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POSTMENOPAUSAL BLEEDINGEvaluation and Management

Anne L. Mounsey, MD

Postmenopausal bleeding is defined as bleeding that occurs after 1 yearof amenorrhea in a woman who is not receiving hormone replacement therapy(HRT). Women on continuous progesterone and estrogen hormone therapy canexpect to have irregular vaginal bleeding, especially for the first 6 months. Thisbleeding should cease after 1 year. Women on estrogen and cyclical progesteroneshould have a regular withdrawal bleeding after stopping the progesterone. Anyunexpected bleeding or significant change in withdrawal bleeding should promptfurther investigation. Women with abnormal postmenopausal bleeding include

Women with bleeding after 1 year of amenorrheaWomen with bleeding after 1 year of continuous combined HRTWomen with unexpected bleeding while receiving cyclic HRT

CAUSES OF POSTMENOPAUSAL BLEEDING

Postmenopausal bleeding should always be investigated, because it could bea sign of endometrial carcinoma, which has a much higher cure rate if diagnosedearly. Stage 1 endometrial carcinoma has a 5-year survival rate of 98%, so earlydiscovery greatly improves the chances of cure. It is estimated that endometrialcarcinoma is the cause of postmenopausal bleeding in 10% of cases.9 All womenwith unexplained postmenopausal bleeding should undergo investigation and eval-uation of the endometrium, if necessary.

Although endometrial carcinoma is the most serious cause of postmenopausalbleeding, an atrophic endometrium with dyssynchronous shedding is the common-est cause. A less common cause is cervical or endometrial polyps. A completelist 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

..................................................................................................................................................................CLINICS IN FAMILY PRACTICEVolume 4 • Number 1 • March 2002 173

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TABLE 1.Causes of Postmenopausal Bleeding

Cause of Bleeding Frequency (%)

Endometrial or cervical polyps 2–12Endometrial hyperplasia 5–10Endometrial carcinoma 10Exogenous estrogens 15–25Atrophic endometritis and vaginitis 60–80Other∗

∗Vaginal trauma, urethral caruncle, uterine sarcoma, cervical cancer, atrophic vaginitis.Adapted from Lurain J: Uterine cancer. In Berek JS, Adashi EY, Hillard PA (eds): Novak’sGynecology, ed 12. Baltimore, Lippincott, Williams & Wilkins, 1996, 1058–1101; with permission.

diagnoses can be made only after further investigation, such as transvaginal en-dovaginal ultrasound (EVUS) or endometrial biopsy.

Cervical Polyps

Cervical polyps can originate from the endocervix or the ectocervix as a resultof focal hyperplasia. They are composed of a central vascular and connective tis-sue stroma covered by squamous, columnar, or squamocolumnar epithelium. Thesurface epithelium may show squamous metaplasia, and the tissue at the tip of thepolyp is often necrotic. Malignant change can occur but is estimated to be less than1%.50 The cause of cervical polyps is unknown, although there may be an associa-tion with chronic cervicitis. They most often are found in women in their reproduc-tive years but can occur after menopause. Asymptomatic polyps often are foundon routine vaginal examination or may present with postcoital, intermenstrual, orpostmenopausal bleeding.

Endocervical Polyps

Endocervical polyps are commoner than ectocervical polyps. On vaginal ex-amination, they appear as cherry-red tumors protruding on a pedicle from thecervical os. They can vary in length and diameter from a few millimeters up to3 cm.

Ectocervical Polyps

Ectocervical polyps tend to be less vascular and more fibrous than endocervi-cal polyps. They are paler and smoother in appearance and less likely to bleed thanendocervical polyps.

Treatment of Cervical Polyps

Most cervical polyps can be treated in the office by grasping the pedicle withsponge forceps and twisting it until the polyp is avulsed. Any bleeding can bestopped 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 thepedicle to be visualized and the whole polyp to be removed. Larger polyps and mul-tiple polyps may cause significant bleeding and are removed best in the operatingroom.50

Endometrial Polyps

The incidence of endometrial polyps varies with age, reaching a peak in thefifth decade of life.60 Because they are estrogen sensitive, their incidence declinesafter menopause. The origin of endometrial polyps is unclear. Most polyps occur inthe fundal region and project down into the uterine cavity. Larger polyps can ex-tend to the vaginal introitus. They are composed of a central fibrous stroma con-taining large vascular channels covered by endometrial epithelium. Endometrialpolyps may undergo malignant change into a carcinoma or sarcoma.50

In postmenopausal women, endometrial polyps can cause postmenopausalbleeding that is usually light. Sometimes, a polyp may infarct, and there is a moresudden onset of bleeding accompanied by crampy abdominal pain.

Diagnosis

Hysteroscopy can identify endometrial polyps by direct visualization. Saline-infusion sonograms have been used to identify the polyps that show up as fillingdefects. Pelvic ultrasound usually does not reveal endometrial polyps unless theyare 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 pa-tient may complain of a sore vagina and pain on intercourse with or without bleed-ing. On direct inspection, the vagina looks atrophic, thin, and red and may showevidence of bleeding. Atrophic vaginitis is best treated with oral or topical estro-gen. If oral estrogens are used and the woman has an intact uterus, progesteronealso should be used. It is not necessary to use progesterone in conjunction withtopical 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, fol-lowed by a treatment-free week. This cyclical regimen can be continued, or thepatient 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 vaginalring that is inserted into the vagina and changed every 3 months. There is some ev-idence that topical estrogen does not increase the risk for developing uterine can-cer; however, it is prudent to use the lowest dose of estrogen that maintains thevaginal tissue to decrease any possible risk for uterine cancer.4

If the vagina is atrophic, it is likely that the endometrium is also atrophic. En-dometrial atrophy with dyssynchronous shedding of the endometrium is the com-monest cause of postmenopausal bleeding, accounting for up to 80% of cases. Thisdiagnosis only can be made after evaluation of the endometrium to exclude uterinecancer. The options available for evaluation of the endometrium are listed later inthis article.

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Endometrial Carcinoma

Epidemiology

Uterine cancer is the fourth commonest cancer in women and is the common-est cancer of the female genital tract. In 2001, it is estimated that there will be38,300 new cases of uterine cancer and 6600 deaths from uterine cancer, account-ing for approximately 2% of all cancer deaths.8 In the United States, the incidenceamong whites is almost double that in blacks, but the overall incidence of uterinecancer is declining.47 Mortality rates are declining but still remain higher for blacksthan for whites. This racial difference in mortality is not explained entirely by dif-ferences in the stage of disease at diagnosis.8 Uterine cancer is a disease of afflu-ent communities with a Westernized lifestyle and is commoner in urban than ruralcommunities.

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 hypoth-esized that this increase was associated with the use of unopposed estrogen inpostmenopausal women.42, 65 This hypothesis was supported, because by the mid-1980s, the incidence of uterine cancer had decreased as postmenopausal womenwith intact uteri were given progesterone with estrogen. Since this time, morestudies have confirmed the association between estrogen use and an increasedrisk for uterine cancer.4 The increased exposure to endogenous estrogens that oc-curs with early menarche, late menopause, low parity or nulliparity, and estrogen-secreting ovarian tumors also increases the risk for uterine cancer, which givesadded support to this hypothesis.35, 47 The major risk factors and relative risks areshown in Table 2.

There is an increasing risk for uterine cancer with increasing age. Its inci-dence in women under age 40 is low, but its rate peaks in women between ages 70and 74, after which it declines.53

Tamoxifen, used extensively in the treatment of breast cancer, seems to havea carcinogenic effect on endometrial tissue. The Stockholm Adjuvant TamoxifenTrial found that postmenopausal women receiving 40 mg/d of tamoxifen for 3 to4 years have an increased risk for developing uterine cancer with a relative riskof 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 Relative Risk

Nulliparity 2–3Late menopause 2.4Obesity

21–50 1b overweight 3> 50 1b overweight 10

Diabetes mellitus 2.8Unopposed estrogen therapy 4–8Tamoxifen 2–3Atypical endometrial hyperplasia 8–29

From Lurain J: Uterine cancer. In Berek JS, Adashi EY, Hillard PA (eds): Novak’s Gyne-cology, ed 12. Baltimore, Lippincott, Williams & Wilkins, 1996, pp 1058–1101; with permission.

tamoxifen and duration of treatment.22, 23 This finding has been confirmed byFisher et al, who found an increased risk for uterine cancer in women given tamox-ifen to prevent breast cancer.20

Obesity also increases the risk, because obese women have high levels ofestrone formed by the peripheral conversion of androstenedione in muscle andfat cells.5, 15 The risk for uterine cancer seems to increase with the increase inobesity.47 A small study in Sweden looking at body-fat distribution in women withendometrial hyperplasia showed that upper and lower body-fat distribution werenot characteristic of women with atypical hyperplasia.28

Diabetes and hypertension have been associated with an increased risk foruterine 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, possiblybecause of its antiestrogenic effects.47 Women on a combined oral contraceptivehave an increased exposure to progesterone that lowers their risk for uterinecancer.15, 35 It is estimated that use of a combined oral contraceptive pill decreasesthe risk for uterine cancer by 11.7% per year.32

Screening

There are only a few studies evaluating screening for endometrial carci-noma. One of the largest studies examined 2964 peri- and postmenopausal womenwho were candidates for HRT. Endometrial biopsy specimens were obtainedusing a vabra aspirator, and 0.07% of the endometrial biopsies were found tobe adenocarcinoma.38 This low yield indicates that screening for endometrialcarcinoma with an endometrial biopsy is not cost effective and would not fulfillscreening criteria developed by Sackett et al.52

Holbert examined the value of transvaginal ultrasonography in screeningfor endometrial and ovarian abnormalities.34 He screened 478 postmenopausalwomen. 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. Fleis-cher et al screened 1926 postmenopausal women with EVUS, of which 1792 alsohad an endometrial biopsy. He found that the positive predictive value of an en-dometrial thickness of more than 5 mm in detecting adenocarcinoma was only2%.21 Langer et al found similar results when they screened 448 women with en-dovaginal ultrasound (EVUS) and endometrial biopsy. Thirty percent of womenhad an endometrial thickness over 4 mm and on biopsy, and 11 of these womenhad a serious abnormality (1 had adenocarcinoma, 2 had atypical simple hyper-plasias, and 8 had complex hyperplasias). These results translate to a low positivepredictive value of 3%.40

The low yield that EVUS and endometrial biopsy have for detecting seriousendometrial disease demonstrate that they are probably not effective screeningtests for uterine cancer. It may be cost effective to screen women with multiplerisk factors for uterine cancer, and further studies need to be performed in thisgroup.

Most patients with uterine cancer have elevated CA 125 antigen levels. Studieshave shown that once the CA 125 antigen is detectable in peripheral blood, the tu-mor already has spread to extra-uterine sites, which lessens its value as a screen-ing test.44, 48

The American Cancer Society (ACS) updated their screening recommenda-tions in 2001 and concluded that there is no indication that screening for uterinecancer is warranted. The one exception is for women who are at increased risk forhereditary nonpolyposis colorectal cancer. This group of women should be offeredannual screening with an endometrial biopsy by age 35.8

Pathology

Uterine cancer may develop from hyperplasia, which is associated with in-creased estrogen exposure. It also may develop from endometrial atrophy, whichis not estrogen related.66 This latter type of uterine cancer is poorly differentiatedand has a worse prognosis. Studies are underway to examine these atrophy- andhyperplasia-associated uterine cancers and the importance of different risk factorsin their formation.

Tumors of the uterus are classified broadly into endometrial carcinomas anduterine sarcomas. Endometrial carinomas as classified by the International Societyof Gynecologic Pathologists include

Endometrial adenocarcinomaPapillarySecretoryCiliated cellAdenocarcinoma with squamous differentiation

Mucinous carcinomaSerous carcinomaClear cell carcinomaSquamous carcinomaUndifferentiated carcinomaMixed typesMiscellaneous carcinomaMetastatic carcinoma

The commonest uterine cancer is endometrioid adenocarcinoma, which accountsfor over 75% of uterine carcinomas. Endometriod adenocarcinomas are sub

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classified into four types: (1) papillary, (2) secretory, (3) ciliated cell, and (4) ade-nocarcinoma with squamous differentiation, depending on the predominant pat-tern of cells seen in the tumor.

Uterine sarcomas are far less common than endometrial carcinomas, account-ing for less than 5% of all uterine malignancies. These less common tumors tendto occur in older women and are associated with a lower overall survival rate anda higher risk for metastatic disease at the time of diagnosis. The stage-one 5-yeardisease-free survival rate is only 52%.1

Staging

Surgical staging is performed by an exploratory laparotomy, total hysterec-tomy, bilateral salpingo-oophorectomy, and cytology. Para-aortic and pelvic lymphnode sampling is performed unless there is grade 1 cancer with less than half my-ometrial invasion. The depth of myometrial invasion is determined by intraoper-ative frozen section. Lymph node sampling is considered unnecessary in obviousmetastatic disease.

Treatment

Surgery with a total abdominal hysterectomy and bilateral salpingo-oophorectomy is the mainstay of treatment. Subsequent treatment with radiationor chemotherapy depends on the staging of the tumor. Survival rates are related tothe stage at diagnosis as shown in Table 3.

Prevention

The US Preventive Task Force (USPTF) Guidelines conclude that there isinsufficient evidence to recommend for or against routine counseling of womenabout measures to prevent uterine cancer; however, women who are counseled onthe use of contraception should be informed of the reduced risk for uterine cancerin users of an oral contraceptive pill.59

Prevention in Women on Hormone Replacement Therapy. Because ithas been recognized that unopposed estrogen in postmenopausal women withan intact uterus increases their risks of developing uterine cancer, it is standard

TABLE 3.Staging of Uterine Cancer and 5-Year Survival

Stage Definition 5-Year Survival (%)

I Tumor limited to the uterine fundus 90II Tumor extends to the cervix 75

III Regional tumor spread to the pelvis 40IV Advanced pelvic disease or distant spread < 10

Adapted from Burke TW, Tortolero-Luna G, Malpica A, et al: Endometrial hyperplasia andendometrial cancer. Obstetrics and Gynecology Clinics 23:411–456, 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 thecycle. The woman has a withdrawal bleed at the end of the progesterone and es-trogen phase. To prevent endometrial hyperplasia, the progesterone needs to begiven for 10 or more days each month.49, 67 A continuous combined hormone re-placement regime has been established with the administration of both estrogenand 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 cancerrelative to women who are not on any HRT.33

The Cochrane Database of Systematic Reviews examines which HRT regi-mens provide effective protection against the development of endometrialhyperplasia.41 Eighteen randomized controlled trials are included in an analysisthat found that unopposed moderate- or high-dose estrogen therapy is associatedwith an increased risk for endometrial hyperplasia. There is a direct relationshipbetween the length of estrogen treatment and the rates of endometrial hyperplasia.The addition of progesterone in a continuous or cyclical regimen gives protectionagainst the development of endometrial hyperplasia. With a longer duration oftreatment, 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 thesestudies, although the longest duration of follow-up was only 3 years.

Prevention in Women Not on Hormone Replacement Therapy. It hasbeen suggested that use of a progestin-releasing intrauterine contraceptive device(IUCD) delivering progestin directly to the endometrium (avoiding systemic sideeffects) would decrease the rate of uterine cancer. Use of this IUCD for 5 yearsis predicted to reduce the lifetime risk for uterine cancer by 55%. No studies havebeen done to demonstrate this finding.51

Endometrial Hyperplasia

The classification of endometrial hyperplasia according to the InternationalSociety of Gynecological Pathologists is as follows:

Atypical hyperplasia:SimpleComplex

Hyperplasia:SimpleComplex

Pathology

Endometrial hyperplasia covers a spectrum of pathologic changes in theglands and stroma of the endometrium. These changes can range from hyperpla-sia to atypical hyperplasia and carcinoma. Hyperplasia can be simple or complexdepending on the architecture of the glandular elements. Simple hyperplasia ischaracterized by an increased glandular–stroma ratio without glandular crowdingand cytologic atypia. In complex hyperplasia, the glands are crowded with buddingand infolding of the glands, but no cytologic atypia is found.

In atypical hyperplasia, there is cytologic atypia that can be simple or com-plex, depending on the architecture of its glands. Cytologic atypia is characterized

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by large nuclei with varying shapes and sizes, increased nuclear–cytoplasm ratio,coarse chromatin clumping, and prominent nucleoli.

Kurman et al39 studied the natural history of endometrial hyperplasia in170 patients who were followed for 13.4 years. They found that the risk for pro-gression to carcinoma increases as the degree of nuclear atypia increases. Pro-gression to carcinoma occurs in 1% of patients with simple hyperplasia, 3% of pa-tients with complex hyperplasia, 8% of patients with atypical simple hyperplasia,and 29% of patients with atypical complex hyperplasia. Tavassoli et al58 found that25% of patients with atypical hyperplasia diagnosed by dilatation and curettage hada well-differentiated carcinoma between 3 days and 9 months later at the time ofhysterectomy.

Treatment

Endometrial hyperplasia in patients without cytologic atypia responds wellto progestin therapy. Ferenczy and Gelfand studied 85 postmenopausal womenwith endometrial hyperplasia treated with progestin. Out of 65 patients withoutcytologic atypia, 52 (80%) had complete reversal of their lesions.17 None of thesepatients developed cancer during 7 years of follow-up. Of the 20 patients withcytologic atypia, only 25% regressed with progestin therapy, and adenocarcinomadeveloped in 25%.

In treating endometrial hyperplasia without atypia, it is reasonable to startwith 20 mg of medroxyprogesterone twice a day for 3 to 6 months, and then an en-dometrial biopsy should be repeated. If hyperplasia is still present, a hysteroscopyshould be performed for a definitive diagnosis. If hysteroscopy confirms the pres-ence of hyperplasia, an additional 3 months of progesterone therapy can be givenfollowed by another endometrial biopsy, or a hysterectomy may be performed.

Hyperplasia with cytologic atypia should be treated with a hysterectomy be-cause of the higher progression rate to cancer. When the patient is a poor operativerisk, it may be treated with progesterone for 3 months, and then repeat evaluationof the endometrium is performed.

MANAGEMENT OF POSTMENOPAUSAL BLEEDING

History

The physician must take a clear history to ensure that the bleeding is comingfrom the vagina and not the urinary tract or bowel. Risk factors for uterine can-cer can be sought in the history. It is important to ascertain any nonprescribed sub-stances 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 abnor-mality, and so frequently, the physical examination gives no indication as to thesource of bleeding. The abdominal examination is usually unremarkable unless thepatient 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 undertakento exclude any visible tumors or trauma of the vulva and vagina. The cervix is in-spected for polyps, and a Papanicolaou smear is done. A bimanual examinationis performed to assess for enlargement, position, and mobility of the uterus. Anenlarged, fixed uterus may indicate advanced malignant disease. The position ofthe 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 sec-ondary 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 Pa-panicolaou smear should be done in any woman presenting with postmenopausalbleeding. Studies have shown that in pre- and postmenopausal women, the pres-ence of endometrial cells, particularly atypical glandular cells, in a Papanico-laou smear may be associated with uterine cancer.24, 43, 70 Veljovich et al studied199 asymptomatic pre- and postmenopausal women who had atypical glandularcells of undetermined significance (AGUS) on their Papanicolaou smears. Thirty-two percent of women had preinvasive or invasive lesions of the cervix orendometrium.62 The presence of endometrial cells or atypical glandular cells on aPapanicolaou smear necessitates evaluation of the endometrium and cervix withan endometrial biopsy and colposcopy, respectively.

Laboratory Investigations

It may be necessary to look for blood in the stool or urine if the source ofbleeding is not clear. A full blood count may be needed if the bleeding is heavy andprolonged. Other laboratory investigations do not contribute to the evaluation ofpostmenopausal bleeding.

Studies trying to identify independent risk factors for endometrial neoplasiahave not shown sufficient predictive ability to determine which women with abnor-mal peri- or postmenopausal bleeding should have diagnostic testing.64 If the physi-cal examination does not reveal cause for the postmenopausal bleeding, it is neces-sary to evaluate the endometrium.

EVALUATION OF THE ENDOMETRIUMIN POSTMENOPAUSAL BLEEDING

About 10% of women with postmenopausal bleeding are found subsequentlyto have endometrial carcinoma.2 Because of the high incidence of malignancyas a cause of postmenopausal bleeding, all women presenting with this com-plaint should be evaluated. The evaluation involves direct assessment of the en-dometrium with a biopsy or indirect assessment with ultrasound. Techniques usedto evaluate the endometrium include

Endometrial biopsyEVUSHysteroscopySaline infusion sonography (SIS)

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Methods for Endometrial Sampling

Endometrial sampling originally was done with a Novak curette. This diagnos-tic procedure was introduced in 1935 by Novak as an alternative to dilatation andcurettage. The Novak curette is a rigid reusable stainless steel cannula available insizes ranging from 1 to 4 mm. A syringe attached to the end is withdrawn to cre-ate negative pressure and suck an endometrial sample into the cannula. Its use hasbeen superseded by the pipelle, which has the advantage of flexibility and dispos-ability and causes less discomfort for the patient.55

Aspiration Sampling

The pipelle is a clear, flexible polypropylene sheath that is 23 cm long with asmall hole in the distal end. Inside the sheath is a piston. When this piston is with-drawn, it creates negative pressure in the endometrial cavity, and tissue is suckedinto the sheath.

Technique. The patient is advised to take a nonsteroidal anti-inflammatorydrug 1 hour before the procedure to decrease uterine cramping. A pelvic examina-tion initially is performed to determine whether the uterus is anteflexed or antev-erted. In a severely flexed 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 difficulty with insertion is encountered, a tenaculum can be applied to the ante-rior or posterior lip of the cervix to apply gentle countertraction. If the pipelle stilldoes not pass through the os, a uterine sound can be used in an attempt to dilatethe os. When resistance to the pipelle still is encountered, the procedure should beabandoned because of the danger of creating a false passage through the cervicalos and risk for perforation. In cases in which there is difficulty 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 eval-uating this use of misoprostol, but it has become an accepted technique. The onlysignificant side effects are some uterine cramping and a possible increase in bleed-ing from the uterus. Once the pipelle is in the uterine cavity, usually at a depth of7 to 9 mm, suction is created by withdrawing the piston. While moving the pipellein and out, the cannula is slowly rotated 360◦ so that the sample is taken from awide area of the uterine cavity. To increase the area of sampling, the cannula canbe advanced again into the cavity before it is withdrawn entirely. Once the pipelleis full, another pipelle can be used if there is believed to be a lot more tissue in thecavity. The tissue then is placed in a container of formaline and sent to histologyfor examination.26

The American Heart Association does not recommend antibiotic prophylaxisagainst subacute bacterial endocarditis, because endometrial sampling is unlikelyto cause bacteremia. There are no studies that specifically evaluate the risks.11

Effectiveness. The sensitivity of aspiration sampling in detecting uterine can-cer varies in studies from 67% to 100%, as shown in Table 4.19, 30, 56, 61 The over-all specificity is around 100%.61 In studies by Guido and Ferry et al, the lower sen-sitivities are explained by various factors in the study population. In Guido’s study,5 of the 11 false-negative results were patients in whom the malignancy was con-fined to a polyp. When there is a small focus of malignancy, the pipelle is morelikely to miss it, because it samples a small percentage of the endometrial area.The low sensitivity found in Ferry et al’s study may have resulted from the fact thatall of the patients previously had had a D and C, so much of the tissue in the en-dometrial cavity had been removed already.

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TABLE 4.Sensitivities of Endometrial Pipelle Sampling in Detecting Cancer

Study Sensitivity (%)

Ferry et al19 67Guido et al30 83Stovall et al56 97.5Van Den Bosch et al61 100

Pipelle sampling has been shown in repeated randomized studies to be as ef-fective as a D and C in diagnosing malignancy.29, 46, 57 Its advantages include thatit is lower in cost, it does not require anesthesia, and it easily can be carriedout in the office setting. It does have some limitations, however. There is a 4% to10% chance of cervical stenosis, which prevents insertion of the pipelle into theuterine cavity, and an alternative evaluation technique is needed. Although pipellebiopsies can detect cancer accurately, they are not able to detect any structuralabnormalities such as fibroids and polyps. The biopsies are least sensitive inearly disease and disease confined to polyps. When the biopsy sample is normaland postmenopausal bleeding continues, further evaluation of the endometrium isrecommended.

Hysteroscopy

The advancement of endoscopic techniques has established hysteroscopy asa means to evaluate abnormal uterine bleeding. Hysteroscopy involves direct visu-alization of the endometrium and can be useful when endometrial biopsies are in-conclusive or abnormal bleeding persists in the face of normal endometrial biop-sies. The main advantage of hysteroscopy is direct inspection of any endometrialabnormality that is biopsied. It detects endometrial polyps that can be removedand examined. Hysteroscopy is carried out in the office or the operating room.A flexible fiberoptic cable usually is used with carbon dioxide as the distend-ing medium, which gives clear visualization of the intrauterine cavity. The disad-vantage of office hysteroscopy is that it cannot be used in patients with cervicalstenosis.

Technique. For office hysteroscopy, the patient is advised to take a non-steroidal anti-inflammatory drug 1 hour before the procedure to decrease uter-ine cramping. A paracervical block of lidocaine and vasopressin may be used tolessen pain and bleeding during the procedure.69 Hysteroscopes are available inseveral diameters ranging from 3 to 10 mm. Scopes that are 4 mm and largerhave an operating port through which biopsy forceps can be used. Biopsies canbe taken under direct vision using a larger hysteroscope or, if the hysteroscopeis less than 4 mm, using a pipelle cannula guided by knowledge of the site ofthe abnormality. With the hysteroscope inside the uterine cavity, the fundus is in-spected first. The scope then is rotated to each side while visualizing the ostiaof the fallopian tubes. The lower segment of the uterus and the cervix is exam-ined as the hysteroscope is withdrawn. The entire procedure takes only a fewminutes.3

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Complications. Complications are unusual but include perforation and infec-tion. Perforation most likely will occur when there is difficulty inserting the hys-teroscope because of cervical stenosis. The incidence of infection is probably nogreater than with endometrial biopsy, and there is no evidence to support the useof prophylactic antibiotics. Hysteroscopy has the theoretic concern that malignantcells may be spread into the peritoneal cavity, but there is no evidence to substanti-ate this concern

Effectiveness. Gimpleson and Rappold compared the diagnostic abilities ofhysteroscopy and directed biopsy with those of dilatation and curettage. Hys-teroscopy with directed biopsy was the superior method, with a false-negative rateof 3%.25 In a smaller study, Brooks and Serden also found that hysteroscopy withdirected biopsy was superior to curettage.6 Hysteroscopy has superceded dilata-tion and curettage as the gold standard by which other methods of endometrialassessment are compared.

Endovaginal Ultrasonography

Over the past 12 years, EVUS or transvaginal ultrasound increasingly has beenused to assess the endometrium. A vaginal probe gives better visualization of theendometrium than does transabdominal imaging and allows measurement of en-dometrial thickness. The accuracy of EVUS is highly operator dependent, andradiologists and gynecologists performing EVUS should have experience and ex-pertise with interpretation of the image. Many studies have been published thatcompare the measured thickness of the endometrium with the histopathologic di-agnosis in an attempt to determine the endometrial thickness below which the riskfor cancer is acceptably small.14, 18, 27, 45 In the Nordic trial,36 the largest study todate, 1168 women with postmenopausal bleeding had an EVUS and subsequentcurettage. No uterine cancer was found among postmenopausal women who hadan endometrial thickness of 4 mm or less. If this set point had been used to de-termine the necessity of an endometrial biopsy, 46% of the endometrial biopsieswould not have been necessary. In this trial, the percentage of women with en-dometrial carcinoma increased in a linear fashion with increasing endometrialthickness. Some studies, however, have shown that uterine cancers occasionallywill 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 theaccuracy of EVUS in diagnosing endometrial abnormalities in women with post-menopausal bleeding.54 The analysis included prospective studies that evaluatedEVUS before obtaining an endometrial tissue sample. The meta-analysis included5892 women with a mean age of 61. The prevalence of uterine cancer was 13%. Theprevalence of endometrial polyps and hyperplasia was 40%. The results showedthat with a normal endometrial thickness of 4 mm or less and a pretest probabil-ity of 10%, the probability of cancer following a normal EVUS is 1%. Table 5 showsthe sensitivities and specificities of various thickness thresholds for endometrialdisease. Endometrial thicknesses of 4 and 5 mm have sensitivities for uterine can-cer of 96%, although the specificity of a 5-mm thickness is slightly higher. Thelower the endometrial thickness cutoff point used to define an abnormal thick-ness, the higher the number of false-positive tests and subsequent normal histo-logic findings.

There is only one study, which looked at follow-up of women with post-menopausal bleeding, and an endometrial thickness of less than 4 mm detected byEVUS.31 This study of expectant management showed that none of the women de-veloped cancer over 1 year of follow-up. An endometrial thickness of over 4 mm

TABLE 5.Summary of Sensitivity and Specificity for Endometrial Disease and Cancer Using Different Endovaginal Thickness Measurements toDefine an Abnormal Result

Endometrial Disease∗ Cancer

Threshold No. of Sensitivity %, No. of Specificity %, No. of Sensitivity %, No. of Specificity %,(mm)† Women¶ (95% CI) Women¶ (95% CI) Women¶ (95% CI) Women¶ (95% CI)

3 114 98 (94–100) 121 62 (53–71) 31 100 (89–100) 204 38 (32–45)4§ 1001 91 (89–93) 1756 69 (67–71) 284 96 (93–98) 2422 53 (51–55)5 1306 92 (90–93) 2137 81 (79–83) 457 96 (94–98) 2986 61 (59–63)6‡ 1361 87 (85–89) 1717 82 (80–84) 454 95 (92–97) 2661 55 (53–57)7∗∗ 691 85 (82–88) 1011 90 (88–92) 131 95 (89–98) 442 64 (59–69)8∗∗∗ 381 85 (81–88) 369 80 (75–84) 151 97 (92–99) 530 60 (56–64)

10∗∗∗ 207 66 (59–73) 445 88 (85–91) 51 90 (79–97) 532 79 (75–82)

∗Includes cancer, atypical and complex hyperplasia, and polyps.†Thickness threshold used to define an abnormal test result.¶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 = confidence interval.From Smith-Bindman R, Kerlikowske K, Feldstein VA, et al: Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. JAMA 280:

1510–1517, 1998; with permission.

186

POSTMENOPAUSAL BLEEDING 187

has become the threshold at which further evaluation of the endometrium with anendometrial biopsy is recommended.

Disadvantages. The specificity of EVUS in detecting uterine cancer is lowerthan the specificity of endometrial biopsy because there are other pathologiccauses of a thickened endometrial stripe.

The sensitivity of EVUS compares favorably with office biopsy, although un-der some conditions the sensitivity of EVUS is lower. In obese patients, the view ofthe endometrium may not be clear, especially if the uterus is enlarged. It is also dif-ficult to differentiate intracavity abnormalities, such as polyps, fibroids, and blood,from each other. When there is any evidence of an intrauterine mass detected byEVUS, a biopsy is required.

Saline Infusion Sonography

Saline infusion sonography infuses saline into the uterine cavity duringultrasound to improve the image. The saline separates the two walls of the en-dometrium, allowing their thicknesses to be measured. It also allows the clinicianto evaluate the uterus for intracavity lesions such as fibroids or polyps.

Technique. The ultrasound can be performed transvaginally or transabdom-inally, but usually the transvaginal technique is used because the resultant imageis clearer. Nonsteroidal anti-inflammatory drugs can be given 1 hour before theprocedure; however, pain scores do not drop appreciably.69 A paracervical blockcan be used for pain relief if the procedure is not tolerated. The bladder shouldbe emptied before the procedure, because bladder distension can shift an antev-erted uterus to a retroverted position, making evaluation with the transvaginalprobe difficult. The sterile saline is infused into the uterus through a flexible in-trauterine catheter inserted through the cervix. The ultrasound examination thenis performed.3

Complications. SIS is associated with few complications. In Widrich’s studyof 132 patients comparing hysteroscopy with SIS, there were no complications,and patients felt significantly more pain with hysteroscopy than with SIS.68

In this study, there was no statistically significant difference between SIS andhyteroscopy in the detection of endometrial polyps and cancer. In cases in whichan EVUS shows a thickened endometrium but the endometrial biopsy is normal, anSIS allows more detailed evaluation of the uterine cavity, particularly in detectingintraluminal masses.13 There are no large studies evaluating the accuracy of SIS, sooffice biopsy, EVUS, and hysteroscopy are still the methods of choice.

Cost Analysis of the Evaluationof Postmenopausal Bleeding

Curettage Versus Office Endometrial Biopsy

Historically, curettage was considered the gold standard for diagnosis of post-menopausal bleeding. Analyses now have shown that it is more costly and nomore accurate in diagnosing endometrial abnormalities than office endometrialbiopsy.16

Endometrial Biopsy Versus Endovaginal Ultrasound

Weber et al conducted a study comparing the predicted outcomes and costsof two diagnostic algorithms for the diagnosis of postmenopausal bleeding. They

188 MOUNSEY

compared office endometrial biopsy with EVUS for the initial evaluation. From anextensive Medline search, they concluded that the probability of a nondiagnosticendometrial biopsy was 28% and that of an abnormal or inconclusive vaginal ultra-sound was 55%. Cost analyses showed that vaginal ultrasonography costs slightlyless than office endometrial biopsy when used as the initial test in the evaluation ofpostmenopausal bleeding. Savings were small, however, ranging between $14 and$20 per patient. Vaginal ultrasound is only more cost effective when it has a muchlower cost than endometrial biopsy, because endometrial sampling still is neededin most cases following EVUS.63 In contrast, Creinin suggested that there is ahigher false-negative rate with endometrial biopsy than with EVUS. Patients witha normal endometrial biopsy but continued postmenopausal bleeding need furtherevaluation; 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 ENDOMETRIUMBY FAMILY PRACTICE PHYSICIANS

Most family practice physicians are able to perform an endometrial biopsywith a pipelle in their office, whereas few physicians have the expertise to doEVUS to assess endometrial stripe thickness. Although endometrial biopsy mayhave a slightly higher false-negative rate and a higher cost, it is an appropriate firstchoice for investigation because of its convenience for patients and physicians. Ifbleeding continues and the endometrial biopsy result was equivocal, further inves-tigation with a hysteroscopy should be performed. When EVUS is the first diagnos-tic test selected, an endometrial biopsy needs to be done if the endometrial stripeis over 4 mm thick. If there is continued bleeding and the EVUS demonstrates auterine stripe of 4 mm or less, hysteroscopy should be performed because the neg-ative predictive value of EVUS is not 100%. An algorithm for the management ofpostmenopausal bleeding is shown in Figure 1.

Key Points• Postmenopausal bleeding always should be investigated, because it may be

a sign of endometrial carcinoma.• The commonest cause of postmenopausal bleeding is an atrophic

endometrium.• In a hormone therapy regimen, the addition of continuous or cyclical

progesterone to estrogen provides protection against the development ofendometrial hyperplasia.

• The progression of hyperplasia to carcinoma increases as atypia of thehyperplasia develops. Endometrial hyperplasia without atypia can betreated with progesterone.

• Atypical hyperplasia should be managed by hysterectomy.• In unexplained postmenopausal bleeding, it is essential to evaluate the

endometrium.

POSTMENOPAUSAL BLEEDING 189

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

POSTMENOPAUSAL BLEEDING

Stripe≤ 4 mm

Endometrial biopsy EVUS

Hysteroscopy

ContinuedPMB

Observe

Normal oratrophy

Hyperplasiawith atypia

Hysterectomy

Hyperplasiawithout atypia

Progesteronetreatment for3–6 months

Repeat biopsy

Persistenthyperplasia

Persistenthyperplasia

Progesteronefor 3 months

Repeat biopsy

NormalConsider annual

endometrialbiopsy

Endometrialbiopsy

Stripe> 4 mm

Hysteroscopy

ContinuedPMB

Observe

ACKNOWLEDGMENT

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

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Anne L. Mounsey, MDDepartment of Family Medicine

Primary Care CentreUniversity of Virginia

Lee StreetPO Box 80079

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e-mail: alm2d@virginia.edu