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POSTMENOPAUSAL BLEEDING
Evaluation and Management
Anne L. Mounsey, MD

Postmenopausal bleeding is dened as bleeding that occurs after 1 year of amenorrhea in a woman who is not receiving hormone replacement therapy (HRT). Women on continuous progesterone and estrogen hormone therapy can expect to have irregular vaginal bleeding, especially for the rst 6 months. This bleeding should cease after 1 year. Women on estrogen and cyclical progesterone should have a regular withdrawal bleeding after stopping the progesterone. Any unexpected bleeding or signicant change in withdrawal bleeding should prompt further investigation. Women with abnormal postmenopausal bleeding include Women with bleeding after 1 year of amenorrhea Women with bleeding after 1 year of continuous combined HRT Women with unexpected bleeding while receiving cyclic HRT CAUSES OF POSTMENOPAUSAL BLEEDING Postmenopausal bleeding should always be investigated, because it could be a sign of endometrial carcinoma, which has a much higher cure rate if diagnosed early. Stage 1 endometrial carcinoma has a 5-year survival rate of 98%, so early discovery greatly improves the chances of cure. It is estimated that endometrial carcinoma is the cause of postmenopausal bleeding in 10% of cases.9 All women with unexplained postmenopausal bleeding should undergo investigation and evaluation of the endometrium, if necessary. Although endometrial carcinoma is the most serious cause of postmenopausal bleeding, an atrophic endometrium with dyssynchronous shedding is the commonest cause. A less common cause is cervical or endometrial polyps. A complete list of the causes of postmenopausal bleeding is given in Table 1. Most of these

From the Department of Family Medicine, Primary Care Centre, University of Virginia, Charlottesville, Virginia

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TABLE 1. Causes of Postmenopausal Bleeding Cause of Bleeding Endometrial or cervical polyps Endometrial hyperplasia Endometrial carcinoma Exogenous estrogens Atrophic endometritis and vaginitis Other Frequency (%) 212 510 10 1525 6080

Vaginal trauma, urethral caruncle, uterine sarcoma, cervical cancer, atrophic vaginitis. Adapted from Lurain J: Uterine cancer. In Berek JS, Adashi EY, Hillard PA (eds): Novaks Gynecology, ed 12. Baltimore, Lippincott, Williams & Wilkins, 1996, 10581101; with permission.

diagnoses can be made only after further investigation, such as transvaginal endovaginal ultrasound (EVUS) or endometrial biopsy. Cervical Polyps Cervical polyps can originate from the endocervix or the ectocervix as a result of focal hyperplasia. They are composed of a central vascular and connective tissue stroma covered by squamous, columnar, or squamocolumnar epithelium. The surface epithelium may show squamous metaplasia, and the tissue at the tip of the polyp is often necrotic. Malignant change can occur but is estimated to be less than 1%.50 The cause of cervical polyps is unknown, although there may be an association with chronic cervicitis. They most often are found in women in their reproductive years but can occur after menopause. Asymptomatic polyps often are found on routine vaginal examination or may present with postcoital, intermenstrual, or postmenopausal bleeding. Endocervical Polyps Endocervical polyps are commoner than ectocervical polyps. On vaginal examination, they appear as cherry-red tumors protruding on a pedicle from the cervical os. They can vary in length and diameter from a few millimeters up to 3 cm. Ectocervical Polyps Ectocervical polyps tend to be less vascular and more brous than endocervical polyps. They are paler and smoother in appearance and less likely to bleed than endocervical polyps. Treatment of Cervical Polyps Most cervical polyps can be treated in the ofce by grasping the pedicle with sponge forceps and twisting it until the polyp is avulsed. Any bleeding can be stopped with cautery or Monsels solution. Polyps in which the pedicle is not

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visible are removed best by a dilatation and curettage (D and C), which allows the pedicle to be visualized and the whole polyp to be removed. Larger polyps and multiple polyps may cause signicant bleeding and are removed best in the operating room.50 Endometrial Polyps The incidence of endometrial polyps varies with age, reaching a peak in the fth decade of life.60 Because they are estrogen sensitive, their incidence declines after menopause. The origin of endometrial polyps is unclear. Most polyps occur in the fundal region and project down into the uterine cavity. Larger polyps can extend to the vaginal introitus. They are composed of a central brous stroma containing large vascular channels covered by endometrial epithelium. Endometrial polyps may undergo malignant change into a carcinoma or sarcoma.50 In postmenopausal women, endometrial polyps can cause postmenopausal bleeding that is usually light. Sometimes, a polyp may infarct, and there is a more sudden onset of bleeding accompanied by crampy abdominal pain. Diagnosis Hysteroscopy can identify endometrial polyps by direct visualization. Salineinfusion sonograms have been used to identify the polyps that show up as lling defects. Pelvic ultrasound usually does not reveal endometrial polyps unless they are particularly large. Treatment The polyp can be removed during hysteroscopy and sent to pathology. Atrophic Endometritis and Vaginitis Atrophic vaginitis can be diagnosed by direct inspection of the vagina. The patient may complain of a sore vagina and pain on intercourse with or without bleeding. On direct inspection, the vagina looks atrophic, thin, and red and may show evidence of bleeding. Atrophic vaginitis is best treated with oral or topical estrogen. If oral estrogens are used and the woman has an intact uterus, progesterone also should be used. It is not necessary to use progesterone in conjunction with topical estrogens, although the estrogen cream should be used on a cyclical basis. The patient should be instructed to apply the cream every night for 3 weeks, followed by a treatment-free week. This cyclical regimen can be continued, or the patient can reduce use to a maintenance level at which she is still asymptomatic. Topical estrogen also can be applied in the form of an estrogen-containing vaginal ring that is inserted into the vagina and changed every 3 months. There is some evidence that topical estrogen does not increase the risk for developing uterine cancer; however, it is prudent to use the lowest dose of estrogen that maintains the vaginal tissue to decrease any possible risk for uterine cancer.4 If the vagina is atrophic, it is likely that the endometrium is also atrophic. Endometrial atrophy with dyssynchronous shedding of the endometrium is the commonest cause of postmenopausal bleeding, accounting for up to 80% of cases. This diagnosis only can be made after evaluation of the endometrium to exclude uterine cancer. The options available for evaluation of the endometrium are listed later in this article.

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Endometrial Carcinoma Epidemiology Uterine cancer is the fourth commonest cancer in women and is the commonest cancer of the female genital tract. In 2001, it is estimated that there will be 38,300 new cases of uterine cancer and 6600 deaths from uterine cancer, accounting for approximately 2% of all cancer deaths.8 In the United States, the incidence among whites is almost double that in blacks, but the overall incidence of uterine cancer is declining.47 Mortality rates are declining but still remain higher for blacks than for whites. This racial difference in mortality is not explained entirely by differences in the stage of disease at diagnosis.8 Uterine cancer is a disease of afuent communities with a Westernized lifestyle and is commoner in urban than rural communities. Risk Factors Risk factors for uterine cancer include

Unopposed estrogen therapy Antiestrogen therapy (e.g., tamoxifen) Estrogen-secreting tumors Chronic anovulation Nulliparity Early menarche Late menopause Infertility Obesity Diabetes mellitus Estrogen-secreting tumors Hypertension History of breast or colon cancer Age

In the 1970s, the incidence of uterine cancer increased, and it was hypothesized that this increase was associated with the use of unopposed estrogen in postmenopausal women.42, 65 This hypothesis was supported, because by the mid1980s, the incidence of uterine cancer had decreased as postmenopausal women with intact uteri were given progesterone with estrogen. Since this time, more studies have conrmed the association between estrogen use and an increased risk for uterine cancer.4 The increased exposure to endogenous estrogens that occurs with early menarche, late menopause, low parity or nulliparity, and estrogensecreting ovarian tumors also increases the risk for uterine cancer, which gives added support to this hypothesis.35, 47 The major risk factors and relative risks are shown in Table 2. There is an increasing risk for uterine cancer with increasing age. Its incidence in women under age 40 is low, but its rate peaks in women between ages 70 and 74, after which it declines.53 Tamoxifen, used extensively in the treatment of breast cancer, seems to have a carcinogenic effect on endometrial tissue. The Stockholm Adjuvant Tamoxifen Trial found that postmenopausal women receiving 40 mg/d of tamoxifen for 3 to 4 years have an increased risk for developing uterine cancer with a relative risk of 6.4. This increased risk for uterine cancer is related directly to the dose of

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TABLE 2. Relative Risks for Endometrial Cancer Characteristic Nulliparity Late menopause Obesity 2150 1b overweight > 50 1b overweight Diabetes mellitus Unopposed estrogen therapy Tamoxifen Atypical endometrial hyperplasia Relative Risk 23 2.4 3 10 2.8 48 23 829

From Lurain J: Uterine cancer. In Berek JS, Adashi EY, Hillard PA (eds): Novaks Gynecology, ed 12. Baltimore, Lippincott, Williams & Wilkins, 1996, pp 10581101; with permission.

tamoxifen and duration of treatment.22, 23 This nding has been conrmed by Fisher et al, who found an increased risk for uterine cancer in women given tamoxifen to prevent breast cancer.20 Obesity also increases the risk, because obese women have high levels of estrone formed by the peripheral conversion of androstenedione in muscle and fat cells.5, 15 The risk for uterine cancer seems to increase with the increase in obesity.47 A small study in Sweden looking at body-fat distribution in women with endometrial hyperplasia showed that upper and lower body-fat distribution were not characteristic of women with atypical hyperplasia.28 Diabetes and hypertension have been associated with an increased risk for uterine cancer. This risk is independent of their association with obesity.47 Factors that Reduce Risk Smoking has been shown to decrease the risk for uterine cancer, possibly because of its antiestrogenic effects.47 Women on a combined oral contraceptive have an increased exposure to progesterone that lowers their risk for uterine cancer.15, 35 It is estimated that use of a combined oral contraceptive pill decreases the risk for uterine cancer by 11.7% per year.32 Screening There are only a few studies evaluating screening for endometrial carcinoma. One of the largest studies examined 2964 peri- and postmenopausal women who were candidates for HRT. Endometrial biopsy specimens were obtained using a vabra aspirator, and 0.07% of the endometrial biopsies were found to be adenocarcinoma.38 This low yield indicates that screening for endometrial carcinoma with an endometrial biopsy is not cost effective and would not fulll screening criteria developed by Sackett et al.52 Holbert examined the value of transvaginal ultrasonography in screening for endometrial and ovarian abnormalities.34 He screened 478 postmenopausal women. Four women with an endometrium thicker than 5 mm had endometrial

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biopsies, and one women was found to have endometrial adenocarcinoma. Fleischer et al screened 1926 postmenopausal women with EVUS, of which 1792 also had an endometrial biopsy. He found that the positive predictive value of an endometrial thickness of more than 5 mm in detecting adenocarcinoma was only 2%.21 Langer et al found similar results when they screened 448 women with endovaginal ultrasound (EVUS) and endometrial biopsy. Thirty percent of women had an endometrial thickness over 4 mm and on biopsy, and 11 of these women had a serious abnormality (1 had adenocarcinoma, 2 had atypical simple hyperplasias, and 8 had complex hyperplasias). These results translate to a low positive predictive value of 3%.40 The low yield that EVUS and endometrial biopsy have for detecting serious endometrial disease demonstrate that they are probably not effective screening tests for uterine cancer. It may be cost effective to screen women with multiple risk factors for uterine cancer, and further studies need to be performed in this group. Most patients with uterine cancer have elevated CA 125 antigen levels. Studies have shown that once the CA 125 antigen is detectable in peripheral blood, the tumor already has spread to extra-uterine sites, which lessens its value as a screening test.44, 48 The American Cancer Society (ACS) updated their screening recommendations in 2001 and concluded that there is no indication that screening for uterine cancer is warranted. The one exception is for women who are at increased risk for hereditary nonpolyposis colorectal cancer. This group of women should be offered annual screening with an endometrial biopsy by age 35.8 Pathology Uterine cancer may develop from hyperplasia, which is associated with increased estrogen exposure. It also may develop from endometrial atrophy, which is not estrogen related.66 This latter type of uterine cancer is poorly differentiated and has a worse prognosis. Studies are underway to examine these atrophy- and hyperplasia-associated uterine cancers and the importance of different risk factors in their formation. Tumors of the uterus are classied broadly into endometrial carcinomas and uterine sarcomas. Endometrial carinomas as classied by the International Society of Gynecologic Pathologists include Endometrial adenocarcinoma Papillary Secretory Ciliated cell Adenocarcinoma with squamous differentiation Mucinous carcinoma Serous carcinoma Clear cell carcinoma Squamous carcinoma Undifferentiated carcinoma Mixed types Miscellaneous carcinoma Metastatic carcinoma The commonest uterine cancer is endometrioid adenocarcinoma, which accounts for over 75% of uterine carcinomas. Endometriod adenocarcinomas are sub

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classied into four types: (1) papillary, (2) secretory, (3) ciliated cell, and (4) adenocarcinoma with squamous differentiation, depending on the predominant pattern of cells seen in the tumor. Uterine sarcomas are far less common than endometrial carcinomas, accounting for less than 5% of all uterine malignancies. These less common tumors tend to occur in older women and are associated with a lower overall survival rate and a higher risk for metastatic disease at the time of diagnosis. The stage-one 5-year disease-free survival rate is only 52%.1 Staging Surgical staging is performed by an exploratory laparotomy, total hysterectomy, bilateral salpingo-oophorectomy, and cytology. Para-aortic and pelvic lymph node sampling is performed unless there is grade 1 cancer with less than half myometrial invasion. The depth of myometrial invasion is determined by intraoperative frozen section. Lymph node sampling is considered unnecessary in obvious metastatic disease. Treatment Surgery with a total abdominal hysterectomy and bilateral salpingooophorectomy is the mainstay of treatment. Subsequent treatment with radiation or chemotherapy depends on the staging of the tumor. Survival rates are related to the stage at diagnosis as shown in Table 3. Prevention The US Preventive Task Force (USPTF) Guidelines conclude that there is insufcient evidence to recommend for or against routine counseling of women about measures to prevent uterine cancer; however, women who are counseled on the use of contraception should be informed of the reduced risk for uterine cancer in users of an oral contraceptive pill.59 Prevention in Women on Hormone Replacement Therapy. Because it has been recognized that unopposed estrogen in postmenopausal women with an intact uterus increases their risks of developing uterine cancer, it is standard

TABLE 3. Staging of Uterine Cancer and 5-Year Survival Stage I II III IV Denition Tumor limited to the uterine fundus Tumor extends to the cervix Regional tumor spread to the pelvis Advanced pelvic disease or distant spread 5-Year Survival (%) 90 75 40 < 10

Adapted from Burke TW, Tortolero-Luna G, Malpica A, et al: Endometrial hyperplasia and endometrial cancer. Obstetrics and Gynecology Clinics 23:411456, 1996; with permission.

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practice to also give progesterone. Traditionally, HRT has been given cyclically, with estrogen given daily and progesterone added for the last 10 to 15 days of the cycle. The woman has a withdrawal bleed at the end of the progesterone and estrogen phase. To prevent endometrial hyperplasia, the progesterone needs to be given for 10 or more days each month.49, 67 A continuous combined hormone replacement regime has been established with the administration of both estrogen and progesterone daily. There is a higher compliance in women on this regimen, partly because after 6 months, most women cease to have any vaginal bleeding.12 This continuous hormone regimen does not increase the risk for uterine cancer relative to women who are not on any HRT.33 The Cochrane Database of Systematic Reviews examines which HRT regimens provide effective protection against the development of endometrial hyperplasia.41 Eighteen randomized controlled trials are included in an analysis that found that unopposed moderate- or high-dose estrogen therapy is associated with an increased risk for endometrial hyperplasia. There is a direct relationship between the length of estrogen treatment and the rates of endometrial hyperplasia. The addition of progesterone in a continuous or cyclical regimen gives protection against the development of endometrial hyperplasia. With a longer duration of treatment, continuous therapy is found to be more protective than cyclical therapy. No increase in uterine cancer is seen in any of the treatment groups in these studies, although the longest duration of follow-up was only 3 years. Prevention in Women Not on Hormone Replacement Therapy. It has been suggested that use of a progestin-releasing intrauterine contraceptive device (IUCD) delivering progestin directly to the endometrium (avoiding systemic side effects) would decrease the rate of uterine cancer. Use of this IUCD for 5 years is predicted to reduce the lifetime risk for uterine cancer by 55%. No studies have been done to demonstrate this nding.51 Endometrial Hyperplasia The classication of endometrial hyperplasia according to the International Society of Gynecological Pathologists is as follows: Atypical hyperplasia: Simple Complex Hyperplasia: Simple Complex Pathology Endometrial hyperplasia covers a spectrum of pathologic changes in the glands and stroma of the endometrium. These changes can range from hyperplasia to atypical hyperplasia and carcinoma. Hyperplasia can be simple or complex depending on the architecture of the glandular elements. Simple hyperplasia is characterized by an increased glandularstroma ratio without glandular crowding and cytologic atypia. In complex hyperplasia, the glands are crowded with budding and infolding of the glands, but no cytologic atypia is found. In atypical hyperplasia, there is cytologic atypia that can be simple or complex, depending on the architecture of its glands. Cytologic atypia is characterized

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by large nuclei with varying shapes and sizes, increased nuclearcytoplasm ratio, coarse chromatin clumping, and prominent nucleoli. Kurman et al39 studied the natural history of endometrial hyperplasia in 170 patients who were followed for 13.4 years. They found that the risk for progression to carcinoma increases as the degree of nuclear atypia increases. Progression to carcinoma occurs in 1% of patients with simple hyperplasia, 3% of patients with complex hyperplasia, 8% of patients with atypical simple hyperplasia, and 29% of patients with atypical complex hyperplasia. Tavassoli et al58 found that 25% of patients with atypical hyperplasia diagnosed by dilatation and curettage had a well-differentiated carcinoma between 3 days and 9 months later at the time of hysterectomy. Treatment Endometrial hyperplasia in patients without cytologic atypia responds well to progestin therapy. Ferenczy and Gelfand studied 85 postmenopausal women with endometrial hyperplasia treated with progestin. Out of 65 patients without cytologic atypia, 52 (80%) had complete reversal of their lesions.17 None of these patients developed cancer during 7 years of follow-up. Of the 20 patients with cytologic atypia, only 25% regressed with progestin therapy, and adenocarcinoma developed in 25%. In treating endometrial hyperplasia without atypia, it is reasonable to start with 20 mg of medroxyprogesterone twice a day for 3 to 6 months, and then an endometrial biopsy should be repeated. If hyperplasia is still present, a hysteroscopy should be performed for a denitive diagnosis. If hysteroscopy conrms the presence of hyperplasia, an additional 3 months of progesterone therapy can be given followed by another endometrial biopsy, or a hysterectomy may be performed. Hyperplasia with cytologic atypia should be treated with a hysterectomy because of the higher progression rate to cancer. When the patient is a poor operative risk, it may be treated with progesterone for 3 months, and then repeat evaluation of the endometrium is performed.

MANAGEMENT OF POSTMENOPAUSAL BLEEDING History The physician must take a clear history to ensure that the bleeding is coming from the vagina and not the urinary tract or bowel. Risk factors for uterine cancer can be sought in the history. It is important to ascertain any nonprescribed substances that the patient is taking, such as soy protein that contains phytoestrogens, in addition to prescribed hormone treatment.

Physical Examination The most likely cause of postmenopausal bleeding is an intrauterine abnormality, and so frequently, the physical examination gives no indication as to the source of bleeding. The abdominal examination is usually unremarkable unless the patient has an advanced cancer, with evidence of metastases causing abdominal

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masses and ascites. A thorough examination of the external genitalia is undertaken to exclude any visible tumors or trauma of the vulva and vagina. The cervix is inspected for polyps, and a Papanicolaou smear is done. A bimanual examination is performed to assess for enlargement, position, and mobility of the uterus. An enlarged, xed uterus may indicate advanced malignant disease. The position of the uterus is noted to determine if an endometrial biopsy needs to be performed, as this is relevant. The ovaries are examined, because uterine cancer can be secondary to an estrogen-secreting ovarian tumor such as a granulosa cell tumor. Value of a Papanicolaou Smear Although it is an insensitive test for detecting endometrial carcinoma, a Papanicolaou smear should be done in any woman presenting with postmenopausal bleeding. Studies have shown that in pre- and postmenopausal women, the presence of endometrial cells, particularly atypical glandular cells, in a Papanicolaou smear may be associated with uterine cancer.24, 43, 70 Veljovich et al studied 199 asymptomatic pre- and postmenopausal women who had atypical glandular cells of undetermined signicance (AGUS) on their Papanicolaou smears. Thirtytwo percent of women had preinvasive or invasive lesions of the cervix or endometrium.62 The presence of endometrial cells or atypical glandular cells on a Papanicolaou smear necessitates evaluation of the endometrium and cervix with an endometrial biopsy and colposcopy, respectively. Laboratory Investigations It may be necessary to look for blood in the stool or urine if the source of bleeding is not clear. A full blood count may be needed if the bleeding is heavy and prolonged. Other laboratory investigations do not contribute to the evaluation of postmenopausal bleeding. Studies trying to identify independent risk factors for endometrial neoplasia have not shown sufcient predictive ability to determine which women with abnormal peri- or postmenopausal bleeding should have diagnostic testing.64 If the physical examination does not reveal cause for the postmenopausal bleeding, it is necessary to evaluate the endometrium.

EVALUATION OF THE ENDOMETRIUM IN POSTMENOPAUSAL BLEEDING About 10% of women with postmenopausal bleeding are found subsequently to have endometrial carcinoma.2 Because of the high incidence of malignancy as a cause of postmenopausal bleeding, all women presenting with this complaint should be evaluated. The evaluation involves direct assessment of the endometrium with a biopsy or indirect assessment with ultrasound. Techniques used to evaluate the endometrium include Endometrial biopsy EVUS Hysteroscopy Saline infusion sonography (SIS)

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Methods for Endometrial Sampling Endometrial sampling originally was done with a Novak curette. This diagnostic procedure was introduced in 1935 by Novak as an alternative to dilatation and curettage. The Novak curette is a rigid reusable stainless steel cannula available in sizes ranging from 1 to 4 mm. A syringe attached to the end is withdrawn to create negative pressure and suck an endometrial sample into the cannula. Its use has been superseded by the pipelle, which has the advantage of exibility and disposability and causes less discomfort for the patient.55 Aspiration Sampling The pipelle is a clear, exible polypropylene sheath that is 23 cm long with a small hole in the distal end. Inside the sheath is a piston. When this piston is withdrawn, it creates negative pressure in the endometrial cavity, and tissue is sucked into the sheath. Technique. The patient is advised to take a nonsteroidal anti-inammatory drug 1 hour before the procedure to decrease uterine cramping. A pelvic examination initially is performed to determine whether the uterus is anteexed or anteverted. In a severely exed uterus, it may be necessary to put a bend in the pipelle. The cervix is swabbed with iodine, and the pipelle inserted through the cervical os. If difculty with insertion is encountered, a tenaculum can be applied to the anterior or posterior lip of the cervix to apply gentle countertraction. If the pipelle still does not pass through the os, a uterine sound can be used in an attempt to dilate the os. When resistance to the pipelle still is encountered, the procedure should be abandoned because of the danger of creating a false passage through the cervical os and risk for perforation. In cases in which there is difculty inserting the pipelle, a 200-mg tablet of misoprostol can be inserted into the vagina to dilate the cervix, and the patient returns to the hospital the following day. There are no studies evaluating this use of misoprostol, but it has become an accepted technique. The only signicant side effects are some uterine cramping and a possible increase in bleeding from the uterus. Once the pipelle is in the uterine cavity, usually at a depth of 7 to 9 mm, suction is created by withdrawing the piston. While moving the pipelle in and out, the cannula is slowly rotated 360 so that the sample is taken from a wide area of the uterine cavity. To increase the area of sampling, the cannula can be advanced again into the cavity before it is withdrawn entirely. Once the pipelle is full, another pipelle can be used if there is believed to be a lot more tissue in the cavity. The tissue then is placed in a container of formaline and sent to histology for examination.26 The American Heart Association does not recommend antibiotic prophylaxis against subacute bacterial endocarditis, because endometrial sampling is unlikely to cause bacteremia. There are no studies that specically evaluate the risks.11 Effectiveness. The sensitivity of aspiration sampling in detecting uterine cancer varies in studies from 67% to 100%, as shown in Table 4.19, 30, 56, 61 The overall specicity is around 100%.61 In studies by Guido and Ferry et al, the lower sensitivities are explained by various factors in the study population. In Guidos study, 5 of the 11 false-negative results were patients in whom the malignancy was conned to a polyp. When there is a small focus of malignancy, the pipelle is more likely to miss it, because it samples a small percentage of the endometrial area. The low sensitivity found in Ferry et als study may have resulted from the fact that all of the patients previously had had a D and C, so much of the tissue in the endometrial cavity had been removed already.

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TABLE 4. Sensitivities of Endometrial Pipelle Sampling in Detecting Cancer Study Ferry et al Guido et al30 Stovall et al56 Van Den Bosch et al61
19

Sensitivity (%) 67 83 97.5 100

Pipelle sampling has been shown in repeated randomized studies to be as effective as a D and C in diagnosing malignancy.29, 46, 57 Its advantages include that it is lower in cost, it does not require anesthesia, and it easily can be carried out in the ofce setting. It does have some limitations, however. There is a 4% to 10% chance of cervical stenosis, which prevents insertion of the pipelle into the uterine cavity, and an alternative evaluation technique is needed. Although pipelle biopsies can detect cancer accurately, they are not able to detect any structural abnormalities such as broids and polyps. The biopsies are least sensitive in early disease and disease conned to polyps. When the biopsy sample is normal and postmenopausal bleeding continues, further evaluation of the endometrium is recommended. Hysteroscopy The advancement of endoscopic techniques has established hysteroscopy as a means to evaluate abnormal uterine bleeding. Hysteroscopy involves direct visualization of the endometrium and can be useful when endometrial biopsies are inconclusive or abnormal bleeding persists in the face of normal endometrial biopsies. The main advantage of hysteroscopy is direct inspection of any endometrial abnormality that is biopsied. It detects endometrial polyps that can be removed and examined. Hysteroscopy is carried out in the ofce or the operating room. A exible beroptic cable usually is used with carbon dioxide as the distending medium, which gives clear visualization of the intrauterine cavity. The disadvantage of ofce hysteroscopy is that it cannot be used in patients with cervical stenosis. Technique. For ofce hysteroscopy, the patient is advised to take a nonsteroidal anti-inammatory drug 1 hour before the procedure to decrease uterine cramping. A paracervical block of lidocaine and vasopressin may be used to lessen pain and bleeding during the procedure.69 Hysteroscopes are available in several diameters ranging from 3 to 10 mm. Scopes that are 4 mm and larger have an operating port through which biopsy forceps can be used. Biopsies can be taken under direct vision using a larger hysteroscope or, if the hysteroscope is less than 4 mm, using a pipelle cannula guided by knowledge of the site of the abnormality. With the hysteroscope inside the uterine cavity, the fundus is inspected rst. The scope then is rotated to each side while visualizing the ostia of the fallopian tubes. The lower segment of the uterus and the cervix is examined as the hysteroscope is withdrawn. The entire procedure takes only a few minutes.3

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Complications. Complications are unusual but include perforation and infection. Perforation most likely will occur when there is difculty inserting the hysteroscope because of cervical stenosis. The incidence of infection is probably no greater than with endometrial biopsy, and there is no evidence to support the use of prophylactic antibiotics. Hysteroscopy has the theoretic concern that malignant cells may be spread into the peritoneal cavity, but there is no evidence to substantiate this concern Effectiveness. Gimpleson and Rappold compared the diagnostic abilities of hysteroscopy and directed biopsy with those of dilatation and curettage. Hysteroscopy with directed biopsy was the superior method, with a false-negative rate of 3%.25 In a smaller study, Brooks and Serden also found that hysteroscopy with directed biopsy was superior to curettage.6 Hysteroscopy has superceded dilatation and curettage as the gold standard by which other methods of endometrial assessment are compared. Endovaginal Ultrasonography Over the past 12 years, EVUS or transvaginal ultrasound increasingly has been used to assess the endometrium. A vaginal probe gives better visualization of the endometrium than does transabdominal imaging and allows measurement of endometrial thickness. The accuracy of EVUS is highly operator dependent, and radiologists and gynecologists performing EVUS should have experience and expertise with interpretation of the image. Many studies have been published that compare the measured thickness of the endometrium with the histopathologic diagnosis in an attempt to determine the endometrial thickness below which the risk for cancer is acceptably small.14, 18, 27, 45 In the Nordic trial,36 the largest study to date, 1168 women with postmenopausal bleeding had an EVUS and subsequent curettage. No uterine cancer was found among postmenopausal women who had an endometrial thickness of 4 mm or less. If this set point had been used to determine the necessity of an endometrial biopsy, 46% of the endometrial biopsies would not have been necessary. In this trial, the percentage of women with endometrial carcinoma increased in a linear fashion with increasing endometrial thickness. Some studies, however, have shown that uterine cancers occasionally will be missed when the threshold for normal is 4 mm and below.38 Smith-Bindman et al completed a meta-analysis of 35 studies to determine the accuracy of EVUS in diagnosing endometrial abnormalities in women with postmenopausal bleeding.54 The analysis included prospective studies that evaluated EVUS before obtaining an endometrial tissue sample. The meta-analysis included 5892 women with a mean age of 61. The prevalence of uterine cancer was 13%. The prevalence of endometrial polyps and hyperplasia was 40%. The results showed that with a normal endometrial thickness of 4 mm or less and a pretest probability of 10%, the probability of cancer following a normal EVUS is 1%. Table 5 shows the sensitivities and specicities of various thickness thresholds for endometrial disease. Endometrial thicknesses of 4 and 5 mm have sensitivities for uterine cancer of 96%, although the specicity of a 5-mm thickness is slightly higher. The lower the endometrial thickness cutoff point used to dene an abnormal thickness, the higher the number of false-positive tests and subsequent normal histologic ndings. There is only one study, which looked at follow-up of women with postmenopausal bleeding, and an endometrial thickness of less than 4 mm detected by EVUS.31 This study of expectant management showed that none of the women developed cancer over 1 year of follow-up. An endometrial thickness of over 4 mm

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TABLE 5. Summary of Sensitivity and Specicity for Endometrial Disease and Cancer Using Different Endovaginal Thickness Measurements to Dene an Abnormal Result Endometrial Disease Threshold (mm) 3 4 5 6 7 8 10

Cancer Specicity %, (95% CI) 62 (5371) 69 (6771) 81 (7983) 82 (8084) 90 (8892) 80 (7584) 88 (8591) No. of Women 31 284 457 454 131 151 51 Sensitivity %, (95% CI) 100 (89100) 96 (9398) 96 (9498) 95 (9297) 95 (8998) 97 (9299) 90 (7997) No. of Women 204 2422 2986 2661 442 530 532 Specicity %, (95% CI) 38 (3245) 53 (5155) 61 (5963) 55 (5357) 64 (5969) 60 (5664) 79 (7582)

No. of Women 114 1001 1306 1361 691 381 207

Sensitivity %, (95% CI) 98 (94100) 91 (8993) 92 (9093) 87 (8589) 85 (8288) 85 (8188) 66 (5973)

No. of Women 121 1756 2137 1717 1011 369 445

Thickness threshold used to dene an abnormal test result.

Includes cancer, atypical and complex hyperplasia, and polyps. The number of women for whom data were available.

Results from Karlsson et al36 are included only for endometrial disease.

Results from Dengenhardt et al36 are not included for endometrial disease. Results from Karlsson et al36 are not included for cancer. Results from Dijkhuizen et al37 are not included for cancer. CI = condence interval. From Smith-Bindman R, Kerlikowske K, Feldstein VA, et al: Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. JAMA 280: 15101517, 1998; with permission.

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has become the threshold at which further evaluation of the endometrium with an endometrial biopsy is recommended. Disadvantages. The specicity of EVUS in detecting uterine cancer is lower than the specicity of endometrial biopsy because there are other pathologic causes of a thickened endometrial stripe. The sensitivity of EVUS compares favorably with ofce biopsy, although under some conditions the sensitivity of EVUS is lower. In obese patients, the view of the endometrium may not be clear, especially if the uterus is enlarged. It is also difcult to differentiate intracavity abnormalities, such as polyps, broids, and blood, from each other. When there is any evidence of an intrauterine mass detected by EVUS, a biopsy is required. Saline Infusion Sonography Saline infusion sonography infuses saline into the uterine cavity during ultrasound to improve the image. The saline separates the two walls of the endometrium, allowing their thicknesses to be measured. It also allows the clinician to evaluate the uterus for intracavity lesions such as broids or polyps. Technique. The ultrasound can be performed transvaginally or transabdominally, but usually the transvaginal technique is used because the resultant image is clearer. Nonsteroidal anti-inammatory drugs can be given 1 hour before the procedure; however, pain scores do not drop appreciably.69 A paracervical block can be used for pain relief if the procedure is not tolerated. The bladder should be emptied before the procedure, because bladder distension can shift an anteverted uterus to a retroverted position, making evaluation with the transvaginal probe difcult. The sterile saline is infused into the uterus through a exible intrauterine catheter inserted through the cervix. The ultrasound examination then is performed.3 Complications. SIS is associated with few complications. In Widrichs study of 132 patients comparing hysteroscopy with SIS, there were no complications, and patients felt signicantly more pain with hysteroscopy than with SIS.68 In this study, there was no statistically signicant difference between SIS and hyteroscopy in the detection of endometrial polyps and cancer. In cases in which an EVUS shows a thickened endometrium but the endometrial biopsy is normal, an SIS allows more detailed evaluation of the uterine cavity, particularly in detecting intraluminal masses.13 There are no large studies evaluating the accuracy of SIS, so ofce biopsy, EVUS, and hysteroscopy are still the methods of choice. Cost Analysis of the Evaluation of Postmenopausal Bleeding Curettage Versus Ofce Endometrial Biopsy Historically, curettage was considered the gold standard for diagnosis of postmenopausal bleeding. Analyses now have shown that it is more costly and no more accurate in diagnosing endometrial abnormalities than ofce endometrial biopsy.16 Endometrial Biopsy Versus Endovaginal Ultrasound Weber et al conducted a study comparing the predicted outcomes and costs of two diagnostic algorithms for the diagnosis of postmenopausal bleeding. They

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compared ofce endometrial biopsy with EVUS for the initial evaluation. From an extensive Medline search, they concluded that the probability of a nondiagnostic endometrial biopsy was 28% and that of an abnormal or inconclusive vaginal ultrasound was 55%. Cost analyses showed that vaginal ultrasonography costs slightly less than ofce endometrial biopsy when used as the initial test in the evaluation of postmenopausal bleeding. Savings were small, however, ranging between $14 and $20 per patient. Vaginal ultrasound is only more cost effective when it has a much lower cost than endometrial biopsy, because endometrial sampling still is needed in most cases following EVUS.63 In contrast, Creinin suggested that there is a higher false-negative rate with endometrial biopsy than with EVUS. Patients with a normal endometrial biopsy but continued postmenopausal bleeding need further evaluation; in this situation, the cost savings of an initial EVUS is higher than the $14 to $20 suggested by Weber et al.10

EVALUATION OF THE ENDOMETRIUM BY FAMILY PRACTICE PHYSICIANS Most family practice physicians are able to perform an endometrial biopsy with a pipelle in their ofce, whereas few physicians have the expertise to do EVUS to assess endometrial stripe thickness. Although endometrial biopsy may have a slightly higher false-negative rate and a higher cost, it is an appropriate rst choice for investigation because of its convenience for patients and physicians. If bleeding continues and the endometrial biopsy result was equivocal, further investigation with a hysteroscopy should be performed. When EVUS is the rst diagnostic test selected, an endometrial biopsy needs to be done if the endometrial stripe is over 4 mm thick. If there is continued bleeding and the EVUS demonstrates a uterine stripe of 4 mm or less, hysteroscopy should be performed because the negative predictive value of EVUS is not 100%. An algorithm for the management of postmenopausal bleeding is shown in Figure 1.

Key Points
Postmenopausal bleeding always should be investigated, because it may be The commonest cause of postmenopausal bleeding is an atrophic In a hormone therapy regimen, the addition of continuous or cyclical

a sign of endometrial carcinoma. endometrium.

progesterone to estrogen provides protection against the development of endometrial hyperplasia. The progression of hyperplasia to carcinoma increases as atypia of the hyperplasia develops. Endometrial hyperplasia without atypia can be treated with progesterone. Atypical hyperplasia should be managed by hysterectomy. In unexplained postmenopausal bleeding, it is essential to evaluate the endometrium.

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FIGURE 1. Postmenopausal bleeding. PMB = Postmenopausal bleeding; EVUS = endovaginal ultrasound.

POSTMENOPAUSAL BLEEDING

Endometrial biopsy

EVUS

Normal or atrophy Observe Continued PMB Hysteroscopy

Hyperplasia with atypia

Hyperplasia without atypia

Stripe 4 mm Observe Continued PMB Hysteroscopy

Stripe > 4 mm Endometrial biopsy

Hysterectomy

Progesterone treatment for 36 months Repeat biopsy Persistent hyperplasia Progesterone for 3 months Repeat biopsy Persistent hyperplasia Normal Consider annual endometrial biopsy

ACKNOWLEDGMENT
The author is extremely grateful to Sim Galazka, MD, James Finnerty, MD, and Wanda Hudson for their help in the preparation of this article.

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