurs, we then perform a D&C and hysteroscopy regardless of previous evaluations. (See "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening", section on 'Approach to patients with nondiagnostic histopathology'.)

Incidental findings on pelvic ultrasound — Uterine pathology may be noted incidentally on pelvic imaging that is performed for an indication other than AUB (eg, pelvic pain). The evaluation of a finding of a thickened endometrium in an asymptomatic postmenopausal patient is controversial and is discussed in detail separately. (See "Overview of the evaluation of the endometrium for malignant or premalignant disease", section on 'Incidental finding on TVUS for another indication'.)

An incidental finding of an endometrial polyp should be managed in the same manner as in a symptomatic patient.

Tamoxifen may result in an unusual ultrasound appearance of the endometrium in postmenopausal patients [21]. This may be reported as endometrial thickening or cystic changes in the endometrium or myometrium. Originally, the ultrasound appearance associated with tamoxifen was postulated to be microcystic changes that represented glandular cystic atrophy in the basalis of the endometrium, proximal myometrium, or even within polyps [22]. Further evaluation of these changes with saline infusion sonohysterography most often reveals these changes to be associated with atrophic endometrium covering microcystic areas. Other selective estrogen receptor modulators are also associated with similar endometrial hydrodynamics. These changes make it virtually impossible to measure endometrial thickness without sonohysterography [23,24]. The presence of these findings alone without vaginal bleeding does not require further endometrial assessment.

A uterine mass consistent with a leiomyoma is a common finding on pelvic imaging. It is difficult to differentiate these common benign masses for a rare occurrence of uterine sarcoma. Imaging for suspected uterine sarcoma is discussed in detail separately. (See "Uterine fibroids (leiomyomas): Differentiating fibroids from uterine sarcomas", section on 'Imaging'.)

RISKS AND MANAGEMENT OF UTERINE PATHOLOGY — Patients on tamoxifen therapy are at an increased risk of developing uterine pathology, including endometrial polyps. Within four years of initiating tamoxifen, there is up to a 67 percent rate of developing a tamoxifen-associated endometrial pathology, most of which are benign polyps [25-27]. Postmenopausal patients are at an increased risk of developing endometrial hyperplasia or carcinoma. Tamoxifen is also associated with an increased risk of uterine sarcoma and carcinosarcoma.

This section will discuss the risks of these conditions in patients on tamoxifen and aspects of management in this population. Other types of uterine pathology, such as cervical neoplasia, fibroids, adenomyosis, and other pathology are not thought to be associated with tamoxifen, should be treated as appropriate, and are most often compatible with continuing tamoxifen.

The overall risk of endometrial pathology in patients on tamoxifen is illustrated in the following studies:

●Patients with breast cancer

•In a small prospective study including 115 patients with breast cancer and AUB symptoms, those who had compared with those who had not been treated with tamoxifen had a higher rate of endometrial pathology (endometrial carcinoma [EC], endometrial hyperplasia, endometrial polyps, or proliferative endometrial glands) [9]. The degree of increase in risk for any of these pathologies in the setting of tamoxifen use was much higher in postmenopausal patients (tamoxifen: 67 percent versus no tamoxifen: 30 percent) than in premenopausal patients (24 versus 12 percent). There were three cases of atypical hyperplasia and one case of EC in the postmenopausal patients on tamoxifen (n = 33). Importantly, however, there were no cases of EC or atypical hyperplasia in the premenopausal patients on tamoxifen (n = 34).

•In a study including patients with breast cancer (n = 414) who underwent hysteroscopic evaluation [18], among postmenopausal participants (n = 262 on tamoxifen and 50 not on tamoxifen), the rate of any type of endometrial pathology was higher in the tamoxifen group (32 versus 8 percent). The study included symptomatic and asymptomatic patients. In postmenopausal patients on tamoxifen who had uterine bleeding, the rate of uterine malignancy was 7.8 percent, while in postmenopausal patients not on tamoxifen, there were no cases of hyperplasia or endometrial cancer. Among premenopausal patients on tamoxifen (n = 72), 13.9 percent were diagnosed with an endometrial pathology; only two were atypical hyperplasia, and there were no endometrial cancers.

•In a retrospective study including over 78,000 premenopausal patients (mean age 42 years) with breast cancer in Korea, those treated with versus without tamoxifen had higher rates of endometrial polyps (20.1 versus 5.5 cases per 1000 person-years, hazard ratio [HR] 3.9, 95% CI 3.7-4.2), endometrial hyperplasia (13.5 versus 2.1, HR 5.6, 95% CI 5.1-6.1), endometrial cancer (2 versus 0.5, HR 3.8, 95% CI 3-4.7), and other uterine cancers (0.5 versus 0.2, HR, 2.3, 95% CI 1.5-3.3) at six years of follow-up [28].

●Patients without breast cancer but with an elevated risk

•In the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-2 study, among the 4693 postmenopausal patients with an intact uterus who were treated with tamoxifen for chemoprevention of breast cancer and completed the quality-of-life portion of the study, 24.4 percent experienced some degree of vaginal bleeding. The average annual rate while on tamoxifen of endometrial cancer was 2.25 per 1000 women, endometrial hyperplasia was 4.40 per 1000 women, and endometrial polyps was 21.06 per 1000 women [12]. Among those diagnosed with hyperplasia, 82.5 percent were without atypia.

•In a randomized trial including over 13,000 patients with an elevated risk of developing breast cancer, those treated with versus without tamoxifen chemoprevention had a higher rate of invasive endometrial cancer (average annual rate per 1000 participants: 2.3 versus 0.91; risk ratio 2.53, 95% CI 1.35-4.97) [10]. The increased risk was greater in patients ≥50 years compared with <50 years (risk ratio 4, 95% CI 1.7-10.9 versus 1.21, 95% CI 0.41-3.6).

Endometrial polyps — Endometrial polyps are the most common type of endometrial pathology associated with tamoxifen use; they develop in >11 percent of postmenopausal patients on tamoxifen ≥4 years [12,27,29,30]. Polyps associated with tamoxifen may be large (>2 cm), multiple, or show molecular alterations [31-34]. Patients with a history of an endometrial polyp prior to tamoxifen therapy appear to have a higher rate of recurrent endometrial polyps while on tamoxifen [13].

Up to 5 percent of endometrial polyps in postmenopausal patients on tamoxifen contain a malignancy [35-37]. Malignant transformation of an endometrial polyp appears to occur more frequently in patients on tamoxifen (up to 11 percent) than in others [31]. There is no evidence for an association between malignancy and polyp size or duration of tamoxifen therapy. In the general population, the risk of malignancy in an endometrial polyp is approximately 5 percent in postmenopausal patients and 2 percent in premenopausal patients [38].

The rate of benign endometrial polyps in premenopausal patients on tamoxifen is approximately 7 percent and not significantly different from the rate in premenopausal patients not on tamoxifen [39].

For patients on tamoxifen, we recommend that endometrial polyps be resected. Use of a hysteroscopic approach allows for visualization of the polyp and confirmation of removal. Resection is the management of choice in both postmenopausal and premenopausal patients. This is a more conservative approach than for premenopausal patients who are not on tamoxifen since asymptomatic polyps in these patients may be managed expectantly. For benign polyps, hysterectomy is not warranted.

The diagnosis and management of endometrial polyps are discussed in detail separately. (See "Endometrial polyps".)

Endometrial hyperplasia — Postmenopausal patients on tamoxifen have an increased risk of endometrial hyperplasia; an increased risk of endometrial hyperplasia has not been demonstrated in premenopausal patients.

Representative studies include:

●In the NSABP P-2 trial (also referred to as the STAR trial) trial, among postmenopausal patients on tamoxifen, the annual rate of atypical endometrial hyperplasia was 0.77 per 1000 women and simple hyperplasia was 3.63 per 1000 women [12].

●In a retrospective study, among postmenopausal breast cancer patients with up to four years of tamoxifen treatment, the risk of simple hyperplasia was nearly 12 percent, complex hyperplasia 3 percent, and EC nearly 2 percent [27].

Postmenopausal patients on tamoxifen who are diagnosed with endometrial hyperplasia, even without atypia, are treated with hysterectomy as endometrial hyperplasia (with or without atypia) may progress to, or coexist with, EC. (See "Endometrial hyperplasia: Clinical features, diagnosis, and differential diagnosis", section on 'Natural history'.)

In premenopausal patients on tamoxifen, management of endometrial hyperplasia represents a complex clinical scenario. If the patient is on tamoxifen for chemoprevention of breast cancer and desires fertility preservation, in our practice, we discontinue tamoxifen and treat the hyperplasia with progestin therapy. If fertility is not desired and the patient wishes to continue on tamoxifen, hysterectomy may be considered, even in the setting of hyperplasia without atypia.

In patients with breast cancer, progestins are generally contraindicated. Hysterectomy is the usual treatment for atypical hyperplasia. In the setting of hyperplasia without atypia, hysterectomy is an option, but close observation with serial endometrial biopsies is also reasonable.

Use of a levonorgestrel-releasing intrauterine device (LNG IUD) appears to decrease the risk of endometrial hyperplasia among patients treated with tamoxifen for breast cancer [40]; however, numbers are limited and long-term effects of the potent LNG progestin on breast cancer recurrence is not well elucidated. As such, utilization of the LNG IUD should be individualized based on a discussion with the patient and the breast oncologist. (See 'Progestins for prevention and treatment' below.)

Endometrial carcinoma

Risk of malignancy — Tamoxifen results in an increased risk of EC in postmenopausal patients. This risk increases with increased duration of therapy and persists for at least two years after tamoxifen treatment is discontinued. An increased risk has not been established in premenopausal patients.

Most studies have found that the rate of EC in postmenopausal patients on tamoxifen is two to three times that of the general population [13,27,29,41]. The rate of EC at five years of tamoxifen therapy is approximately 0.3 percent in postmenopausal patients and 0.1 percent in premenopausal patients.

Postmenopausal versus premenopausal patients — The increased risk of EC with tamoxifen use in postmenopausal patients is well established based on data from randomized trials [10,42].

In premenopausal patients, an increased risk of EC has not been proven. The best evidence regarding this issue is from randomized trials of tamoxifen for breast cancer prevention. These studies were large; however, there were few EC events in premenopausal patients and inadequate statistical power to detect a difference in this outcome. Other studies focusing on the response of the premenopausal endometrium to tamoxifen are limited in number and contain relatively small numbers of participants. Thus, the absolute risk of EC in premenopausal patients on tamoxifen appears to be low, but it remains uncertain whether the risk is higher than in the general population.

High-quality data regarding the risk of EC due to tamoxifen include the NSABP P-1 trial, a randomized trial of breast cancer prevention in 13,388 participants [10,42]. The trial reported results at five years (tamoxifen 20 mg/day was given for five years) and at seven years. A subset analysis based on age at study entry found the following risks of EC in patients on tamoxifen compared with placebo:

●At five years [10]:

•<50 years (1.32 versus 1.09 per 1000 women; relative risk [RR] 1.21, 95% CI 0.41-3.60)

•≥50 years (3.05 versus 0.76 per 1000 women; RR 4.01, 95% CI 1.70-10.90)

●The risk in those ≥50 years of age persisted and appeared to increase at seven years (tamoxifen was discontinued at five years in this trial) [42]:

•<50 years (RR 1.42, 95% CI 0.55-3.81)

•≥50 years (RR 5.33, 95% CI 2.47-13.17)

The number of cases of EC in premenopausal patients was low (at seven years: 12 in the tamoxifen group versus 9 in the placebo group), so for premenopausal patients, the confidence interval includes both an increase and decrease in risk; therefore, there was insufficient statistical power to show an effect.

A subsequent meta-analysis that pooled data from NSABP P-1 with another randomized trial of tamoxifen for breast cancer prevention, the International Breast Cancer Intervention Study-1 (IBIS-1; n = 7154), found the following risks of EC in patients on tamoxifen compared with placebo at five years [43]:

●<50 years (RR 1.19, 95% CI 0.53-2.65)

●≥50 years (RR 3.32, 95% CI 1.95-5.67)

The STAR trial randomly assigned postmenopausal patients (n = 9456) to breast cancer prevention with either tamoxifen (20 mg/day for five years) or raloxifene [12]. In the tamoxifen group, the average annual rate of uterine cancer was 2.25 per 1000 women.

In a cohort study of 262 postmenopausal patients who developed uterine bleeding while on tamoxifen, the overall rate of EC was 7.8 percent and the EC rate increased with duration of therapy (<3 years: 1.3 percent versus >3 years: 11.7 percent) [18]. Among the 72 premenopausal patients on tamoxifen in this study, there were no ECs diagnosed and only two cases of atypical hyperplasia.

Occult hyperplasia and EC appear to be extremely rare in asymptomatic premenopausal patients; however, low numbers included in published studies limit definitive risk prediction. In a study of 121 premenopausal patients treated with tamoxifen for breast cancer, assessment of the impact of tamoxifen included pelvic ultrasound. Among those with a thickened endometrium (defined in this study as >12 mm; n = 8) endometrial sampling revealed no malignancy [8]. In a smaller study of 30 asymptomatic premenopausal patients on tamoxifen, endometrial sampling after a median treatment duration of one year also revealed no malignancies [39].

Duration of therapy — The risk of EC increases with increased duration of tamoxifen therapy. This is an important clinical issue, particularly because extending tamoxifen treatment from 5 to 10 years has become an option in breast cancer therapy.

Studies that evaluated the impact of duration of tamoxifen therapy on EC risk include:

●In the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial (n = 12,894), the risk of EC was significantly higher at 10 years compared with 5 years (RR 1.74, 95% CI 1.30-2.34) [44]. Absolute cumulative risk of EC during years 5 to 14 of the ATLAS study was 3.1 percent compared with 1.6 percent in those who stopped after 5 years of tamoxifen.

●A case-control study compared patients with breast cancer (n = 299) who developed EC after diagnosis with controls found that the odds increased 2.3-fold with ≥2 years of tamoxifen and 6.6-fold with ≥6 years [45].

Dose — It is unclear whether the tamoxifen dose impacts the EC risk. The tamoxifen dose for breast cancer adjuvant therapy dose is 20 or 40 mg/day.

An analysis of individual patient data from participants in randomized trials of adjuvant tamoxifen therapy included 37,000 female patients from 55 trials. The analysis found no difference in the EC risk compared with placebo in patients treated with 20 mg/day versus with 30 to 40 mg/day (ratio of incidence rates: 2.7 and 2.4, respectively) [46]. These risks are similar to those found in breast cancer chemoprevention trials, which used 20 mg/day and found an increase the risk of EC in postmenopausal patients approximately two- to threefold [42,47].

Increasing cumulative dose of tamoxifen may increase the risk of EC. A case-control study of 324 patients with breast cancer showed an increased risk of EC associated with increasing cumulative dose, for each cumulative dose range the risks compared with no tamoxifen were: ≤7500 mg (odds ratio [OR] 0.94), 7501 to 15,000 mg (OR 1.37), 15,001 to 30,000 (OR 1.86), and >30,000 OR (3.30) [48]. However, EC risk associated with cumulative dose may reflect either duration or daily dose.

Risk after discontinuation of tamoxifen — Data are limited regarding the risk of EC after tamoxifen therapy is discontinued. Both clinical and molecular data suggest that the risk of EC decreases and is similar to patients who have not been treated with tamoxifen by approximately two years after cessation of tamoxifen [49,50].

In the International Breast Cancer Intervention Study-1 (IBIS-1; n = 7154), the risk of EC during the five-year tamoxifen chemoprevention period was nearly fourfold (OR 3.76) higher with tamoxifen compared with placebo. After discontinuation of tamoxifen, during the subsequent five-year surveillance period, the risk of EC was equivalent in the tamoxifen and placebo arms. And with a mean follow-up of 16 years, the overall risk of EC was no different between arms. The data suggest that the elevated risk for EC is present during tamoxifen treatment and regresses after cessation of tamoxifen [51].

Studies have used ultrasound determination of endometrial thickness as a surrogate for endometrial pathology both during and after tamoxifen therapy. In one study, a cohort of 153 patients were followed with ultrasound measurement of endometrial thickness after discontinuing tamoxifen, and no patients developed EC. Endometrial thickness decreased gradually over time, as did the diagnosis of any endometrial pathology. Those who had persistent thickening of the endometrium underwent hysteroscopic assessment and, in the overall cohort, 14 percent had benign endometrial pathology, 77 percent of which were benign endometrial polyps [49].

In another study of patients who switched to an aromatase inhibitor (AI) due to thickened endometrium found while on tamoxifen, endometrial thickness progressively decreased after 3, 6, and 12 months of AI administration. However, after 24 months of AI use, no further reduction in endometrial thickness was observed [50]. As there was no control group, it is unknown whether the endometrial thickness decrease was secondary to AI use or to stopping tamoxifen alone.

As noted above, from a molecular standpoint, KRAS mutations occur at a high rate (40 to 75 percent) in the endometria of patients on tamoxifen [5,6]. However, after cessation of tamoxifen, KRAS mutations appear to resolve and remain absent even in long-term follow-up [6]. (See 'Pathophysiology' above.)

Management — For patients with EC, standard surgical treatment is hysterectomy and bilateral salpingo-oophorectomy with appropriate staging and adjuvant therapy where indicated. (See "Overview of resectable endometrial carcinoma".)

For patients with EC in general, progestin therapy may be an option in selected cases of premenopausal low-risk EC for patients who wish to temporarily preserve fertility. However, the safety of systemic progestins is unknown in patients with progesterone receptor-positive breast cancer. Available data are discussed below. (See 'Progestins for prevention and treatment' below.)

Prognosis — Tamoxifen appears to be associated with a worse EC prognosis than in cases not associated with tamoxifen [30,45,52]. In addition, longer duration of use and higher cumulative doses have been associated with poor prognosis histologies and advanced stage (III and IV) disease [35,45,52-54].

Early studies suggested that EC in the setting of tamoxifen use was not histologically different from EC arising in patients not on tamoxifen [41,55]. However, additional data suggest that tamoxifen-associated ECs are more likely to have poor prognostic features, including nonendometrioid histology, be both estrogen and progesterone receptor negative, and p53 positive [45,52]. This was illustrated in a large retrospective study and follow-up data from 641 patients with breast cancer who subsequently developed uterine cancer [45,52]. Tamoxifen use for ≥2 years compared with no tamoxifen was associated with an increased risk of nonendometrioid histologies (clear cell and serous: 15.9 versus 8.7 percent; carcinosarcoma: 8.4 versus 3.7 percent) and stage III or IV disease (20.0 versus 11.3 percent). Additionally, tamoxifen use was associated with decreased uterine cancer-specific survival at three years (82 versus 93 percent).

Screening — For patients on tamoxifen therapy, routine screening for EC in asymptomatic patients is not performed. The benefits of screening for EC have not been found to outweigh the risks and burdens in average-risk patients. Likewise, no studies have demonstrated a benefit in patients on tamoxifen [56,57]. As an example, in one study, 304 asymptomatic patients on tamoxifen for breast cancer adjuvant therapy underwent yearly transvaginal ultrasound (TVUS) for six years [56]. Using an endometrial thickness of >9 mm, the sensitivity and specificity for EC were low: 63.3 percent and 60.4 percent, respectively. Similarly, routine endometrial biopsy in asymptomatic patients on tamoxifen is also not beneficial [58-60]. In a prospective study of 159 asymptomatic patients on tamoxifen undergoing screening endometrial biopsies, no cases of endometrial cancer were diagnosed during the five-year surveillance period; an average of 5.8 endometrial biopsies were performed per patient [60]. However, screening led to an increase in operative procedures; 14 of 111 assessable patients (13 percent) underwent dilation and curettage (all for benign pathology) and 3 underwent hysterectomy. Thus, the American College of Obstetricians and Gynecologists (ACOG) recommends against screening asymptomatic patients on tamoxifen for EC [13]. (See "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening", section on 'Screening'.)

Screening for uterine pathology prior to initiation of tamoxifen therapy in postmenopausal patients has been proposed. Some data suggest that as many as 17 percent of newly diagnosed postmenopausal breast cancer patients have a benign endometrial polyp prior to initiating tamoxifen therapy [61]. In a prospective study (n = 510), postmenopausal patients with breast cancer, prior to initiation of tamoxifen (20 mg/day), underwent TVUS (endometrial thickness >5 mm was considered abnormal and further evaluated with outpatient hysteroscopy and endometrial biopsy) [62]. Screening identified uterine pathology in 16.7 percent of participants, all cases were endometrial polyps, and polyps were then removed. Patients with versus without pretreatment uterine pathology have a significantly higher rate of atypical endometrial lesions during tamoxifen therapy (11.7 versus 0.7 percent person-years). Of note, endometrial polyps are not considered a precursor of EC or atypical endometrial hyperplasia.

In our experience, pretreatment screening, however, is not widely practiced. This strategy could benefit from further study. Implementation would require coordination between medical oncology and gynecology clinicians.

Before and following initiation of tamoxifen, routine gynecologic examinations should be performed, as well as evaluation of any new or recurrent AUB [13]. Patients should be counseled that any level of abnormal vaginal bleeding should be brought to medical attention, including pink or brown staining or spotting, bloody discharge, or any other color or volume of bleeding.

Uterine sarcoma and carcinosarcoma — Tamoxifen appears to be associated with an increased risk of uterine sarcoma and carcinosarcoma [26,45,63], leiomyosarcomas [64], adenosarcomas [65], and endometrial stromal sarcomas [66]. Uterine carcinosarcoma, also previously referred to as malignant mixed Müllerian tumor (MMMT), is no longer classified as a sarcoma but rather a histology of endometrial cancer. However, studies performed before this reclassification often include carcinosarcoma cases in reported rates of uterine sarcoma.

These are rare diseases (representing 2 to 8 percent of all cancers of the uterus), and the absolute risk is low [67,68].

However, given the association between tamoxifen use and increased risk of uterine sarcoma, the US Food and Drug Administration issued a black box warning regarding the use of tamoxifen [69]. ACOG advises that patients taking tamoxifen be advised of the risk of uterine sarcoma, along with other risks [13].

Uterine sarcoma and carcinosarcoma typically present with AUB and patients may also have a uterine mass. Findings of sarcoma on imaging are often indistinguishable from benign leiomyomas. While endometrial sampling may diagnose a uterine carcinosarcoma, it cannot be used to reliably diagnose or rule out a uterine sarcoma. If sarcoma is suspected, the patient should undergo surgical evaluation. In our practice, we have a low threshold for hysterectomy when a suspicious myometrial or endometrial mass is identified in a symptomatic patient on tamoxifen. (See "Uterine sarcoma: Classification, epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis' and "Clinical features, diagnosis, staging, and treatment of uterine carcinosarcoma", section on 'Diagnosis' and "Uterine fibroids (leiomyomas): Differentiating fibroids from uterine sarcomas".)

In general, sarcomas present two to five years following the start of therapy and are often at an advanced stage at presentation [70,71]. Long-term use of tamoxifen (five years or more) appears to be associated with an increased risk of uterine sarcoma [64,70,72]. There also may be a persistent risk of uterine sarcoma after completion of tamoxifen therapy, as sarcomas have been reported 4 to 20 years after tamoxifen has been completed [66,68].

Representative studies regarding tamoxifen and the risk of uterine sarcoma include:

●In the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 randomized trial discussed above (see 'Postmenopausal versus premenopausal patients' above), uterine sarcoma occurred more frequently in patients on tamoxifen therapy (17/100,000 person-years) compared with placebo (no cases) [26].

●In data derived from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute including over 39,000 patients diagnosed with breast cancer between 1980 and 2000 who were treated with tamoxifen, compared with the general SEER population, the relative risk of a subsequent uterine corpus cancer (observed to expected [O/E] ratio) was 2.2 and was substantially higher for carcinosarcomas (referred to in this study as MMMTs) than for other endometrial adenocarcinomas (O/E 4.6 and 2.1, respectively) [73]. The relative risk of carcinosarcoma rose further in patients surviving five years, while the risk of adenocarcinoma did not change appreciably. However, because of the rarity of carcinosarcoma, this translated into a smaller excess absolute risk for carcinosarcoma than for uterine adenocarcinomas (an additional 1.4 versus 8.4 cancers per 10,000 patients per year, respectively). Prognosis was poor among patients diagnosed with carcinosarcoma, with 25 deaths among the 34 diagnosed patients.

●In a case-control study in the Netherlands comparing patients with breast cancer (n = 299) who developed EC after diagnosis with controls found that the risk of uterine sarcoma and carcinosarcoma increased with ≥2 years of tamoxifen therapy (15.4 percent on tamoxifen versus 2.9 percent in nonusers) [45].

The ATLAS trial did not separately report uterine sarcoma risk in the setting of 10 years of adjuvant tamoxifen therapy [44].

MANAGEMENT ISSUES

Persistent AUB without uterine pathology — Many patients on tamoxifen experience AUB in the absence of uterine pathology or another known etiology. If an etiology is not identified, expectant management is the preferred approach for persistent and manageable AUB. Other options for symptom control are limited and hysterectomy may be required if symptoms are unmanageable.

If the initial evaluation is negative and symptoms persist or recur, a repeat evaluation or additional testing is performed if uterine pathology is suspected. The components of this evaluation are discussed above. (See 'Abnormal uterine bleeding' above.)

In patients with no structural pathology, AUB may be due to endocrine effects of tamoxifen or to other etiologies (figure 3). Evaluation for other etiologies should be performed as needed. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis" and "Approach to the patient with postmenopausal uterine bleeding".)

If there is no etiology identified, we manage expectantly with the following goals: reassurance in the setting of benign findings, control of unmanageable symptoms, and periodic follow-up visits to monitor symptoms and detect changes in bleeding characteristics or persistence of symptoms that may warrant additional evaluation.

There are limited other options for symptom control. Estrogens or progestins are the most common medications used for AUB, but their use is restricted in patients on adjuvant tamoxifen for breast cancer treatment because they may increase the risk of breast cancer recurrence.

The levonorgestrel-releasing intrauterine device (LNG IUD) increases the rate of AUB in patients on tamoxifen during the first year of use, but AUB normalizes by five years [40]. Based on concerns about breast cancer recurrence, use of a LNG IUD is not standard practice in patients with breast cancer. However, control of severe AUB is a clinical scenario in which clinicians may choose to counsel patients about risk and benefits and, with the patient's oncologist, make a shared decision as to whether to use this therapy. (See 'Progestins for prevention and treatment' below.)

Endometrial ablation has been proposed as a management option for AUB in the setting of tamoxifen, but we suggest not performing endometrial ablation in such patients. Residual endometrium remains after global endometrial ablation (GEA) and uterine cavity assessment with office biopsy or sonohysterography after GEA is unsuccessful in one-quarter of patients [74]. In addition, while GEA does not appear to increase the risk of endometrial carcinoma (EC) [75,76], this has not been well-studied in the context of tamoxifen use.

Hysterectomy is a definitive treatment option for premenopausal patients who have completed childbearing and have uncontrolled AUB associated with tamoxifen use and for postmenopausal patients with recurrent bleeding on tamoxifen and no biopsy-proven etiology. In particular, in postmenopausal patients, recurrent or persistent AUB raises a concern of a missed diagnosis of uterine malignancy. As an example, a study that followed patients in the general population with peri- or postmenopausal bleeding who had an initial endometrial biopsy that was negative or had insufficient tissue, 4 of 86 developed a uterine malignancy (3 adenocarcinomas; 1 case was stage IV and 1 sarcoma) within two years [77].

Progestins for prevention and treatment — The safety of systemic progestins is unknown in patients with progesterone receptor-positive breast cancer. Synthetic progestins appear to increase the risk of breast cancer development [78], but megestrol acetate is used to treat recurrent breast cancer [79], and both megestrol acetate and medroxyprogesterone acetate have been used to treat hot flashes in patients receiving tamoxifen for breast cancer [80].

A LNG IUD is a more localized route of administration for progestin therapy, although there is some systemic absorption. The most commonly studied device is the LNG IUD containing 52 mg LNG, release rate of 20 mcg/day, and five-year duration (Mirena, Liletta; LNG 52). There are a lack of high-quality data regarding the safety of the LNG IUD in progesterone receptor-positive breast cancer. The LNG 52 labeling lists breast cancer as a contraindication for its use.

There are few studies of LNG IUD use in breast cancer survivors:

●A systematic review of two randomized trials of LNG IUD versus endometrial surveillance in patients on tamoxifen as adjuvant treatment for hormone-positive breast cancer, compared with surveillance, LNG IUD use resulted in [81]:

•A significant reduction in the incidence of endometrial polyps (1.6 versus 10.6 percent, respectively, odds ratio [OR] 0.14, 95% CI 0.03-0.61)

•A trend towards a lower incidence of endometrial hyperplasia (OR 0.30, 95% CI 0.01-7.44)

•A trend towards a lower incidence of submucosal fibroids (1.6 versus 4.1 percent, OR 0.37, 95% CI 0.07-1.95)

●A small retrospective study found that a subgroup of patients who had a LNG 52 in place at the time of breast cancer diagnosis and continued use (n = 38) compared with nonusers had a threefold increase in the risk of breast cancer recurrence [82]. There was no significant increase in recurrence risk in patients who had the LNG 52 placed after breast cancer diagnosis; however, the study lacked sufficient power to detect a difference.

Some data suggest an increase in the risk of developing breast cancer associated with a LNG IUD. A case-control study in patients ages 50 to 62 years reported that the risk of a new breast cancer diagnosis is 1.5 times higher in patients using the LNG IUD [83].

The development of uterine pathology associated with tamoxifen is mainly due to estrogen agonist activity with insufficient progestin opposition. LNG IUDs have been studied for potential prevention of tamoxifen-associated uterine pathology.

Meta-analyses including four randomized trials and 543 patients (pre- and postmenopausal patients were included) on tamoxifen found that the LNG 52 reduced the risk of some endometrial pathologies but increased the rate of AUB symptoms [40,84-88]. Patients using the LNG 52 compared with controls had lower rates of endometrial polyps (over 24 to 60 months: OR 0.22, 95% CI 0.13-0.39) and endometrial hyperplasia (over 24 to 60 months: OR 0.13, 95% CI 0.03-0.67). However, the number of events of endometrial hyperplasia was low (six cases); none of the trials were adequately powered to detect a difference in endometrial cancer rates [88]. The rate of AUB symptoms was higher in patients using the LNG 52, although the odds compared with no IUD decreased from 12 to 24 months of follow-up (12 months: sevenfold; 24 months: threefold), and by 60 months of follow-up, no cases of AUB were reported in either group. The numbers of events for the following outcomes were low: fibroids (n = 13), breast cancer recurrence (n = 18), and breast cancer-related deaths (n = 16). Rates of breast cancer recurrence and breast cancer-related deaths were similar between the IUD and control groups; however, there was insufficient power to detect a difference in these outcomes. Given the unclear risks of breast cancer recurrence in the setting of long-term LNG exposure, use of the LNG IUD for polyp and hyperplasia prophylaxis in patients receiving tamoxifen for adjuvant breast cancer therapy is not the standard of care. (See "Approach to the patient following treatment for breast cancer", section on 'Contraception after breast cancer'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Abnormal uterine bleeding" and "Society guideline links: Uterine cancer".)

SUMMARY AND RECOMMENDATIONS

●Tamoxifen is a nonsteroidal selective estrogen receptor modulator that is used primarily for adjuvant treatment of estrogen receptor-positive breast cancer in premenopausal patients and in some postmenopausal patients. Tamoxifen is associated with increased risks of uterine pathology, including endometrial polyps, endometrial carcinoma (EC) and hyperplasia, and uterine sarcoma. (See 'Introduction' above.)

●Tamoxifen results in a two- to threefold increased risk of EC in postmenopausal patients at 5 years; at 10 years, the risk is approximately twice the risk at 5 years. This risk persists for at least two years after tamoxifen treatment is discontinued. Tamoxifen does not appear to result in an increased EC risk in premenopausal patients. Routine screening for EC is not performed for patients on tamoxifen. (See 'Screening' above and 'Endometrial carcinoma' above.)

●Tamoxifen has an estrogen agonist effect on the postmenopausal endometrium and an estrogen antagonist effect on premenopausal endometrium. (See 'Pathophysiology' above.)

●Uterine pathology in patients on tamoxifen therapy usually presents in one of two ways: abnormal uterine bleeding (AUB) or an incidental finding of uterine pathology on pelvic imaging. (See 'Clinical presentation and evaluation' above.)

●Determining menopausal status is of key importance in the evaluation of AUB associated with tamoxifen. Based on the high prevalence of amenorrhea among patients on tamoxifen, menstrual history is not a reliable method of determining menopausal status. For laboratory testing, we order serum estradiol (E2) and follicle-stimulating hormone (FSH) levels. These remain reliable endocrinologic markers in the setting of tamoxifen use. Tamoxifen can slightly raise FSH levels, but typically not to postmenopausal levels. (See 'Determining menopausal status' above.)

●For postmenopausal patients with any bleeding, spotting, staining, or bloody vaginal discharge, evaluation of the endometrium for EC is required. In our practice, we often perform both an office endometrial biopsy and transvaginal ultrasound (TVUS). (See 'Pelvic ultrasound and endometrial sampling' above.)

●The evaluation for premenopausal patients on tamoxifen depends upon the bleeding pattern. For patients with amenorrhea or oligomenorrhea and no risk factors for EC, we manage expectantly. For patients with heavy menstrual bleeding, intermenstrual bleeding, or frequent irregular bleeding, we perform an endometrial biopsy, and in some cases, TVUS. (See 'Pelvic ultrasound and endometrial sampling' above.)

●Endometrial polyps are the most common type of endometrial pathology associated with tamoxifen use; they develop in >11 percent of postmenopausal patients on tamoxifen ≥4 years. For patients on tamoxifen, we recommend that endometrial polyps be resected rather than managed expectantly (Grade 1B). (See 'Endometrial polyps' above.)

●Levonorgestrel-releasing intrauterine devices have been proposed from prevention and treatment of uterine pathology in patients on tamoxifen. However, the safety of this treatment in patients with progesterone receptor-positive breast cancer has not been established. Use must be individualized and discussed with the patient's oncologist. (See 'Progestins for prevention and treatment' above.)