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    Diagnosis & Management ofAbnormal Uterine Bleeding

    Paul H. Taylor, PA-C

    Department of Gyn/Ob

    Emory University

    Atlanta, Georgia

    Dysfunctional UterineBleeding

    Abnormal uterine bleeding without organic cause.

    R/O pregnancy, tumor, infection coagulopathy, andpelvic or systemic disease

    Virtually all women will experience bleeding that sheconsiders abnormal

    Interference with work, home and sex life; causes

    emotional, medical, and functional burdens

    Ineffective management may drain health care and

    financial resources; however, anemia, missed serious

    pathology, and even hysterectomy may result

    Background

    Dysfunctional uterine bleeding (DUB) is the most common

    cause of abnormal vaginal bleeding during a woman's

    reproductive years. The diagnosis of DUB should be usedonly when other organic and structural causes for

    abnormal vaginal bleeding have been ruled out

    DUB comprises one third of all out-patient gynecologic

    visits, is the most common cause of iron-deficiency

    anemia in the developed world

    This lecture focuses on understanding the

    pathophysiology and principles of management

    The Menstrual Cycle

    A normal menst rual cycle occurs every 23-39

    ( average of 29 ) days with menstruation for

    2-7 days. Blood loss ranges from 25-69 mL

    total, with average being 40 ml. This

    represents 8 or fewer soaked pads per daywith usually no more than 2 heavy days.

    Loss of 80 ml or more of blood during a cycle

    is considered excessive

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    The menstrual phase usually lasts 4 days and involves the disintegration

    and sloughing of the functionalis layer of the endometrium. The

    proliferation (follicular) phase extends from day 5 to day 14 of the typical

    cycle. It is marked byendometrial proliferation brought on by estrogen

    stimulation. The estrogen is produced by the developing ovarian

    follicles under the influence of follicle-stimulating hormone (FSH). Cellular

    proliferation of the endometrium is marked, and the length andconvolutedness of the spiral arteries increases. This phase ends as

    estrogen production peaks, triggering the FSH andluteinizing hormone

    (LH) surge. Rupture of the ovarian follicle follows, with release of the ovum

    (ovulation). The secretory (luteal ) phase is marked by production of

    progesterone and less potent estrogens by the corpus luteu m. It extends

    from day 15 to day 28 of the typical cycle. The functionalis layer of the

    endometrium increases in thickness, and the stroma becomes edematous.

    If pregnancy does not occur, the estrogen and progesterone feedbackto the hypothalamus, and FSH and LH production falls. The spiral

    arteries become coiled and have decreased flow. At the end of the cycle,

    they alternately contract and relax, causing a breakdown of the

    functionalis layer and menses to begin.

    The Menstrual Cycle

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    Approximately 90% of DUB results from anovulation, and

    10% occur with ovulatory cycles. During an anovulatory

    cycle, the corpus luteum fails to form, which causes failureof normal cyclical progesterone secretion ( low

    progesterone levels ). This results in continuous

    unopposed production of estradiol, stimulating overgrowth

    of the endometrium. Without progesterone, the

    endometrium proliferates and eventually outgrows itsvascular support, leading to necrosis: conditions such as

    polycyst ic ovarian syndrome and obesity stimulate

    continual growth.

    Conversely, there may be minimal bleeding if the estrogenlevel is not high enough to stimulate endometrial growth,

    as in amenorrhea associated with stress exercise, orweight loss.

    Etiology of DUB

    In ovulatory DUB,women have heavy menstrual

    bleeding, yet no serious cause is found. They

    have normal levels of progesterone and other

    hormones. Experts do not fully understand

    ovulatory dysfunctional bleeding, and whatcauses it. Ovulatory DUB is thought to be

    secondary to defects in local hemostasis?

    Ovulatory DUB

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    Prevalence of Ovulatory DUB

    In the US:As many as 10% of women with

    normal ovulatory cycles reportedly have

    experienced DUB. Obese females tend to have

    irregularities in their menstrual cycles due to non-ovarian endogenous production of estrogen often

    related to their degree of adipose tissue. This

    usually results in prolonged cycles of

    amenorrhea that alternate with cycles of

    metrorrhagia ormenometrorrhagia

    Dysfunctional Bleeding from the UterusCan be Described as Follows:

    Menorrhagia - Prolonged (>7 d) or excessive (>80 mL daily)

    uterine bleeding occurring at regular intervals

    Metrorrhagia - Uterine bleeding occurring at irregular and morefrequent than normal intervals

    Menometrorrhagia- Prolonged or excessive uterine bleeding

    occurring at irregular and more frequent than normal intervals

    Intermenstrual bleeding (spotting) - Uterine bleeding of variable

    amounts occurring between regular menstrual periods

    Polymenorrhea - Uterine bleeding occurring at regular intervals of

    less than 21 days

    Oligomenorrhea - Uterine bleeding occurring at intervals of 35

    days to 6 months

    Amenorrhea - No uterine bleeding for 6 months or longer

    Estrogen Breakthrough Bleeding

    Anovulatory cycles have no corpus luteal formation.

    Progesterone is not produced. The endometrium

    continues to proliferate under the influence of

    unopposed estrogen.

    Eventually, this out-of-phase endometrium is shed in

    an irregular manner that might be prolonged and

    heavy. This pattern is known as estrogenbreakthrough bleeding and occurs in the absence of

    estrogen decline

    Estrogen Withdrawal Bleeding

    This frequently occurs in women approaching the end ofreproductive life.

    In older women, the mean length of menstrual cycle isshortened significantly due to aberrant follicular recruitment,resulting in a shortenedproliferative phase. Ovarian follicles inthese women secrete less estradiol. Fluctuating estradiol levelsmight lead to insufficient endometrial proliferation with irregularmenstrual shedding. This bleeding might be experienced aslight, irregular spotting.

    Eventually, the duration of theluteal phase shortens, and,finally, ovulation stops. Dyssynchronous endometrial histologywith irregular menstrual shedding and eventual amenorrhearesult

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    Oral contraceptives, progestin-onlypreparations, or postmenopausal steroid

    replacement therapy

    Treatment with oral contraceptives, progestin-only preparations, or

    postmenopausal steroid replacement therapy might be associated

    withiatrogenicallyinduced uterine bleeding.

    Progesterone breakthrough bleeding occurs in the presence of an

    unfavorably high ratio of progestin to estrogen.

    Intermittent bleeding of variable duration can occur with progesti n-

    only oral contraceptives, depo-medroxyprogesterone, and depo-

    levonorgestrel .

    Progesterone withdrawal bleeding can occur if the endometrium

    initially has been primed with endogenous or exogenous estrogen,

    exposed to progestin, and then withdrawn from progestin. Such apattern is seen in cyclic hormonal replacement therapy

    Adolescents with DUB

    The primary defect in the anovulatory bleeding of adolescents is

    failure to mount an ovulatory luteinizing hormone (LH) surge in

    response to rising estradiol levels. Failure occurs secondary to delayed

    maturation of the hypothalamic-pituitary axis. Because a corpus luteum

    is not formed, progesterone levels remain low.

    The existing estrogen primed endometrium does not become

    secretory. Instead, the endometrium continues to proliferate under the

    influence of unopposed estrogen. Eventually, this out-of-phase

    endometriumis shed in an irregular manner that might be prolonged

    and heavy, such as that seen in estrogen breakthrough bleeding.

    Climacteric

    Anovulatory bleeding in menopausal

    transition is related to declining ovarian

    follicular function.

    Estradiol levels will vary with the quality and

    state of follicular recruitment and growth. In patients who are 40 years or older, the number and quality of

    ovarian follicles diminishes. Follicles continue to develop but donot produce enough estrogen in response to FSH to trigger

    ovulation. The estrogen that is produced usually results in late-

    cycle estrogen breakthrough bleeding

    Bleeding might be light or heavy depending

    on the individual cycle response.

    Endometrial Cancer

    One of the most important goals in work-up of DUB is

    to rule out endometrial cancer, especially in older

    women. Development of endometrial cancer is

    related to estrogen stimulation and endometrial

    hyperplasia.

    Bleeding prevalence may be as high as 1/3 of cases,and the presence of uterine myomasshould NOT

    delay appropriate work-up.

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    Risk Factors for Endometrial Cancer Age - 75% of cases occur after menopause

    with peak incidence in the late 60s.

    Obesity - especially upper body fat. This maybe secondary to increased estrogen production and bioavailability.

    Polycystic ovary disease.

    Unopposed exogenous estrogen.

    When progestins are added (oral contraceptivesor with replacement therapy), relative risk is lessthan for the general population.

    Diabetes (all types grouped).

    Personal or family historyof ovarian or breastcancer. Women who are overweight and havehad breast cancer are at even greater risk.

    Nullipari ty.

    Late menopause.

    Tamoxifen therap y- Use for greater than one

    year is an independent risk factor.

    Mortality/Morbidity

    DUB in itself is rarely fatal, distinguishing this presentation from that ofendometrialcancer is important. Development of endometrialcancer is related to estrogenstimulation and endometrial hyperplasia.

    Race: DUB has no predilection for race; however, black women have a higherincidence of leiomyomas and higher levels of estrogen. As a result, they are prone toexperiencing more episodes of abnormal vaginal bleeding.

    Age: DUB is most common at the extreme ages of a woman's reproductive years,either at the beginning or near the end

    Most severecases of DUB occur in adolescent girls during the first 18 months afterthe onset of menstruation, when their immature hypothalamic-pituitary axis may fail torespond to estrogen and progesterone, resulting in anovulation.

    In the perimenopausal period, DUB may be an early manifestation of ovarian failurecausing decreased hormone levels or responsiveness to hormones, thus also leading toanovulatory cycles.

    Physical Examination

    Initial evaluation should be directed at assessing

    patient's volume status and degree of anemia. Examinefor pallor and absence of conjunctival vessels to gauge

    anemia.

    Patients who are hemodynamicallystable require a

    pelvic speculum and bimanual examination to define the

    etiology of vaginal bleeding. The examination should

    look for the following:

    Trauma to the vaginal walls or cervix

    Foreign body

    Cervical or vaginal lacerationBleeding from the os

    Physcial Exam Findings

    Uterine or ovarian structural abnormalities may be noted on bimanual

    examination, but a negative examination is insensitive for finding

    abnormalities.

    Patients with hematologic pathology also may have cutaneous

    evidence of bleeding diathesis. Physical findings include petechiae,purpura, and mucosal bleeding (eg, gums) in addition to vaginal bleeding.

    Patients with liver disease that has resulted in a coagulopathymay

    manifest additional symptomatolo gybecause of abnormal hepatic

    function. Evaluate patients for spider angioma, palmar erythem a,

    splenomegaly, ascites, jaundice, and asterixis.

    Women with polycystic ovary disease present with signs of

    hyperandrogenism, including hirsutism, obesity, and palpable enlarged

    ovaries.

    Hyperactive and hypoactive thyroid can cause menstrual

    irregularities. Patients may have varying degrees of characteristic vital

    sign abnormalities, eye findings, tremors, changes in skin textu re, andweight change. Goiter may be present

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    Etiology of DUBthrombocytopenia, hypothyroidism, hyperthyroidism, Cushing disease, liverdisease, hypertension, diabetes mellitus, and adrenal disorders

    Pregnancy may be associated with vaginal bleeding

    Trauma to the cervix, vulva, or vagina may cause abnormal bleeding.

    Carcinomas of the vagina, cervix, uterus, and ovaries always mus t be considered

    Other causes of DUB include structural disorders, such as functi onal ovarian cysts,cerviciti s, endometritis, salpingitis, and leiomyomas.

    Polycystic ovary disease, vaginal infection, polyps,ectopicpregnancy, hydatidiformmole, blood dyscrasias, excessive weight gain, increased exercise performance, orstressmay also contribute to DUB.

    Breakthrough bleeding may occur in patients taking oral contraceptivesThe most common drug interactions withOCPs occur with phenobarbital, carbamazepine,some penicillins, tetracycline, and trimethoprim-sulfamethoxazole.

    An iatrogeniccause of DUB is the use ofprogestin-only compounds for birth control.Medroxyprogesteroneacetate (Depo-Provera), a long-acting injection given every 3months, inhibits ovulation.

    Contraceptive intrauterine devices (IUDs) can cause variable vaginal bleeding for thefirst few cycles after placement and intermittent spotting subsequently. The

    progesterone impregnated IUD (Mirena) is associated with less menometrorrhagia andusually results in secondaryamenorrhea

    Causes of Dysfunctional Uterine Bleeding

    EndocrineCushing's diseaseimmature hypothalamin-pituitaryaxishyperprolacinemiahypothyroidismmenopauseobesitypolycystic ovary diseasepremature ovarian failure

    Stuctural lesionsadenomyosiscoagulopathiescondyloma acuminatadysplastic or malignant lesion of thecervix or vaginaendometiosisendometrial canceruterine or cervical polypsuterine leiomyomatatrauma

    InfectionschlamydiagonorrheaPID Medicationshormonal agentslow-dose oral contraceptive pills(OCPs)nonprogestin-containing IUDsnonsteroidal anti-inflammatorydrugs(NSAIDS)Norplant Systemprogestin-only contraceptivetamoxifenwarfarin

    Pregnancyectopic pregnancyincomplete abortionpregnancy complications

    Differential Diagnosis

    Abdominal Trauma,PenetratingAbortion, CompleteAbortion, ComplicationsAbortion, IncompleteAbortion, InevitableAbortion, MissedAbortion, SepticAbortion, Threatened

    Abruptio PlacentaeAnemia, AcuteAnemia, ChronicEndometriosis

    Hypothyroidism andMyxedema ComaIdiopathic ThrombocytopenicPurpuraOvarian CystsOvarian TorsionPelvic Inflammatory DiseasePregnancy, EctopicPregnancy, PostpartumHemorrhagePregnancy, TraumaShock, HemorrhagicShock, HypovolemicThrombocytopenic Purpura

    Other Problems to be Considered:

    Advanced liver d isease

    Anabolic steroids

    Cervical cancer

    Cervicitis

    Cervical polyps

    CirrhosisEndometrial cancer

    Leiomyoma

    Leukemia

    Postcoital bleeding

    Salpingitis

    Thrombocytopenia

    Uterine cancer

    UterineleiomyomasVaginal lacerations

    Von Willebranddisease

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    Laboratory Tests

    urine pregnancy test

    CBC

    PT/PTT

    Pap smear*

    FSH / LHliver function tests

    TSH

    Prolactinlevel

    DHEASO4 Dehydroepiandrosterone

    sulfate

    Rule out pregnancy

    Anemia?

    coagulpathycervical cancer

    > 40 IU/L menopausal?Liver disease

    Thyroid disease

    pituitary adenoma

    polycystic ovary

    disease

    Presentation Suggestive of

    Hyper-androgenism?

    Addi tional Labs: thyrotropin, free T4,testosterone, 17-OH progesterone, andfasting insulin and glucose

    Anovulation is most common, which resultsfrom a disturbance in the hypothalamic-pituitary-ovarian axis.

    Ovulatory DUB is thought to be secondary todefects in local hemostatis, no disturbance inthe HPO axis occurs, nor are thereabnormalities in the steroid hormone profiles

    Imaging Studies: Ultrasound

    Generally, patients with DUB can be managed appropriately

    without the use of expensive imaging studies.

    In obese patients withsuboptimal pelvic examination or in patients

    with suspected ovarian tumors, pelvic ultrasound evaluation might

    be most helpful.

    Pelvic ultrasound also might be confirmatory for polycystic ovaries(PCO). The absence of the traditional string of pearls appearance

    does not exclude polycystic ovarian syndrome diagnosis.

    Confirmation of PCO by imaging is not mandatory for the

    diagnosis.

    Ultrasound can be used to examine the status of the endometrium.

    Endometrial hyperplasia, endometrial carcinoma, endometrial

    polyps, and uterine fibroids can be identified easily by thistechnology

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    Endometrial Biopsy

    Risk of endometrial cancer increases with

    age, ACOG recommends endometrial biopsy

    in all women > 35 who have a change in

    bleeding pattern

    Biopsy is also indicated for patients aged 18-

    35 years with risk factors for endometrial

    cancer; such as being anovulatory for at least

    one year

    Dilation & Curettage withHysteroscopy

    If contraindications to endometrial sampling such as acute PID, cervical stricture, or bleeding

    disorders, or if EMS was inadaquate, or issymptoms continue despite medical management

    This procedure is expensive and invasive, but isconsidered the Gold Standard to obtainhistopathologic diagnosis

    Visualize endometrium polyps, lesions, etc

    It is sometimes avoided in adolescents because ofconcerns about possible infertility. Repeatedprocedures may result in intrauterine adhesions.

    Treatment

    There are medical, surgical, and

    combined methods of treating DUB.

    The choice of approach depends on the

    cause, severity of bleeding, patient'sfertility status, need for contraception,

    and treatment options available at the

    care site

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    Treatment GoalsIn women of childbearing age, treatment is aimed at

    achieving regular menstrual cycles, prevent future

    episodes, replenish iron stores, prevent serious long

    term consequences of anovulation, preserve desired

    fertility.

    Oral contraceptives or progestogen therapy are

    frequently used for this purpose. If anemia is present,iron supplementation may be recommended. If

    pregnancy is desired, ovulation induction may be

    attempted with medication.

    Women whose symptoms are severe and resistant to

    medical therapy may choose surgical treatmentsinclud ing endometrial ablation (a procedure that burns orremoves the linin of the uterus or h sterectom

    Drug Therapy

    Acute Heavy Bleeding

    Cases of acute, heavy, uncontrolled bleeding should

    be treated with intravenous estrogen, 25mg every 4

    hours, to a maximum of 3 doses or until bleeding stops.

    Oral conjugated estrogenalso may be given in

    divided doses up to 10mg per day, although this

    regimen often causes nausea and vomiting

    Oral Contraceptives 3-4 tabs of monophasic pill per

    day ( 35 mcg EE tab ), in one week one pill per dayuntil pack finished

    Upon completion, use cyclic OCPs for the following 3-4

    cycles for endometrial support

    Treatment Regimens

    Chronic Anovulatory DUB

    Cyclic Regulation Oral Medroxyprogesterone 5-10 mg/d x 5-14 days month

    Oral Norethindrone acetate 1- 10 mg x 5-14 days per month

    Oral Norethindrone 5-15 mg/d x 10 days per month

    Oral micronized progesterone 200-300 mg/d x 10-12 days per

    month

    Contraception IM Medroxprogestrone 150mg q 3 months ( monthly? )

    Levonorgestrel IUS

    Combined Oral contraceptives or Transdermal patch

    Induction of Ovulation

    Clomiphene 50 mg/d x 5 days

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    Treatment RegimensChronic Ovulatory DUB / Menorrhagia

    Reduction in amount and duration of menstrual flow Ibuprofen 800 mg Q 8 hr

    Naproxen sodium 275 mg q 6hr after loading dose of 550 mg

    Diclofenac, indomethacin, etc..

    Mefenamic (Ponstel ) FDA approved for menorrhagia

    500 - 1,500 mg/d in divided doses

    Reduction in menstrual flow and contraception Depo Provera and Mirena IU S

    These drugs are safe for long-term usage, and thelong-term effects are well studied. Aspirin does notappear to be effective

    In cases of moderately heavy DUB, oral contraceptive pills (OCPs) may be given up to fourtimes a day for 5 to 7 days or until bleeding stops. 2, 3 The rest of the pills may then be takenonce a day until the pack is finished and withdrawal bleeding occurs. In anovulatory patients, thisis followed by an additional 2 months of OCPs as usually prescribed. This regimen will stabilizethe epithelium, slough excessive build-up, and provide contraception. OCPs may also be startedinitially at one pill every day in milder cases of DUB. 2 - 4, 7 If the patient is already onOCPs andexperiencing DUB, a change to a higher estrogen activity OPC is indicated. 3Medroxyprogesterone (Provera) at 10mg PO per day for 10 to 12 days has traditionally beenone of the most common methods used to control DUB. This "medical curettage" works well tocorrect midcyclespotting and when the EMB demonstrates proliferative endometruim.1 - 3 Depo-medroxyprogesterone (150mg) or progesterone in oil (100 - 200mg) may be givenintramuscularly to achieve similar effects. 2, 3 The progestin-only contraceptive pills also workwell and, like depo-Provera, have the added benefit of providing contraception.3 Breasttenderness and mood swings are possible side-effects of therapy. These regimens workespecially well with chronic or milder acute DUB. Progestin-containing IUDs, together with oralor transdermal estrogen, may control DUB in postmenopausal patients.26, 27Nonsteroidal anti-inflammatory drugs (NSAIDS) can decrease DUB, probably throughinihibition of prostaglandin synthesis. 27 Naproxen (Naprosyn) 500mg twice daily, mefenamic

    acid (Ponstel) 500mg three times daily, or ethamsylate500mg four times a day has been shownto decrease menstrual flow. 28- 30 Once bleeding is controlled, NSAIDS need only be usedduring menstruation.27

    Refractory to Conventional Treatment

    The androgenic synthetic steroid danazol(Danocri ne), which is

    traditionally used to treat endometriosis, can be used to treat DUB.

    Similarly, theGnRH agonistsgoserelin acetate (Zoladex ,)

    leuprolide acetate (L upron,) or nafarelin acetate (Syneral) inducea hypogonadotropic state which stops dysfunctional bleeding. ,

    They all produce hypogonadism and induce

    ammenorrhea. Because of their side effects, these drugs are used

    when hormonal methods have failed or are contraindicated. These

    agents are primarily used to thin the endometrium prior to surgical

    intervention.

    Research involving estrogen and progesterone "add back" therapy

    may provide a means of overcoming the long- and short-term side-

    effects. DUB will recur in up to 50% of women treated.

    Endometrial AblationKeeping Uterus / Loss of FertilityNeodymium:yttrium-aluminum-garnet (Nd:YAG) laserendometrial ablation

    Success rate of approximately 85% and is more effective in patents over the age of 35years. Amenorrheamay occur in 29% of patients. There is some concern that cancerscould be missed, since no tissue is available for pathologic study. Possible risks includefluid overload, endometritis, and uterine perforation. Laser equipment is expensive andrequires special safety precautions.

    Hysteroscopic transcervicalresection of the endometrium(TCRE)makes use of anelectrocautery loop or ball to remove or coagulate theendometrium to stop DUB. It mayreduce the need for hysterectomy by up to 90%, and has been shown to have a loweroverall procedure cost (including retreatmentcosts and eventual hysterectomies) thanimmediate hysterectomy for more severe DUB. The goal is to ablate theendometriumand encourage endometrial adhesions resulting in hypo-or amenorrhea. Thehysteroscope is considerably less expensive to buy and maintain than the las er butcarries the risks of fluid overload, endometritis, and uterine perforation.

    The enometriummay also be hysteroscopicallyablated via the insertion of a thermaluterine balloon. The system consists of a control system attached to a 16cm by 5mmcatheter with a latex balloon on the end that houses a heating element. A steril e5%dextrose solution is instilled until the pressure reaches between 160 and180mmHg. The solution is heated to 87 degrees C. for 8 minutes and then the device isremoved. The treatment has been found to be as efficacious as roller-ball ablation withless complications

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    Hysterectomy

    Hysterectomy remains the most absolutely curative

    treatment for DUB. Elective hysterectomy has a mortality

    rate of six per 10,000 operations.

    One randomized study found that hysterectomy was

    associated with more morbidity and much longer healing

    times than endometrial ablation.

    Another recent study fo und that sexual fu nctionin g improv edoverall after hysterectomy with an increase in sexual activity

    and a decrease in problems with sexual functioning.

    Summary DUB

    There is a wide range of normal menstruation duringthe reproductive years, this fact alone may alleviatestress and unnecessary visits to Gyn

    Educating the patient about underlying causes ofDUB and the rational for treatment is a challenge

    The majority of DUB is anovulatory Hyper- estrogen states increase the risk of developing

    endometrial cancer

    Women of all ages should be assessed forendometrial carcinoma risk factors and educatedappropriately