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CLINICAL OBSTETRICS AND GYNECOLOGY

Volume 55, Number 3, 635–650


r 2012, Lippincott Williams & Wilkins

Office Diagnosis and


Management of
Abnormal Uterine
Bleeding
MING C. TSAI, MD and STEVEN R. GOLDSTEIN, MD
Department of Obstetrics and Gynecology, New York University
School of Medicine, New York, New York

Abstract: Abnormal uterine bleeding is one of the most medicine, accounting for up to 30% of
common presenting complaints encountered in a gyne- outpatient visits to gynecologists. Abnor-
cologist’s office or primary care setting. The availability of
diagnostic tools, such as ultrasound, endometrial sam- mal uterine bleeding (AUB) describes
pling, and diagnostic hysteroscopy has made it possible to bleeding that is excessive or occurs outside
promptly diagnose and treat an increasing number of of normal cyclic menstruation and ac-
menstrual disorders in an office setting. The incorpora- counts for two thirds of hysterectomies.
tion of newer medical therapies: antifibrinolytic drugs, Apart from its social inconvenience, in
shorter hormone-free interval oral contraceptive pills, and
levonorgestrel inserts along with office minimally invasive many cases, AUB can result in anemia,
treatments operative hysteroscopy and endometrial abla- impaired quality of life, and psychological
tions have proven to be powerful therapeutic arsenals to distress. The role of the clinician in a
provide short-term relief of abnormal uterine bleeding, patient who presents with bleeding is
and potentially, avoiding or delaying the hysterectomy. two-fold: first, to exclude endometrial
Key words: abnormal uterine bleeding, conservative
treatment, office diagnosis and management, men- carcinoma in women older than 35 years
strual disorder, minimally invasive procedure, heavy and second, to identify the source of
menstrual bleeding bleeding so it can be stopped or managed.
Because of its broad range of differential
diagnosis, the diagnosis of AUB can be
Introduction quite challenging; despite a detailed his-
Disorders of the menstrual cycle are tory, various blood tests, and a thorough
a common problem in ambulatory pelvic examination, often involving trans-
Correspondence: Ming C. Tsai, MD, Department of Ob-
vaginal ultrasonography (TVS), the cause
stetrics and Gynecology, New York University School of of the bleeding is established in only 50%
Medicine, New York, NY. E-mail: ming.tsai@nyumc.org to 60% of the cases. Deciding on the best
S.R.G. serves as consultant for Cook ObGyn and medical therapy for AUB can be difficult
Phillips Ultrasound. He is on Gyn Advisory board of because of the numerous treatment op-
Shionogi, Bayer and Amgen and Speaker Bureau for
Warner Chilcott and Amgen. The other author declares tions available and complicated by a lack
that he has nothing to disclose. of standardized treatment protocol.

CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 55 / NUMBER 3 / SEPTEMBER 2012

www.clinicalobgyn.com | 635
636 Tsai and Goldstein

Definition objectively measured with an alkaline hem-


AUB is a nonspecific term that describes a atin test, in clinical practice, the diagnosis of
broad range of clinical presentations. It is type of menstrual disorder often relies on
best defined as bleeding that is excessive or patient perception of what represents their
occurs outside of normal cyclic menstrua- own ‘‘normal’’ or ‘‘abnormal’’ bleeding in
tion. It can have a variety of menstrual terms of quantity, duration, and frequency,
patterns, which, by clinical experience, have and more importantly, whether it is affect-
yielded empirical definitions (Table 1). ing the patient’s quality of life.
There is an inconsistency in the nomencla-
ture used to describe AUB, and does not
provide necessary information on etiology Pathophysiology Underlying
of bleeding, coexisting uterine pathology,
or underlying systemic diseases. The Inter-
Abnormal Endometrial
national Federation of Gynecology and Bleeding
Obstetrics working group on menstrual In contrast to normal menstrual cycle,
disorders has recently developed a classifi- AUB reflects disruption at any point of
cation system (PALM-COEIN) for causes physiological control of hypothalamic-
of AUB in nongravid women of reproduc- pituitary-gonadal axis. Impaired endome-
tive age.1 There are 9 main categories, trial hemostasis and vasculature fragility as
which are arranged according to the acro- the result of aberrant angiogenesis consti-
nym PALM-COEIN: polyp; adenomyosis; tute 2 principal causes of abnormal endo-
leiomyoma; malignancy and hyperplasia; metrial bleeding.1 Anovulatory bleeding is
coagulopathy; ovulatory dysfunction; endo- one of the most common causes of AUB
metrial; iatrogenic; and not yet classified. especially in early and late reproductive
According to the proposed classification ages. Unlike the uniform synchronized
system, nonspecific term such as dysfunc- sloughing and bleeding that occurs with
tional uterine bleeding (DUB) should be cyclic estrogen and progesterone stimula-
abandoned to favor a more specific etiology tion, endometrial shedding during contin-
such as ovulatory dysfunction. These termi- uous estrogen stimulation is irregular and
nologies are, however, not yet endorsed by incomplete resulting in the potential for
American Congress of Obstetricians and irregular and prolonged menstrual flow.
Gynecologists. It is important to emphasize The precise mechanism underlying bleed-
that although menstrual blood loss can be ing in leiomyoma and endometrial polyps
remains elusive. The fragile abnormal an-
giogenesis with large-caliber vessels present
TABLE 1. Definition of Abnormal Uterine in stretched and thin endometrium over
Bleeding submucosal fibroids can be a cause of
Intermenstrual Bleeding between menstrual bleeding and denuded endometrium pre-
bleeding cycles venting adequate hemostasis. Endometrial
Metrorrhagia Irregular bleeding
Menorrhagia Excessive bleeding at
polyps can result in bleeding mainly be-
regular intervals cause of vascular fragility and endometrial
Polymenorrhea Menstrual cycle interval erosion secondary to friction of the pro-
<21 d truding mass.
Oligomenorrhea Menstrual cycle interval
>35 d
Menometrorrhagia Excessive bleeding at
irregular interval Differential Diagnosis
Postmenopausal Genital tract bleeding One of the most challenging aspects of
bleeding occurring >12 months after diagnosis and treatment of AUB is the
the last menstrual period
wide array of differential diagnose for the

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Office Management of Menstrual Disorder 637

TABLE 2. Differential Diagnosis of Abnormal Uterine Bleeding According to Age Groups


Neonate Reproductive Year
Estrogen withdrawal Anovulation
Premenarchal Pregnancy
Foreign body Cancer
Trauma, sexual abuse Polyps, fibroid, adenomyosis
Infection Infection
Urethral prolapse Endocrine dysfunction (PCOS, thyroid, pituitary adenoma)
Ovarian and vaginal tumor Bleeding diasthesis
Precocious puberty Medication-related (OCP, antipsychotic)
Early postmenarchal Perimenopausal
Anovulation Anovulation
Bleeding diathesis Polyps, fibroid, adenomyosis
Stress Cancer
Pregnancy Menopause
Infection Atrophy
PCOS Cancer
Estrogen replacement therapy

PCOS indicates polycystic ovarian syndrome.

same bleeding symptom (Table 2). Ruling contrast to benign lesions that seldom
out nongynecologic source of bleeding cause bleeding. Bright red spotting should
such as urethral or rectal bleeding is man- alert the health care provider about the
datory. The likely diagnosis can be sus- possibility of malignancy as they are usu-
pected by history, thorough physical ally not palpable by rectal examination
examination, the patient’s age, and repro- and not detected by vaginal smear cytol-
ductive status. Although considerable ogy. The remaining 26% of prepubertal
overlap in etiologies may occur, there bleeding is uterine in origin and attributed
are important differences regarding dif- to some form of precocious puberty, with
ferential diagnosis, evaluation, and man- a hormone producing ovarian tumor is
agement in each group. the underlying cause in majority of the
cases.
NEONATE AND PREPUBERTAL GIRLS
The high estrogen level during pregnancy ADOLESCENTS
can induce stimulation of intrauterine Anovulation should be considered as the
endometrial proliferation, resulting in most likely diagnosis of AUB in most
uterine bleeding in female neonate after adolescents especially those close to me-
birth. Such bleeding is usually self-limited narche. The etiology is related to imma-
and characterized by spotting. When vag- turity of hypothalamic-pituitary axis,
inal bleeding occurs in prepubertal pa- which results in unpredictable anovula-
tients, 74% of the bleeding originates tory cycles. It is estimated that up to 85%
from the lower genital tract. Vulvovagi- of menstrual cycles are anovulatory in the
nitis is the most common etiology, fol- first year after menarche and 56% of
lowed by urethral prolapse, trauma, and menstrual cycles are ovulatory 4 years
foreign body. Malignant lesions in the after the menarche. In case of oligome-
lower genital tract, such as adenocarcino- norrhea or amenorrhea, pregnancy
ma, endodermal sinus tumor of the vagi- should be suspected. Although anovula-
na, and sarcoma botryoides, will usually tion is the most common cause, practi-
bleed early in their development, in tioners should be alerted that 10% to 47%

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638 Tsai and Goldstein

of adolescents with heavy menstrual Any vaginal bleeding in postmenopausal


bleeding may have an underlying bleeding patients should be considered abnormal
disorder. Von Willebrand disease and until proven otherwise. Although an atro-
platelet dysfunction account for the phic endometrium is the most likely cause
most common hematologic disorders of postmenopausal bleeding, it is imperative
in this age group. Other bleeding dyscra- to rule out endometrial cancer. Hormonal
sias include Factor XI deficiency, hemo- therapy (HT) using combined estrogen and
phillia carrier states, and rare factor progesterone therapy given continuously
deficiencies. without break is associated with a variable
incidence of unscheduled spotting and
bleeding, with an incidence estimated to
REPRODUCTIVE AGE WOMEN be approximately 40%. Health care pro-
When a pregnancy event has been ex- viders should use their experience and the
cluded, the most likely cause of bleeding degree of patient concern to determine
in reproductive age women is DUB. As when and to what extent endometrial eval-
women age, organic pathologies such as uation is necessary.
leiomyoma, polyps, adenomyosis, endo-
metrial hyperplasias, and even frank car-
cinoma become more likely. Fibroids, Diagnosis and Initial Work-up
along with intracavitary lesions, distort- Although many authors and experts have
ing the uterine cavity are the most com- advocated the need to establish protocols
mon etiology of organic cause of AUB in for management of AUB, in our opinion,
this age group. Focal intracavitary lesions such an evaluation should be individual-
maybe present in up to 56% of premeno- ized and will be based on the physician’s
pausal women presenting with AUB re- clinical judgment as to the underlying
fractory to medical treatment. Chronic cause of the bleeding. If AUB is not severe
medical problems such as disorders of and does not require emergent interven-
liver, kidney, thyroid or adrenal glands, tion, evaluation should begin with a care-
or other medical problems that can affect ful medical history and thorough physical
the production and metabolism of estro- examination. The history should carefully
gen, progesterone, and prolactin can re- inquire about the pattern, quantity, and
sult in abnormal bleeding. Emotional or extent of recent bleeding. To quantify
physical stress, and significant changes in blood loss, it is useful to ask the patient
body weight, may disrupt the release of how many pads or tampons she uses each
follicle stimulation hormone (FSH) and period (<21 would be normal), how often
luteinizing hormone (LH) and prevent she has to change pads (every 3 h is usual).
ovulation. Although quantification of blood loss is
important to establish the diagnosis of
menorrhagia by textbook definition,
PERIMENOPAUSAL AND nonetheless, in clinical practice, it is often
POSTMENOPAUSAL WOMEN a woman’s subjective perception of what
For those perimenopausal women pre- is considered as a ‘‘normal menstrual
senting with menorrhagia and metrorrha- period’’ that determines the diagnosis of
gia, organic pathology and endometrial AUB. The temporal relationship of pa-
cancer should be mandatorily ruled out. tient complaints and other information
Eventual worsening of bleeding symp- from her history may also provide valua-
toms can sometimes be explained by the ble clinical information. A single episode
coexistence of anovulatory cycles and or- of AUB in premenopausal women favors
ganic pathology. expectant management in contrast to

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Office Management of Menstrual Disorder 639

persistent abnormal bleeding for several LABORATORY TESTING


months, which mandates investigation. Laboratory investigation includes preg-
For example, a 30-year-old woman with nancy testing in all patients of reproduc-
oligoamenorrheic cycles found to be tive age. A complete blood count provides
obese and having signs of virilization on a measure of blood loss and platelet ad-
physical examination is suggestive of pol- equacy. Cervical cultures and a Pap smear
ycystic ovarian syndrome (PCOS) in con- are appropriate initial steps to evaluate
trast, a similar aged athletic woman with for the presence of sexually transmitted
an identical menstrual pattern but low diseases or cervical dysplasia. In patients
body mass index the diagnosis would presenting with irregular periods, ruling
more likely be hypothalamic amenorrhea. out systemic diseases such as hypothyr-
Sexual history, trauma, and symptoms of oidism and abnormal production of pro-
infection or systemic disease should be lactin is mandatory. Ideally, fasting serum
explored as possible underlying etiology prolactin should be obtained and re-
for the uterine bleeding. The patient peated if elevated on first sample. Ele-
should be asked about medication usage vated levels of prolactin, in the absence
both past and present. A thorough bleeding of pregnancy, are often idiopathic but
history may yield important clues about may indicate hypothyroidism or a tumor
bleeding disorders. Bleeding symptoms that of the pituitary gland and cause irregular
are highly predictive of a bleeding disorder or absent ovulation. Evaluation with
is prolonged bleeding after wounds, easy FSH, LH, and estradiol level will help to
bruising, bleeding with minor injury, his- identify the etiologic dysfunction along
tory of frequent and/or difficult to control the hypothalamic-pituitary-gonadal axis.
nose bleeding, bleeding after tooth extrac- FSH/LH/estradiol can be assessed on day
tion, postpartum hemorrhage, and postop- 3 of the menstrual cycle when menses are
erative bleeding. As these disorders are regular but any day of the cycle when
inherited, family history of menorrhagia menstrual cycles are irregular. Increased
or the above symptoms should be elicited levels of FSH and LH and low serum
as well. In addition, health care providers estradiol are consistent with low ovarian
should also be attentive to the clinical signs reserve or primary ovarian failure. Low
of anemia, which can be manifest with: levels of FSH and LH are consistent with
fatigue, exercise-induced fatigue, shortness secondary ovarian dysfunction because of
of breath, syncope, inability to perform a pituitary or hypothalamic causes. High
daily activity, or congestive heart failure in levels of FSH and LH with the develop-
severe cases. ment of secondary sex characteristics at
The physical examination may also elicit an unusually young age are an indication
clues of bleeding etiologies. It should begin of precocious puberty. LH/FSH ratio
with careful inspection of the lower genital greater than 2:1 or 3:1 may be helpful in
tract looking for lacerations, vulvar or vag- the diagnostic for PCOS. FSH results can
inal pathology, and cervical lesions or pol- be increased with use of cimetidine, clo-
yps. The inspection serves the purpose to miphene, digitalis, and levodopa. FSH
confirm the site of bleeding, whether it is results can decrease with oral contracep-
uterine in origin or other nongynecologic tives, phenothiazines, and HT. If symp-
source of bleeding that may prompt referral toms of virilization are not evident in
to appropriate specialists. Bimanual pelvic suspected PCOS patients, androgen ex-
examination helps to detect uterine enlarge- cess can be tested by measuring total and
ment from uterine fibroids, adenomyosis, free testosterone levels or a free androgen
or hormone producing ovarian tumors as index. An elevated free testosterone level
possible underlying causes of bleeding. is a sensitive indicator of androgen excess.

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640 Tsai and Goldstein

If the index of suspicion is high for Von The accuracy of pipelle biopsy to detect
Willebrand disease, consultation with a endometrial malignancy varied widely ac-
hematologist is recommended. cording to different studies. Stovall et al,3
evaluated 40 women with known carcino-
ma, pipelle biopsy performed in the clinic
ENDOMETRIAL SAMPLING the week before hysterectomy yielded
Although the incidence of endometrial cancer in 39. Hence, they reported sensi-
cancer in patients with AUB is relatively tivity of 97.5%. Subsequent reports to
low, the possibility of endometrial hyper- reproduce Stovall’s study on patients with
plasia or malignancy should be consid- known carcinoma demonstrated lower sen-
ered in patients presenting with irregular sitivities ranging as low as 67%,4 83%,5
bleeding. Just which patients should and 92% being reported.6 In another pro-
undergo further assessment of the endo- spective study by Guido and colleagues,
metrium is problematic in premenopausal where pipelle endometrial samplings were
women. Metrorrhagia, persistent spot- performed before hysterectomy for endo-
ting, or bleeding should be more concern- metrial cancer staging, the pipelle biopsy
ing as compared with menorrhagia in the was adequate for analysis in 63 of 65
setting of regular cycle. In fact, the Amer- patients (97%). Malignancy was detected
ican College of Obstetrician and Gynecol- by biopsy in 54 of 65 patients, for a sensi-
ogists Practice Bulletin No. 142 states: tivity of 83 ± 5% (mean ± SD). Of the 11
‘‘There is a distinct increase in the inci- patients with false-negative results, 5 had
dence of endometrial carcinoma from tumors present in only an endometrial
ages 30-34 years (2.3/100,000 in 1995) to polyp. Three of the 11 patients had disease
ages 35-39 (6.1/100,000 in 1995). There- localized to <5% of the surface area of the
fore based on age alone, endometrial as- endometrium.5 The possible explanation
sessment to exclude cancer is indicated in for the limitation of pipelle endometrial
any woman older than 35 years who is biopsy is because many endometrial path-
suspected of having anovulatory uterine ologies including cancer are focal lesions.
bleeding.’’ In addition, women younger In 1 study, pipelle sampled an average of
than 35 years who have sufficient risk 4% of the endometrial surface area (range
factors (eg, morbid obesity, polycystic 0% to 12%).7 Recent evidence has sug-
ovary syndrome) may also require endo- gested saline-infusion sonography (SIS)-
metrial sampling. Women with postme- guided endometrial sampling is superior
nopausal bleeding may be evaluated to blind endometrial biopsy in diagnosing
initially with either TVS or endometrial endometrial pathology in perimenopausal
biopsy. Biopsy is not recommended in and postmenopausal women with AUB.8
postmenopausal bleeding with endometrial Pipelle biopsy is excellent for detecting
thickness of r4 mm as the negative predic- global process; a negative biopsy in light
tive value for endometrial cancer approx- of persistent vaginal bleeding should
imates 99%. Women using tamoxifen and prompt further endometrial evaluation be-
presenting with any abnormal vaginal cause a focal endometrial lesion can be
bleeding, bloody vaginal discharge, stain- missed.
ing, or spotting should be investigated to
exclude endometrial cancer. In asympto-
matic women using tamoxifen, screening OFFICE HYSTEROSCOPY
for endometrial cancer with routine trans- The availability of small-diameter hys-
vaginal ultrasound or endometrial sam- teroscopes and small operative instru-
pling or both, have not been shown to be ments has increased the advantages of
effective. this procedure, enabling hysteroscopy to

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Office Management of Menstrual Disorder 641

be performed in an awake patient in an an overall sensitivity of 86.4% and specific-


office setting. As intracavitary lesions are ity of 99.6% according to a quantitative
common in women with complaints of meta-analysis based on 56 studies,10 but
AUB, hysteroscopy constitutes an impor- inaccurate for endometrial hyperplasia,
tant diagnostic tool. Lasmar and col- an overall sensitivity, specificity, negative
leagues, retrospectively examined 4054 predicdictive value, and positive predic-
patients with AUB who were evaluated dictive value of 63.7%, 91.7%, 91.3%,
with hysteroscopy, endometrial polyps and 64.7%.11 Adding direct biopsy of
were the most frequent hysteroscopic suspicious areas appeared to improve
finding, accounting for 33.9% of the the accuracy of endometrial hyperplasia
cases. Normal uterine cavity and cervical detection by hysteroscopy.9,12
canal were found in 20.1%. Submucous
fibroids were diagnosed in 7.5% of wom-
en. Normal endometrium was the most TRANSVAGINAL
frequent histologic diagnosis, accounting ULTRASONOGRAPHY AND SALINE-
for 46.6% of cases. Endometrial hyper- INFUSION SONOHYSTEROGRAPHY
plasia was diagnosed in 15.1% and endo- TVS is an inexpensive, noninvasive, con-
metrial cancer in 2.6%.9 venient way to indirectly visualize the
Outpatient hysteroscopy has been in- endometrial cavity. Therefore, it is recom-
creasingly utilized for treatment at the mended as a first-line diagnostic instru-
time of diagnosis in a ‘‘1-stop’’ approach. ment for assessing uterine pathology in
To minimize potential complications, pa- reproductive age women presenting with
tients’ eligibility for office hysteroscopy AUB. The argument for using imaging
should be carefully assessed. study is based on the fact that organic
For better diagnostic accuracy, ideally, pathology that may not be obvious on
hysteroscopy should be scheduled in the physical examination may be the under-
follicular phase after the cessation of men- lying cause of uterine bleeding. Ultraso-
struation. Irregular proliferative or luteal nographic assessment is often an
phase endometrium may have irregular extension of the physical examination
topography and can be falsely interpreted and can provide additional information
as endometrial polyps. Overinflation of the affecting management decision. Focal in-
uterine cavity with distension media can tracavitary lesions are common in preme-
cause cavity distortion and partially pro- nopausal women with AUB refractory to
truding fibroids to disappear. Both CO2 medical treatment and this number can be
and saline solution appear to provide equiv- as high as 56%.13
alent clinical outcomes and patient toler- Postmenopausal women have also been
ance, although the superiority of the image evaluated with TVS to exclude endometrial
clarity is still debatable and is operator cancer when bleeding was present. Accord-
dependent. In patients with AUB, there is ing to a 2009 American College of Obste-
an unresolved controversy about the value tricians and Gynecologists Committee
of hysteroscopy for the diagnosis of serious Opinion14 a thin distinct endometrial echo
endometrial disease, such as endometrial on TVSr4 mm has a risk of malignancy of
hyperplasia and cancer. Although visual 1 in 917, and therefore endometrial biopsy
inspection of the uterine cavity is fairly is not required. In fact, if one does a biopsy
sensitive for protruding lesions, adhesions on such patients with a thin distinct endo-
or asymmetric cavity, the accuracy of his- metrial echo on TVS, it is common to not
tologic prediction of endometrial diseases successfully obtain tissue, or when tissue is
based on direct visualization varies. It is present, it is often so scant that it is insuffi-
generally high for endometrial cancer, with cient for evaluation. However, previous

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642 Tsai and Goldstein

surgery, coexisting leiomyomas, axial ori- endometrial pathology although hystero-


entation, marked obesity, and adenomyosis scopy is the most accurate test for poly-
can limit the clear visualization of an endo- poid lesions in the postmenopausal
metrial echo. In those situations, SIS find- group. SIS induces significantly less dis-
ings may be helpful to triage patient to: comfort than office hysteroscopy and
(1) no anatomic pathology (no biopsy nec- should therefore be considered the meth-
essary); (2) globally thick endometrium od of choice. In office practice, whether
(blind biopsy appropriate); and (3) focal SIS or hysteroscopy should be the next
abnormalities (like polyps or focal thicken- step of management after an ultrasonog-
ing best approached with direct visualiza- raphy suspicious for an intracavitary le-
tion of hysteroscopy). The management of sion will basically depend on the
incidental ultrasound finding of a thicken availability of resources, health care pro-
endometrium in an asymptomatic postme- viders’ preference but especially, clinical
nopausal woman remains controversial, the indication. SIS is extremely useful to char-
consensus favors expectant management acterize the depth of myometrial involve-
because of low incidence of endometrial ment of leiomyomata, important for
malignancy in those cases, mostly inactive assessing the feasibility and planning of
polyps, although individualization might be transcervical resection of submucosal fib-
considered if patients are at high risk (dia- roids. In case SIS is unavailable or there is
betes, hypertension, obesity, etc.).15 technical difficulty due to multiple fib-
When compared with TVS, SIS has roids, magnetic resonance imaging
been shown to be superior in detecting (MRI) is an expensive but superior option
endometrial pathologies such as endome- to provide accurate information on size,
trial polyps and fibroids both in preme- location, and type of fibroid. In contrast,
nopausal and postmenopausal women hysteroscopy offers the advantage of di-
with AUB. The accuracy of TVS is im- rect inspection of the uterine cavity, cer-
paired when a small intracavitary lesion is vical canal, and vagina, allowing the
found. When SIS is not available, the use differentiation of fibroid versus polyps
of color flow or power Doppler imaging and direct sampling when a suspicious
to identify a feeder vessel is helpful for the lesion is encountered.
diagnosis of an endometrial polyp, with a
positive predictive value of 81.3%.16 The
diagnostic accuracy of intrauterine le- Office Management of AUB
sions can also be influenced by the timing After pregnancy and malignancy have
of the ultrasound in cycling premeno- been excluded, treatment goals for AUB
pausal women. This was supported in a patients include regulation of menstrual
prospective blinded study by Wolman cycles, minimization of blood loss, and
et al17 in which there was a false-positive improvement in quality of life. For heavy
rate of 27% in SIS performed from day 16 menstrual periods, the treatment aims to
to 28, while there were none when the prevent further worsening of anemia and
procedure was performed before day 10. reduce the need for blood transfusion.
In patients with irregular bleeding, an Quantitative estimation of actual blood
empiric course of a progesterone such as loss using the alkaline hematin method is
medroxyprogesterone acetate 10 mg daily impractical in routine clinical practice.
for 10 to 14 days as a ‘‘medical curettage’’ Thus, therapeutic outcome measurement
and then time the ultrasound evaluation relies on a patient’s subjective perception,
to the withdrawal bleed may be appropri- which correlates fairly with objective
ate.18 SIS and office hysteroscopy are quantification. A patient’s menstrual cal-
equally accurate in the diagnosis of endar is helpful for the monitoring of a

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Office Management of Menstrual Disorder 643

therapeutic response and allows compar- levonorgestrel intrauterine device (LNG-


ison throughout the course of treatment. IUD) was the next most frequently
A simple management guideline that is selected option.19 Combined oral contra-
helpful when dealing with AUB is as ceptive pill (COCP) can correct menstrual
follows. (1) Start always with medical irregularities resulting from oligoovula-
treatment before considering surgery un- tion or anovulation and make menstrua-
less you have a strong reason to do so. (2) tion more predictable. They can also
Not all uterine bleeding needs treatment, reduce excessive menstrual bleeding in
expectant management can be carried out most affected women and is considered a
after serious pathologies have been ruled reasonable option for initial management
out. (3) Any therapeutic options should of menorrhagia. COCP is less effective for
take into consideration a patient’s desire the treatment of heavy menstrual periods
for future fertility and cultural back- in women with organic pathology although
ground. (4) Empiric treatment should be the response can be variable. Menstrual
initiated, based on index of suspicion, if blood loss is reduced about 50% in women
pending test result or a definite diagnosis using COCP, and the reduction is most
cannot yet be established. (5) Uterine bleed- apparent during the first 2 days of the
ing may be the tip of iceberg of an under- menstrual flow. Extended cycle or contin-
lying disease, so treat the patient and not uous COCP with 20 mg ethinyl estradiol/
only the bleeding. (6) Many therapeutic 100 mg levonorgestrel formulation, either
modalities lead to a similar outcome, so be 84/7 regimens that shorten the hormone-
sure to discuss the risk, benefits, and alter- free interval and decrease the number of
natives of the available options. days of bleeding per year, or the 365 regi-
Hysterectomy is the definitive treat- men designed to eliminate bleeding alto-
ment for any AUB, but should not be gether, is associated with significant
used as a first-line treatment for heavy reduced bleeding when compared with cy-
menstrual periods. Office management of clic use. Shortening of the hormone-free
AUB and alternatives to hysterectomy interval from 7 to 4 days significantly de-
should be always considered as they may creases the number of withdrawal bleeding
provide temporary relief of bleeding days in each cycle and increases the ame-
symptoms and delay or eliminate the need norrhea rate. For those women with a
for definitive surgical treatment. Older contraindication to estrogen therapy, pro-
women are more likely to benefit from gesterone therapy or LNG-IUD can be an
uterine preserving treatment because of alternative. Because of the levonorgestrel
the bridge to menopause and such women effect on the endometrium, the duration
experience greater symptom resolution, and amount of menstrual bleeding is re-
compared with women who were younger duced. This effect may begin during the
(first treatment at age 40 y or under). first menstrual cycle after the placement of
device, and bleeding becomes progressively
less over time. Many of the progesterone-
PHARMACOLOGICAL TREATMENT only long acting reversible contraceptive
methods have been used for the treatment
HT of menorrhagia. Patients should be coun-
According to a recent survey conducted seled about the inconvenience of break-
among American Congress of Obstetri- through bleeding observed during the
cians and Gynecologists members, the initial months of treatment. The timing of
most commonly selected first-line choice complete suppression of the menstrual
for AUB treatment in the United States cycle is variable depending on the method.
was combined oral contraceptives. The Amenorrhea is approximately 30% to 40%

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644 Tsai and Goldstein

and 20% to 80% in 12 months for single first 3 days of menstrual cycle to reduce
rod progestin contraceptive implant and blood loss and menstrual cramping.
LNG-IUD, respectively.20 Use of depot
medroxyprogesterone acetate (DMPA) re- TA
sults in relatively high rates of amenorrhea The Food and Drug Administration
by the fourth dose (approximately as (FDA) has recently approved an oral for-
high as 90% in some studies) and has tradi- mula of TA for clinical use in the United
tionally been used extensively to suppress States. Its pharmacological mechanism
menses. In a single randomized controlled involves reversibly blocking lysine-bind-
study to compare the efficacy of LNG-IUD ing sites on plasminogen, preventing plas-
to low-dose COCP for the management of min and fibrin polymer interaction
idiopathic menorrhagia, LNG-IUD was resulting in fibrin degradation, stabilizing
found to be more effective with statistically clots, and reducing bleeding. TA is con-
significantly less treatment failure (defined traindicated in women with increased risk
as requiring medical or surgical treatment) for thromboembolism. TA has been rou-
when compared with COCP, 11% versus tinely used for many years to reduce blood
36%, respectively.21 According to a Co- loss and the need for blood transfusion
chrane review, cyclic progestogens adminis- during and after surgical procedures. TA
tered from day 15 or 19 to day 26 of the cycle has been used for the treatment of heavy
offer no advantage over other medical menstrual bleeding outside the United
therapies such as danazol, tranexamic acid States for several decades. TA’s therapeu-
(TA), nonsteroidal anti-inflammatory drugs tic effect is superior to placebo, NSAIDs,
(NSAIDs), and the LNG-IUD. Instead, ethamsylate, and luteal phase norethister-
21-day oral progestogen therapy taken from one and results in significant reduction in
cycle day 5 to day 26 should be recom- objective measurement of idiopathic
mended because it results in a significant heavy menstrual bleeding.24 Interestingly,
reduction in menstrual blood loss.22 TA treatment has no effect on the dura-
tion of bleeding when compared with a
control group. TA is also effective as a
Nonsteroidal Anti-Inflammatory Drugs treatment for significantly relieving un-
NSAIDs reduce prostaglandin synthesis by scheduled bleeding and menorrhagia in-
inhibiting cyclooxygenase, thus reducing en- duced by DMPA and intrauterine device,
dometrial prostaglandin levels that promote respectively. In all studies analyzed, only
angiogenesis and may have a role in aberrant mild to moderate side effects were re-
neovascularization leading to DUB. Oral ported, mostly gastrointestinal, and there
NSAIDs are an excellent treatment to re- were no reports of thromboembolic
duce heavy menstrual bleeding. When com- events with the use of TA.24 Nonetheless,
pared with placebo, they decrease menstrual the effectiveness of TA treatment on heavy
cramping and reduce menstrual blood loss menstrual bleeding secondary to uterine
by 33%.23 They are less effective than TA, fibroid remains unknown and further study
danazol, or LNG-IUD but comparable with is needed. The FDA has approved TA at a
oral luteal progestogen, COCP, and etham- oral dosage of 1300 mg (two 650-mg tab-
sylate. There is no evidence of a difference lets) 3 times daily for 5 days in each men-
between the individual NSAIDs (nap- strual cycle.25 The oral bioavailability of
roxen and mefenamic acid) in reducing TA is only about 35%, which makes fre-
heavy menstrual bleeding. Mefenamic acid quent administrations necessary. The dis-
500 mg 3 times a day for 5 days and ibupro- advantages of frequent administrations
fen 600 mg every 6 hours or 800 mg every include decreased patient compliance and
8 hours are commonly prescribed during the increased risk of gastrointestinal side

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Office Management of Menstrual Disorder 645

effects most commonly nausea, vomiting, the improvement of a patient’s quality


and diarrhea. The perspective of using a of life with reduction of blood loss but
single antifibrinolytic medication to relieve not necessarily amenorrhea. The relative
a common and multietiologic gynecologic contraindication of using endometrial
condition is exciting, and it is potentially ablation device is the size of uterine cavity
cost saving by decreasing the utilization of and presence of submucosal fibroids.
invasive diagnosis and surgery for treating Most of the manufacturers recommend
heavy menstrual bleeding. maximum uterine length by sounding of
10 cm except MEAS which is 14 cm. Nova-
sure, MEAS, and TermoChoice devices are
ENDOMETRIAL ABLATION licensed for ablation of the uterine cavity
Endometrial ablation is a minimally in- with submuosal fibroids of <3 cm. Abso-
vasive alternative for the treatment of lute contraindications include pregnancy,
heavy menstrual bleeding and is associ- uterine perforation, and endometrial malig-
ated with high level of patient satisfaction. nancy. Although the infection rate is low
It is usually reserved for patients refrac- with ablation procedures, postablation tu-
tory to medical treatment and who wish to bal sterilization syndrome can occur in
avoid a definite treatment with hysterec- patients with prior tubal ligation because
tomy. Although endometrial ablation is a of residual endometrial proliferation form-
less invasive surgical alternative to ing hematometrea in the cornual area.
hysterectomy, it does not eliminate surgi- Treatment requires hysteroscopic decom-
cal risk and is followed by further surgery pression. Serious complications associated
within 4 years in up to 38% of the women with uterine perforation, thermal injury to
who undergo this treatment.26,27 Endo- the bowel, and even death have been re-
metrial ablation should be considered as ported with all 5 FDA-approved endome-
an alternative to hysterectomy especially trial ablation devices.29 Thermal injuries to
in older women who opted to retain their the vagina and vulva have been described
uterus and not in women with desire of with Hydrothermo ablator devices that in-
future fertility. Patient age is an important fuse heated fluid into the uterine cavity to
predictor of treatment success. Younger destroy endometrium.
women who undergo endometrial abla- It is currently unknown what constitutes
tion experience higher rates of hysterec- an appropriate preablation endometrial as-
tomy than older women (40% for women sessment and postablation surveillance; the
40 y old vs. 20% for women 45 to 50 y scarred uterine cavity, as a result of endo-
old), irrespective of the method used.28 In metrial destruction, makes the diagnosis of
contrast to the resectoscopic endometrial malignancy even more difficult, although
ablation, several new ablation devices diagnosis of cancer through endometrial
offer the advantage of being performed sampling has been reported. Careful patient
in an office setting. There are currently 5 selection seems to be the key to decrease the
FDA-approved nonresectoscopic abla- occurrence of endometrial cancer after
tion devices: microwave endometrial ablation. In a recent systematic review
ablation system (MEAS), Novasure, where 22 postablation endometrial cancer
ThermaChoice, Her Option (cryother- cases were reviewed,30 the time to diagnosis
apy), and Hydrothermo ablator. Patient of endometrial cancer ranges from 2 weeks
satisfaction and amenorrhea rate associ- to 10 years after endometrial ablation. Most
ated with endometrial ablation ranges of the patients had symptoms of persistent
from 86% to 96% and 13.2% to 55.3% bleeding or pain after the procedure.
respectively, depending on the devices Eighty-six percent of the cancer patients
used. The desired treatment outcome is presented with risk factors for endometrial

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646 Tsai and Goldstein

cancer such as obesity, complex atypical the treatment of heavy menstrual period.32
endometrial hyperplasia, diabetes, hyperten- Because of the shorter treatment cycle, No-
sion, and postmenopausal status. Thus, en- vasure appears to be better tolerated by
dometrial ablation should be restricted to patients when performed in an office setting
premenopausal women who have low-risk as compared to Thermachoice where 5% of
factors for endometrial cancer and who have the patient could not complete the ablation
documented normal endometrial histopa- due to procedure-related discomfort.
thologic features at preablation evaluation.
In a systematic review and meta-anal-
ysis to compare the effect of levonrgestrel ANOVULATORY BLEEDING
intrauterine system and endometrial abla- Anovulatory uterine bleeding is a com-
tion in reducing heavy menstrual bleed- mon occurrence in reproductive age
ing, 6 randomized controlled trials that patients, especially adolescents and peri-
included 390 women (196 levonorgestrel menopausal women. Most of anovulatory
intrauterine system, N = 196; endome- uterine bleeding will respond to medical
trial ablation, N = 194) were retrieved (3 treatment. The pattern of anovulatory
were first-generation and 3 were second- bleeding varies and ranges from spotting
generation endometrial ablation devices). and oligomenorrhea to heavy and pro-
The efficacy of LNG-IUD in the manage- longed uterine bleeding. In reproductive
ment of heavy menstrual bleeding appears aged women, after excluding pregnancy
to have similar therapeutic effects to that and endometrial malignancy, acute treat-
of endometrial ablation up to 2 years after ment to stop bleeding will usually consist
treatment.31 According to the same study, of progesterone therapy to induce com-
the rate of hysterectomy or (new or re- plete shedding of the dysfunctional endo-
peat) ablation was similar between 2 treat- metrium. Medroxyprogesterone acetate
ment modalities in the studies included in 10 mg is given for 10 to 14 days, and
the meta-analysis: 11% and 10% for the bleeding usually stops a few days after
LNG-IUD and endometrial ablation, re- the initiation of the medication and a self-
spectively. LNG-IUD, an effective contra- limited withdrawal bleed will take place 2
ceptive method, offered an additional to 7 days after progesterone is discontin-
advantage of being a less expensive and ued. After that, monthly cyclic progester-
reversible method as compared with perma- one or COCP can be used to regulate the
nent endometrial destruction with ablation cycle. In adolescent girls with acute and
devices. Both LNG-IUD and nonresecto- profuse bleeding, high doses of conju-
scopic endometrial ablation are not suitable gated equine estrogen can be used orally
for treating menorrhagia with an enlarged at 2.5 mg every 6 hours, or intravenously,
uterine cavity. LNG-IUS has higher rate of 25 mg every 4 hours up to 24 hours fol-
expulsion and endometrial ablation proce- lowed by tapering down with COCP. If
dures are more likely to fail. estrogen therapy is contraindicated, high
According to recent reviews, the different doses of oral medroxyprogesterone acetate
techniques of second-generation endome- has been shown to be an effective alterna-
trial ablation appear to be similar in terms tive in managing acute excessive anovula-
of efficacy. Two of the most commonly used tory bleeding when administered at a total
second-generation office endometrial abla- dose of 60 to 120 mg during the first day
tion devices in the United States: Bipolar and 20 mg/d for the following 10 days.33
radiofrequency ablation device-Novasure For chronic anovulatory bleeding in ado-
and thermal balloon ablation-Therma- lescents, cyclic COCP and progestogens are
choice, have comparable 6-month postabla- equally effective. In treating abnormal
tion amenorrhea rates and same efficacy in bleeding in patients with PCOS, health care

www.clinicalobgyn.com
Office Management of Menstrual Disorder 647

providers should be alert to the possibility of risk is significantly increased with meno-
more serious underlying associated comor- pause and bleeding.34,35 Current consensus
bidities: PCOS is considered to be a risk is any endometrial polyp in postmeno-
factor for the development of metabolic pausal women presenting with abnormal
syndrome due to insulin resistance with or bleeding should be removed, for asympto-
without obesity. Life style modification matic women, expectant management is
along with diet and exercise are important recommended. In premenopausal women,
in obese patients as weight loss is associated because of the low incidence of malignant
with return to spontaneous menstrual polyps, polypectomy is only indicated for
cycles. The use of insulin-sensitizing drugs bleeding symptom relief.
such as metformin to decrease insulin resist-
ance can help to achieve ovulation and
regulate menstrual periods. Treatment with UTERINE LEIOMYOMA
cyclic progesterone or COCP is recom- The most common symptoms in women
mended to prevent endometrial hyperplasia with leiomyoma seeking medical treatment
and cancer, which can be long-term sequelae are pelvic pressure and AUB. The bleeding
of unopposed estrogen. symptoms can vary from heavy menstrual
flow to prolonged and persistent bleeding.
Hysterectomy remains the most common
ENDOMETRIAL POLYPS surgical treatment for leiomyoma because it
The prevalence of symptomatic polyps has is the only definitive treatment and elimi-
been reported to range from 13% to 50% nates the possibility of recurrence. Medical
and is commonly associated with metror- therapy and minimal invasive procedures
rhagia, menorrhagia, and metromenorrha- tend to provide short-term symptom relief
gia. The causative association between and although many patients require defin-
endometrial polyps and abnormal bleeding itive surgical management within a few
remains elusive because up to 34% of years, those alternatives to hysterectomy
polyps are found in asymptomatic women. can delay or eliminate the need for uterine
Although the natural history of endometrial extirpation. Increased size, but not the
polyps is unknown, small polyps have been number or location of fibroids, is associated
described to undergo spontaneous regres- with worsening of uterine bleeding, and
sion in 1 study. COCP use is a known nonsubmucosal leiomyomatas are associ-
protective factor for the development of ated with heavy bleeding to the same extent
endometrial polyps and could be used to as submucosal leiomyomatas. Premeno-
treat symptomatic polyps. Expectant man- pausal women may experience rapid enlarg-
agement or treatment with COCP can be a ing fibroid because of a transient increased
reasonable alternative to transcervical poly- in estrogen levels. It is usually not related to
pectomy in low-risk premenopausal patient. uterine malignancy and should not be used
The wide spread utilization of ultraso- as basis for hysterectomy.
nography for routine pelvis organ screening For women whose only symptom is
by gynecologists has greatly increased the heavy bleeding or prolonged menses,
incidental diagnosis of endometrial polyps. there are several options including ste-
The most common question is whether all roidal therapies such as COCP and
endometrial polyps should be removed be- the LNG-IUD. Contraceptive patches,
cause of malignancy concern? and if not, DMPA, and vaginal rings likely work in
which patients warrant polypectomy? The a similar manner. Hysteroscopic resection
malignant potential of endometrial polyps of type 0 and I submucosal leiomyomas
is relatively low ranging from 0.5% to 4.8% have been shown to decrease heavy men-
depending on the population studied; the strual bleeding,36 even after an incomplete

www.clinicalobgyn.com
648 Tsai and Goldstein

resection. The significant factors for the coagulative necrosis of fibroid tissue. The
risk of failure of treatment include young- real-time monitoring of thermal spread to
er age, increasing number of and larger- nontargeted tissues is possible using MRI in
sized myomas, intramural extension, and the only FDA-approved device (ExAblate
incomplete resection. Fifty percent of pa- 2000/Insightec Corp.). The safety concern
tients with incomplete resection required exists regarding inadvertent thermal spread
no further treatment. in case of pelvic adhesion where the bowel
might be situated next to the fibroid. Pa-
tients are usually excluded from HiFus
UTERINE ARTERY EMBOLIZATION treatment when there is abdominal scarring,
(UAE)
high T2 signal intensity, pedunculated leio-
UAE is a procedure performed to deliver myomas, severe adenomyosis, menopause,
small particles to obstruct the arterial supply leiomyoma >10 cm, 5 or more leiomyomas
of part or all of the uterus causing ischemic >3 cm, contraindications to MRI, weight
degeneration of uterine fibroids. Within 2 to >250 lb, or inability of the patient to lie
4 months after embolization, a 40% to 60% prone for several hours. HiFus is available
reduction of uterine volume may be ex- only in few centers in the United States.
pected, however, symptomatic improve- Several investigators are studying HiFus
ment may be achieved without remarkable that would potentially be provided by trans-
change in myoma size. In reviews of pub- vaginal ultrasound and thus, performed by
lished data, the clinical success rate meas- gynecologists. Leiomyoma symptom relief
ured by improvement in fibroid-related after HiFus at 1 year postprocedure is as
symptoms, eg, menstrual loss, was at least high as 88%.39 In a prospective 3-year
85%.37 UAE is associated with a higher rate follow up study on 51 leiomyomata from
of minor postprocedural complications such 40 patients after Hifus treatment, the mean
as vaginal discharge, postpuncture hemato- baseline volume of treated leiomyomata was
ma, and postembolization syndrome (pain, 336.9 mL. The mean volume decrease
fever, nausea, vomiting), as well as more in treated leiomyomata was 32.0% (P<
unscheduled visits and higher readmission 0.001), and, in the uterus, the volume de-
rates after discharge, compared with crease was 27.7% (P<0.001) at 3 years.
hysterectomy.38 UAE has short-term ad- Thirty-one percent of women who complete
vantages over surgery. Mid-term and long- HiFus elected alternative treatments within
term benefits were similar, except for a high- 3 years secondary to treatment failure.
er reintervention rate after UAE. Although There were no long-term complications.
successful pregnancy has been reported after Further studies are needed to validate the
UAE, patients should be counseled about long-term effectiveness and the extended
the increased risk of uterine rupture and application of HiFus.
abnormal placentation in future pregnan-
cies associated with the procedure. Cur-
rently, UAE is not recommended for Conclusions
women who desire future fertility. Diagnosis and management of AUB still
poses challenges to most gynecologists in
HIGH-INTENSITY FOCUS their office practice. Available evidences
ULTRASOUND (HiFus) suggest that a significant portion of pa-
HiFus is a noninvasive treatment of leio- tients with AUB can be diagnosed and
myoma. The high-intensity ultrasound en- managed in the office with currently avail-
ergy penetrates through the abdominal wall able uterine-sparing treatment. These ap-
to target specifically the fibroid. The heat proaches are likely to result in short-term
generated causes protein denaturation and improvement of the quality of life of

www.clinicalobgyn.com
Office Management of Menstrual Disorder 649

women suffering from the bleeding com- of endometrium in 1500 women. J Am Assoc
plaints and, many times, delaying a Gynecol Laparosc. 2001;8:207–213.
hysterectomy, which is considered the 13. Hauge K, Ekerhovd E, Granberg S. Abnormal
uterine bleeding refractory to medical therapy
definitive treatment for AUB. assessed by saline infusion sonohysterography.
Acta Obstet Gynecol Scand. 2010;89:367–372.
14. American College of Obstetricians and Gynecol-
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