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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
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