Abnormal Uterine Bleeding JANET R. ALBERS, M.D., SHARON K. HULL, M.D., and ROBERT M. WESLEY, M.A.

, Southern Illinois University School of Medicine, Springfield, Illinois Am Fam Physician. 2004 Apr 15;69(8):1915-1926. Patient Information Handout Abnormal uterine bleeding is a common presenting symptom in the family practice setting. In women of child-bearing age, a methodical history, physical examination, and laboratory evaluation may enable the physician to rule out causes such as pregnancy and pregnancy-related disorders, medications, iatrogenic causes, systemic conditions, and obvious genital tract pathology. Dysfunctional uterine bleeding (anovulatory or ovulatory) is diagnosed by exclusion of these causes. In women of childbearing age who are at high risk for endometrial cancer, the initial evaluation includes endometrial biopsy; salineinfusion sonohysterography or diagnostic hysteroscopy is performed if initial studies are inconclusive or the bleeding continues. Women of childbearing age who are at low risk for endometrial cancer may be assessed initially by transvaginal ultrasonography. Post-menopausal women with abnormal uterine bleeding should be offered dilatation and curettage; if they are poor candidates for general anesthesia or decline dilatation and curettage, they may be offered transvaginal ultrasonography or saline-infusion sonohysterography with directed endometrial biopsy. Medical management of anovulatory dysfunctional uterine bleeding may include oral contraceptive pills or cyclic progestins. Menorrhagia is managed most effectively with nonsteroidal anti-inflammatory drugs or the levonorgestrel intrauterine contraceptive device. Surgical management may include hysterectomy or less invasive, uterus-sparing procedures. Abnormal uterine bleeding is a common but complicated clinical presentation. One national study1 found that menstrual disorders were the reason for 19.1 percent of 20.1 million visits to physician offices for gynecologic conditions over a two-year period. Furthermore, a reported 25 percent of gynecologic surgeries involve abnormal uterine bleeding.2 Except for self-limited, physiologic withdrawal bleeding that occurs in some newborns, vaginal bleeding before menarche is abnormal.3 In women of child-bearing age, abnormal uterine bleeding includes any change in menstrual-period frequency or duration, or amount of flow, as well as bleeding between cycles. 4 (Amenorrhea, or the cessation of menses for six months or more in nonmenopausal women, is beyond the scope of this article.) In postmenopausal women, abnormal uterine bleeding includes vaginal bleeding 12 months or more after the cessation of menses, or unpredictable bleeding in postmenopausal women who have been receiving hormone therapy for 12 months or more.5

This article presents a practical approach to determining the cause of abnormal uterine bleeding and briefly reviews medical and surgical management. Etiology and Evaluation of Abnormal Uterine Bleeding BEFORE MENARCHE Malignancy, trauma, and sexual abuse or assault are potential causes of abnormal uterine bleeding before menarche. A pelvic examination (possibly under anesthesia) should be performed, because a reported 54 percent of cases involve focal lesions of the genital tract, and 21 percent of these lesions may be malignant.3 CHILDBEARING YEARS The menstrual cycle has three phases. During the follicular phase, follicle-stimulating hormone levels increase, causing a dominant follicle to mature and produce estrogen in the granulosa cells. With estrogen elevation, menstrual flow ceases, the endometrium proliferates, and positive feedback is exerted on luteinizing hormone (LH), resulting in the ovulatory phase. During the luteal phase, progesterone elevation halts proliferation of the endometrium and promotes its differentiation; progesterone production by the corpus luteum diminishes, causing endometrial shedding, or menstruation. A menstrual cycle of fewer than 21 days or more than 35 days or a menstrual flow of fewer than two days or more than seven days is considered abnormal.6 (pp20138)

Pregnancy is the first consideration in women of childbearing age who present with abnormal uterine bleeding (Table 1).7,8 Potential causes of pregnancy-related bleeding include spontaneous pregnancy loss (miscarriage), ectopic pregnancy, placenta previa, abruptio placentae, and trophoblastic disease. Patients should be questioned about cycle patterns, contraception, and sexual activity. A bimanual pelvic examination (seeking uterine enlargement), a beta-subunit human chorionic gonadotropin test, and pelvic ultrasonography are useful in establishing or ruling out pregnancy and pregnancy-related disorders. Next, iatrogenic causes of abnormal uterine bleeding should be explored. Bleeding may be induced by medications, including anticoagulants, selective serotonin reuptake inhibitors, antipsychotics, corticosteroids, hormonal medications, and tamoxifen (Nolvadex). Herbal substances, including ginseng, ginkgo, and soy supplements, may cause menstrual irregularities by altering estrogen levels or clotting parameters.9

Abnormal Uterine Bleeding in Women of Childbearing Age

Further Evaluation Based on Risk Factors for Endometrial Cancer Further evaluation of abnormal uterine bleeding depends on the patient's age and the presence of risk factors for endometrial cancer, which include anovulatory cycles, obesity, nulliparity, age greater than 35 years, and tamoxifen therapy. 17,18 Initially, medical management is recommended for premenopausal women at low risk for endometrial carcinoma who are diagnosed with presumed dysfunctional uterine bleeding. Diabetes is a demonstrated risk factor for endometrial cancer. 17 Women with long or irregular cycles are at risk for developing type 2 diabetes and therefore should undergo diabetes screening.19

Endometrial cancer is rare in 15- to 18-year-old females.18 Therefore, most adolescents with dysfunctional uterine bleeding can be treated safely with hormone therapy and observation, without diagnostic testing.20 The risk of developing endometrial cancer increases with age.18 The overall incidence of this cancer is 10.2 cases per 100,000 in women aged 19 to 39 years. The incidence more than doubles from 2.8 cases per 100,000 in those aged 30 to 34 years to 6.1 cases per 100,000 in those aged 35 to 39 years. In women aged 40 to 49 years, the incidence of endometrial carcinoma is 36.5 cases per 100,000. Thus, the American College of Obstetricians and Gynecologists recommends endometrial evaluation in women aged 35 years and older who have abnormal uterine bleeding. 21 [SOR C, consensus guideline] Endometrial evaluation (including imaging and tissue sampling) for subtle genital tract pathology is recommended in patients who are at high risk for endometrial cancer and in patients at low risk who continue bleeding abnormally despite medical management.21

Endometrial hyperplasia is a condition of excessive proliferation of the cells of the endometrium, or inner lining of the uterus. Most cases of endometrial hyperplasia result from high levels of estrogens, combined with insufficient levels of the progesterone-like hormones which ordinarily counteract estrogen's proliferative effects on this tissue. This may occur in a number of settings, including obesity, polycystic ovary syndrome, estrogen producing tumours (e.g. granulosa cell tumour) and certain formulations of estrogen replacement therapy. Endometrial hyperplasia is a significant risk factor for the development or even coexistence of endometrial cancer, so careful monitoring and treatment of women with this disorder is essential.

CLASSIFICATION Like other hyperplastic disorders, endometrial hyperplasia initially represents a physiological response of endometrial tissue to the growth-promoting actions of estrogen. However, the gland-forming cells of a hyperplastic endometrium may also undergo changes over time which predispose them tocancerous transformation. Several histopathology subtypes of endometrial hyperplasia are recognisable to the pathologist, with different therapeutic and prognostic implications.[1]

Endometrial hyperplasia (simple or complex) - Irregularity and cystic expansion of glands (simple) or crowding and budding of glands (complex) without worrisome

changes in the appearance of individual gland cells. In one study, 1.6% of patients diagnosed with these abnormalities eventually developed endometrial cancer.[2]

Atypical endometrial hyperplasia (simple or complex) - Simple or complex architectural changes, with worrisome (atypical) changes in gland cells, including cell stratification, tufting, loss of nuclear polarity, enlarged nuclei, and an increase in mitotic activity. These changes are similar to those seen in true cancer cells, but atypical hyperplasia does not show invasion into the connective tissues, the defining characteristic of cancer. The previously mentioned study found that 22% of patients with atypical hyperplasia eventually developed cancer.[2]

DIAGNOSIS Diagnosis of endometrial hyperplasia can be made by endometrial biopsy which is done in the office setting or through curettage of the uterine cavity to obtain endometrial tissue for histopathologic analysis. A workup for endometrial disease may be prompted by abnormal uterine bleeding, or the presence of atypical glandular cells on a pap smear.[3]

Treatment of endometrial hyperplasia is individualized, and may include hormonal therapy, such as cyclic or continuous progestin therapy, or hysterectomy.[3]

PAP SMEAR TEST

The Papanicolaou test (also called Pap smear, Pap test, cervical smear, or smear test) is a screening test used to detect potentially pre-cancerous and cancerous processes in the endocervical canal (transformation zone) of the female reproductive system. Changes can be treated, thus preventing cervical cancer. The test was invented by and named after the prominent Greek doctor Georgios Papanikolaou. In taking a Pap smear, a speculum is used to open the vaginal canal and allow the collection of cells from the outer opening of the cervix of the uterusand the endocervix. The cells are examined under a microscope to look for abnormalities. The test aims to detect potentially pre-cancerous changes (called cervical intraepithelial neoplasia (CIN) or cervical dysplasia), which are usually caused by sexually transmitted human papillomaviruses. The test remains an effective, widely used method for early detection of pre-cancer and cervical cancer. The test may also detect infections and abnormalities in the endocervix and endometrium.

In general, in countries where Pap smear screening is routine, it is recommended that females who have had sex seek regular Pap smear testing. Guidelines on frequency vary from every three to five years.[1][2][3] If results are abnormal, and depending on the nature of the abnormality, the test may need to be repeated in six to twelve months. [4] If the abnormality requires closer scrutiny, the patient may be referred for detailed inspection of the cervix by colposcopy. The patient may also be referred for HPV DNA testing, which can serve as an adjunct to Pap testing. Additional biomarkers which may be applied as ancillary test with Pap test are evolving.[5]

TYPE OF SCREENING

Conventional PapIn a conventional Pap smear, samples are smeared directly onto a microscope slide after collection. Liquid based cytologyThe Pap smear sample is put in a bottle of preservative for transport to the laboratory, where it is then smeared on the slide.

In addition, an HPV test may be performed either as indicated for abnormal Pap results, or in some cases dual testing is done, where both a Pap smear and HPV test are done. For information on other cervical screening tests and Human Papillomavirus testing, see cervical screening. ndications Summary of pap test indications woman's characteristic indication rationale HPV usually transmitted by sexual contact[2] more harms than benefits[6][7]

never had sexual contact no test under age 21, regardless no test of sexual history

age 2025 until age 50 60

test every 3 5 years if broad recommendation[2][8] results normal no further testing recommendation of USPSTF, ACOG,ACS and ASCP;[1][2][9][10] harms of screening after hysterectomy

over age 65; history of normal tests

had total hysterectomy for no further non-cancer disease

cervixremoved had partial hysterectomy cervix remains has received HPV vaccine post-operative transgender woman

testing continue testing as normal continue testing as normal no test

outweigh the benefits[6][7]

vaccine does not cover all cancer-causing types of HPV[8] the neo-vagina does not contain a cervix and cannot be evaluated with a pap smear

Screening guidelines vary from country to country. In general, screening starts about the age of 20 or 25 and continues until about the age of 50 or 60.[9] Screening is typically recommended every three to five years, as long as results are normal. [2][8] Women should wait a few years after they first have intercourse before they start screening, and should not be screened before age 21. American Congress of Obstetricians and Gynecologists (ACOG) and others recommend starting screening at age 21 (since that is a few years after initial sex for most American women). [1][11] Many other countries wait until age 25 or later to start screening. For instance, some parts of Great Britain start screening at age 25. Most women who contract HPV do so soon after becoming sexually active. [3][citation needed][dead link] It takes an average of a year, but can take up to four years, for a woman's immune system to control the initial infection. Screening during this period may show this immune reaction and repair as mild abnormalities, which are usually not associated with cervical cancer, but could cause the woman stress and result in further tests and possible treatment. Cervical cancer usually takes time to develop, so delaying the start of screening a few years poses little risk of missing a potentially precancerous lesion. For instance, screening women under age 25 does not decrease cancer rates under age 30.[12] There is little or no benefit to screening women who have not had sexual contact. For example, United States Preventive Services Task Force (USPSTF) recommends waiting at least three years after first sex.[2] HPV can be transmitted in sex between women, so women who have only had sex with other women should be screened, although they are at somewhat lower risk for cervical cancer.[13] Guidelines on frequency of screening varytypically every three to five years for those who have not had previous abnormal smears.[2][8] Some older recommendations suggested screening as frequently as every one to two years, however there is little evidence to support such frequent screening; annual screening has little benefit but leads to greatly increased cost and many unnecessary procedures and treatments.[1] It has been acknowledged since before 1980 that most women can be screened less

often.[14] In some guidelines, frequency depends on age; for instance in Great Britain, screening is recommended every 3 years for women under 50, and every 5 years for those over. Screening should stop about age 65 unless there is a recent abnormal tests or disease. There is probably no benefit screening women aged 60 or over whose previous tests have been negative.[10] If a woman's last three Pap results were normal, she can stop at age 65, according to the USPSTF, ACOG, ACS and ASCP;[1][2] England's NHS says 64. There is no need to continue screening after a complete hysterectomy for benign disease. Pap smear screening is still recommended for those who have been vaccinated against HPV,[8] since the vaccines do not cover all of the HPV types that can cause cervical cancer. Also, the vaccine does not protect against HPV exposure before vaccination. More frequent Pap smears may be needed to follow-up after an abnormal Pap smear, or after treatment for abnormal Pap or biopsy results, or after treatment for cancer. [edit]Procedure

Cervix in relation to upper part of vagina and posterior portion of uterus. For best results, a Pap test should not occur when a woman is menstruating. However, Pap smears can be performed during a woman's menstrual period, especially if the physician is using a liquid-based test; if bleeding is extremely heavy, endometrial cells can obscure cervical cells, and it is therefore inadvisable to have a Pap smear if bleeding is excessive. Getting a pap smear should not cause pain,[15] but it can if the patient has certain untreated vaginal problems such as cervical stenosis or vaginismus, or if the person performing it is too harsh, or uses the wrong size speculum. The patient should speak up if they are in pain. Many women experience spotting or mild diarrhea afterward. Many health care providers are under the false impression that only sterile water, or no lubricant at all, should be used to lubricate the speculum. This may result in

unnecessary discomfort. A number of studies have shown that using a small amount of water-based gel lubricant does not interfere with, obscure, or distort the PAP smear. Further, cytology is not affected nor some STD testing.[16] The health care worker begins by inserting a speculum into the woman's vagina, which spreads the vagina open and allows access to the cervix. The health care provider then collects a sample of cells from the outer opening or os of the cervix by scraping it with an Aylesbury spatula. An endocervical brush is rotated in the central opening of the cervix. The cells are placed on a glass slide and taken to the laboratory to be checked for abnormalities. A plastic-fronded broom is sometimes used in place of the spatula and brush. The broom is not as good a collection device, since it is much less effective at collecting endocervical material than the spatula and brush.[17] The broom is used more frequently with the advent of liquid-based cytology, although either type of collection device may be used with either type of cytology. The sample is stained using the Papanicolaou technique, in which tinctorial dyes and acids are selectively retained by cells. Unstained cells cannot be seen with a light microscope. Papanicolaou chose stains that highlighted cytoplasmic keratinization, which actually has almost nothing to do with the nuclear features used to make diagnoses now. In some cases, a computer system may prescreen the slides, indicating those that do not need examination by a person or highlighting areas for special attention. The sample is then usually screened by a specially trained and qualified cytotechnologist using a light microscope. The terminology for who screens the sample varies according to the country; in the UK, the personnel are known as cytoscreeners, biomedical scientists (BMS), advanced practitioners and pathologists. The latter two take responsibility for reporting the abnormal sample which may require further investigation. [edit]Automated analysis In the last decade, there have been successful attempts to develop automated, computer image analysis systems for screening.[18] Although, on the available evidence automated cervical screening could not be recommended for implementation into a national screening program, a recent NHS Health technology appraisal concluded that the 'general case for automated image analysis ha(d) probably been made'.[19] Automation may improve sensitivity and reduce unsatisfactory specimens.[20] Two systems have been approved by the FDA and function in highvolume reference laboratories, with human oversight.[citation needed] [edit]Results

Micrograph of a Pap test showing a low-grade intraepithelial lesion (LSIL) and benign endocervical mucosa. Pap stain.

Micrograph of a Pap test showingtrichomoniasis. Trichomonas organism seen in the upper right. Pap stain.

Micrograph of a Pap test showing changes of herpes simplex virus. Pap stain. In screening a general or low-risk population, most Pap results are normal. In the United States, about 23 million abnormal Pap smear results are found each year.[21] Most abnormal results are mildly abnormal (ASC-US (typically 25% of Pap results) or low-grade squamous intraepithelial lesion (LSIL) (about 2% of results)), indicating HPV infection.[citation needed]Although most low-grade cervical dysplasias

spontaneously regress without ever leading to cervical cancer, dysplasia can serve as an indication that increased vigilance is needed. In a typical scenario, about 0.5% of Pap results are high-grade SIL (HSIL), and less than 0.5% of results indicate cancer; 0.2 to 0.8% of results indicate Atypical Glandular Cells of Undetermined Significance (AGC-NOS).[citation needed] As liquid based preparations (LBPs) become a common medium for testing, atypical result rates have increased. The median rate for all preparations with low-grade squamous intraepithelial lesions using LBPs was 2.9% compared with a 2003 median rate of 2.1%. Rates for high-grade squamous intraepithelial lesions (median, 0.5%) and atypical squamous cells have changed little.[22] Abnormal results are reported according to the Bethesda system.[23] They include:

Squamous cell abnormalities (SIL)

Atypical squamous cells of undetermined significance (ASC-US) Low-grade squamous intraepithelial lesion (LGSIL or LSIL) Atypical squamous cells cannot exclude HSIL (ASC-H) High-grade squamous intraepithelial lesion (HGSIL or HSIL) Squamous cell carcinoma

Glandular epithelial cell abnormalities

Atypical Glandular Cells not otherwise specified (AGC or AGC-NOS)

Endocervical and endometrial abnormalities can also be detected, as can a number of infectious processes, including yeast, herpes simplex virus andtrichomoniasis. However it is not very sensitive at detecting these infections, so absence of detection on a Pap does not mean absence of the infection.