Best Practice Issue On "Abnormal Uterine Bleeding"

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Best Practice Issue on “Abnormal Uterine Bleeding”
Article in Bailli&egrave re s Best Practice and Research in Clinical Obstetrics and Gynaecology · January 2017
DOI: 10.1016/j.bpobgyn.2017.01.002
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Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn
Practical aspects of the two FIGO systems for

management of abnormal uterine bleeding in
the reproductive years
Malcolm G. Munro, MD, FACOG, FRCS(c) *
Departments of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los
Angeles and Kaiser Permanente, Los Angeles Medical Center, USA
Keywords:
The FIGO systems defining the nomenclature and symptoms of
abnormal uterine bleeding
abnormal uterine bleeding (AUB) in the reproductive years (System
heavy uterine bleeding
heavy menstrual bleeding 1) and the PALM-COEIN classification of causes of AUB (System 2) are
menorrhagia designed to facilitate research, education, and the provision of opti-
intermenstrual bleeding mum clinical care for affected women. Development of these systems
PALM-COEIN has been the result of a collaborative effort of experts in bench and
translational and clinical research from six continents aided by a
spectrum of representatives from relevant medical societies, jour-
nals, and regulatory bodies. Integral to this development has been a
decision to cease the use of poorly defined and inconsistently used
terms such as menorrhagia, metrorrhagia, and dysfunctional uterine
bleeding, to name a few, and replace them with a set of terms and
definitions that are relatively easily understood and translated into
the spectrum of languages used by medical providers and patients
globally. The utilization of these systems requires a disciplined
approach to obtaining a menstrual history, relatively simple labora-
tory investigations, and the appropriate use of imaging techniques
accessible to most clinicians worldwide. This section describes the
two systems, their crucial role in guiding investigation, and an
approach to implementation, all designed to facilitate the creation of
a menu of therapeutic options, considering the identified factors
contributing to the problem of nongestational AUB.
© 2016 Published by Elsevier Ltd.
* Corresponding author. Departments of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA,
Kaiser Permanente, Los Angeles Medical Center, Station 3-B, 4900 Sunset Boulevard, Los Angeles, CA 90027, USA. Tel.: þ1 323
783 4211.
E-mail address: mmunro@ucla.edu.
http://dx.doi.org/10.1016/j.bpobgyn.2016.09.011
1521-6934/© 2016 Published by Elsevier Ltd.
Please cite this article in press as: Munro MG, Practical aspects of the two FIGO systems for management
of abnormal uterine bleeding in the reproductive years, Best Practice & Research Clinical Obstetrics and
Gynaecology (2016), http://dx.doi.org/10.1016/j.bpobgyn.2016.09.011
2 M.G. Munro / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2016) 1e20
Introduction
Nongestational abnormal uterine bleeding (AUB) in the reproductive years is defined as bleeding
from the uterine corpus that is abnormal in duration, volume, frequency, and/or regularity and has
been present for the majority of the previous six months [1]. AUB may be acute or chronic and can be
caused by disorders of ovulatory function, abnormalities in local or systemic hemostasis, or any of a
number of structural abnormalities including polyps, adenomyosis, leiomyomas (also known as fi-
broids or myomas), and premalignant endometrial disease or uterine carcinoma or sarcoma. In addi-
tion, AUB may be a consequence of the use of intrauterine contraceptive devices or a spectrum of
pharmacologic agents ranging from gonadal steroids to medications that impact dopamine meta-
bolism and, subsequently, ovulatory function. Symptoms experienced by patients comprise one or a
combination of heavy menstrual bleeding (HMB), intermenstrual bleeding (IMB), and irregular men-
strual bleeding as well as associated symptoms that may include dysmenorrhea and fatigue related to
iron deficiency and iron deficiency anemia (IDA).
The worldwide impact of AUB varies from modest to severe disruption of work productivity and
quality of life [2,3] to contribution to maternal morbidity and mortality for pregnant women with pre-
existing AUB-related anemia [4,5]. The importance of effective clinical care cannot be overestimated;
approaches that can range from common-sense interventions such as iron therapy to a range of simple
and complex pharmaceutical and procedural therapies can be employed.
Determination of the extent and severity of symptoms can be difficult as most women lack a
metric that can quantify their menstrual flow and indeed may have been told that their heavy
bleeding is normal, a circumstance that frequently makes them “prisoners” of their own expe-
rience, unaware of the magnitude of their blood loss and the resulting impact on their quality of
life.
Key elements of successful therapy include identification of the potential contributors to the
symptoms as well as determination of the patient's desires including her plans for immediate or future
fertility. Although hysterectomy remains an intervention that reliably treats AUB resulting from any
cause, it is an unreasonable option for those who wish to preserve or enhance fertility, and even for
those who do not, it causes morbidity and incurs time and both direct and indirect costs. Successful
uterus-preserving therapy for women with acute and chronic AUB requires a thoughtful and usually
complete evaluation for the potential causes or contributors to the symptoms.
The process of investigation can be optimized by initiating it with a structured history based upon
use of the two FIGO systems: the first defines normal uterine bleeding and AUB [6,7]; the second is the
PALM-COEIN classification system of AUB in the reproductive years [1]. Together these systems can be
used to structure and organize the investigation that is based upon a structured history, appropriate
laboratory tests, and appropriate imaging procedures.
The system for definition of normal menstrual bleeding and nomenclature of symptoms
The first FIGO system is designed to standardize the nomenclature and parameters of normal
uterine bleeding and AUB defined by the 5the95th percentiles on the basis of the available large-scale
epidemiological studies (Figure 1) [6,7]. First published simultaneously in 2007, in Fertility and Sterility
and Human Reproduction, what is now FIGO's system of nomenclature and definitions has undergone
very modest modifications that will continue to be clarified, modified, and revised as appropriate [6,7].
Important to this system is the replacement of ill-defined terms such as “menorrhagia,” “menome-
trorrhagia,” and “dysfunctional uterine bleeding,” replacing them with unambiguous terms describing
frequency, regularity, duration, and volume. Included in this system is the term HMB, a symptom (not a
diagnosis), that has been described by the National Institute for Health and Clinical Excellence as
“excessive menstrual blood loss, which interferes with a woman's physical, social, emotional and/or
material quality of life” [8]. Details regarding this system can be found elsewhere in this symposium
(Harlow S and Fraser, IS “Internal” Reference “The spectrum of menstrual symptomatology and
patterns of bleeding).
M.G. Munro / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2016) 1e20 3
Figure 1. FIGO System 1. Definitions and Nomenclature for Normal and Abnormal Uterine Bleeding in the Reproductive Years. This
worksheet can guide the evaluation of the patient's menstrual bleeding and AUB symptoms. The top panel describes the four pa-
rameters: the white section represents normal as defined by the 5the95th percentiles from large-scale epidemiological studies. The
definition of regularity has been changed from the original version to reflect reanalysis of the data and the exclusion of the longest
and shortest cycles. The middle and lower panels are new; the middle panel is used to describe the presence or absence of IMB,
whereas the lower panel is for the description of unscheduled bleeding while using gonadal steroid medication, most often pro-
gestogen or estrogen and progestogen-containing preparations.
The PALM-COEIN system for classification of causes
The second of the two FIGO systems is the classification of potential causes of AUB in the repro-
ductive years (Figure 2). The classification system, known by the acronym “PALM-COEIN,” was devel-
oped and first published in a textbook [9], then accepted by FIGO in 2010, and finally published together
with the nomenclature system and definitions in 2011 [1]. The nine basic categories are as follows:
Polyp; Adenomyosis; Leiomyoma; Malignancy and hyperplasia; Coagulopathy; Ovulatory Disorders;
Endometrium; Iatrogenic; and Not Otherwise Classified. The components of the “PALM” group are
discrete structural entities that are measurable using imaging techniques and/or with histopathology,
whereas the “COEI” group comprises entities that are not defined by imaging or histopathology, i.e., they
are “non-structural.” Each of the categories was created to facilitate sub-classification systems designed
to further facilitate clinical management or basic or clinical research. The system was constructed
recognizing that any patient could have one or a spectrum of entities that could cause or contribute to
AUB and that definable entities such as adenomyosis, leiomyomas, and endocervical or endometrial
polyps may frequently be asymptomatic and therefore not contribute to the presenting symptoms.
Polyps (AUB-P)
Polyps are categorized as either being present or absent on the basis of one or a combination of
ultrasound, ideally contrast hysterosonography, and hysteroscopic imaging with or without histopa-
thology. Although there is no distinction regarding the size or number of polyps, it is probably
important to exclude polypoid-appearing endometrium from this category because such an appear-
ance may well be a variant of normal. Although not currently included in the classification system, the
clinician should describe polyp dimensions, location, number, morphology, and, following removal, the
histopathology of the lesion.
Figure 2. FIGO System 2. The PALM-COEIN Classification of Causes of Abnormal Uterine Bleeding in the Reproductive Years. The
categories on the left (PALM) reflect structural abnormalities that can be defined by some combination of appropriate imaging and
histopathological evaluation. The COEI categories all reflect some sort of physiological dysfunction that requires a disciplined, careful
history, in some instances coupled with laboratory evaluation such as demonstration of a coagulopathy (AUB-C) or absence of
ovulatory levels of progesterone (AUB-O). Patients with AUB-E have evidence of normal ovulatory function but have abnormal
bleeding, such as HMB, related to local endometrial factors. The “N” group comprises entities that are rare, of questionable rela-
tionship to the genesis of AUB, or otherwise not classified. The leiomyoma subclassification system first divides leiomyomas into
submucous or “other” fibroids that are not in contact with the endometrium. The subclassification system is based on the original
Wamsteker [18] version (Types 0, 1, and 2) but with additional categorization of intramural myomas that contact (Type 3) or do not
contact the endometrium (Type 4).
Adenomyosis (AUB-A)
Whereas the role of adenomyosis in the genesis of AUB is unclear [10,11], most would consider that in
at least some instances, there is a cause and effect relationship. Although criteria for diagnosing ade-
nomyosis have traditionally been based on the histopathological determination of the depth of
“endometrial” tissue beneath the endometrialemyometrial junction as determined in hysterectomy,
these criteria vary substantially [12] and, regardless, have little value when evaluating women with AUB.
Highly sensitive sonographic and magnetic resonance imaging (MRI)-based diagnostic criteria are
currently in use [13e15]. Given this evidence and recognizing the limited access of women to MRI in the
world community, the FIGO system relies on sonographic criteria for the diagnosis of adenomyosis [16].
As with polyps and leiomyomas, adenomyosis is a disorder that should have its own sub-
classification system [17], and it is clear that there should be an initiative to standardize the
methods of both imaging and histopathological diagnosis.
Leiomyomas (AUB-L)
Leiomyomas are extremely common benign fibromuscular tumors of the myometrium. They
manifest with a spectrum of sizes, numbers, and locations (submucous, intramural, subserous, and
combinations of the same), and because of their prevalence and variable relationship to symptoms,
they have a unique PALM-COEIN sub-classification system.
The primary classification system reflects only the presence or absence of one or more leiomyomas,
regardless of the location, number, and size. The criterion for determining the presence of leiomyomas
requires only sonographic examination confirming that one or more myomas are present.
In the secondary system, the clinician is required to distinguish myomas that contact the endo-
metrium (submucous or “sm”) from others (o) because it is generally considered that such (sm) lesions
are most likely contribute to the genesis of AUB.
The tertiary system is based on the predicate Wamsteker system for submucous leiomyomas (Type
0, 1, and 2) [18] and expanded to include tumors that just contact the endometrium without distorting
the endometrial cavity (Type 3), intramural tumors that have myometrium between their central and
peripheral boundaries and the endometrium and serosa (Type 4), and subserous tumors that are
categorized according to the relative proportions of the tumors within and extruding from the myo-
metrium (Types 5, 6, and 7) (Figure 2). When a myoma abuts or distorts both the endometrium and
serosa, it is categorized first by the sm classification and then by the subserosal location, with these two
numbers separated by a hyphen. This tertiary classification is not only useful for basic and clinical
investigators but also useful for surgeons who perform myomectomy to facilitate the identification of
situations where resectoscopic myomectomy is not appropriate.
Although not part of the system, clinicians and investigators are encouraged to include data such as
the size of the uterus in weeks' gestation and/or the single longest measurement and/or volume in
cubic centimeters, the location of the myoma or myomas (e.g., fundus, lower segment, cervix, and so
on), and the estimated number of tumors.
Malignancy and Premalignant Conditions (AUB-M)
Although relatively uncommon, atypical hyperplasia [now frequently called endometrial intra-
epithelial neoplasia (EIN)] [19] and malignancy are important potential causes of, or findings associated
with, AUB and must be considered in virtually any woman in the reproductive years. The PALM-COEIN
classification system is not designed to replace those of the WHO and FIGO for categorizing endo-
metrial hyperplasia and neoplasia [20,21]. Consequently, when investigation of women in the repro-
ductive years with AUB reveals a premalignant hyperplastic or malignant process, they are classified as
AUB-M and then “sub-classified” by the appropriate WHO or FIGO system.
Coagulopathy (Systemic Disorders of Hemostasis) (AUB-C)
AUB, and particularly HMB, that is associated with any of the spectrum of systemic disorders of
hemostasis known as coagulopathies is designated as AUB-C. There is a relatively high prevalence of
these disorders in several developing [22,23] and developed countries [24e26]. Indeed, there is high-
quality evidence that about 13% of women with HMB have a diagnosis of von Willebrand disease if
adequate laboratory investigation is performed [27]. It is important to understand that most of these
are mild variants and may often have a minor role in the symptoms of AUB in a given individual.
Nevertheless, it also seems important to consider these disorders in part because they likely do
contribute to some cases of AUB, and the information may be valuable for future surgical procedures
and as well as counseling children and other blood relatives. Women with AUB while on therapeutic
anticoagulation, formerly designated AUB-C, are now categorized as AUB-I (below).
Ovulatory Disorders (AUB-O)
When ovulatory dysfunction manifests with AUB, there is generally some combination of unpre-
dictable timing of bleeding and a variable amount of flow, which in some cases results in HMB [28]. In
fact, while anovulation may result in amenorrhea, many women may actually ovulate infrequently or
randomly, a circumstance that results in a variety of symptoms ranging from extremely light and
infrequent bleeding to episodes of unpredictable and extreme HMB that require medical or surgical
intervention. When HMB is associated with delayed or absent ovulation, the loss of luteal progesterone
results in persistent proliferative endometrium, which appears to be associated with reduced local
levels of F2a, one of the necessary ingredients for efficient endometrial hemostasis [29].
Particularly in the later reproductive years, there is emerging evidence that another disorder can
occur in ovulatory women: the “luteal out-of-phase” event [28,30]. These women ovulate but recruit
follicles early in the luteal phase, a circumstance that results in high circulating levels of estradiol and
related HMB.
Although in most instances, there is no definable cause for ovulatory disorders, many can be traced
to endocrinopathies such as polycystic ovarian syndrome, hypothyroidism, and hyperprolactinemia as
well as other factors including mental stress [31], obesity, anorexia, weight loss, and extreme aerobic
exercise [32,33]. In some instances, the disorder may be iatrogenic, caused by gonadal steroids or drugs
that impact dopamine metabolism such as phenothiazines and tricyclic antidepressants; in such in-
stances, they may be included in AUB-I. It is also apparent that otherwise unexplained ovulatory
disorders frequently occur at the extremes of reproductive age [34,35].
Endometrial Causes (AUB-E)
When AUB occurs in the context of predictable and cyclic menstrual cycles, suggesting ovulation
and particularly, but not only, when no other definable causes are identified, the mechanism is likely a
primary disorder residing in the endometrium [36]. If the symptom is HMB (previously called
“menorrhagia”), a primary disorder of local endometrial hemostasis may be present. There is high-
quality evidence demonstrating deficiencies in the local production of vasoconstrictors such as
endothelin-1 [37] and prostaglandin F2a [38,39]. In addition, it is evident that affected women typically
have accelerated breakdown of endometrial clot secondary to excessive production of plasminogen
activator [40] and increased local production of substances that promote vasodilation such as pros-
taglandin E2 and prostacyclin (PGI2) [38,41]. Unfortunately, and despite this longstanding evidence,
laboratory testing for such abnormalities are not currently available to clinicians.
It is likely that there are other primary endometrial disorders that do not result in HMB, instead
causing intermenstrual or prolonged menstrual bleeding. Prolonged bleeding may be a manifestation of
deficiencies in the molecular mechanisms of endometrial repair [42]. These disorders may be secondary
to any or a combination of mechanisms including endometrial inflammation or infection, abnormalities
in local inflammatory response, and abnormal endometrial vasculogenesis [39]. However, the role of
infection and other local inflammatory disorders in the genesis of AUB is not well defined and is
sometimes confounded by the normal presence of inflammatory cells in the endometrium [39].
Currently, despite this evidence and spectrum of potential mechanisms, and for the foreseeable
future, the FIGO system will categorize all suspected primary endometrial disorders as AUB-E and will
encourage clinicians to consider the diagnosis in women with apparently normal ovulatory function
and with no other definable cause or when it is suspected that a structural abnormality is asymp-
tomatic (e.g., Type-6 leiomyoma).
Iatrogenic (AUB-I)
There is a spectrum of medical devices and pharmacological interventions that can cause or
contribute to AUB and are collectively termed iatrogenic. These include both inert and drug-eluting
intrauterine systems (IUSs) [e.g., levonorgestrel-releasing IUS (LNG-IUS)] and pharmacologic agents
that directly affect the endometrium (e.g., all oral or systemic progestins), interfere with blood coag-
ulation mechanisms (e.g. warfarin, low-molecular-weight heparin preparations), or influence the
systemic control of ovulation. When abnormal bleeding is deemed to be related to iatrogenic causes, it
is categorized as AUB-I.
If combination estrogen and progestogen (EþP) formulations are administered cyclically, scheduled
uterine bleeding generally occurs in conjunction with the periodic withdrawal of the steroidal agents.
Unscheduled endometrial bleeding is termed “breakthrough bleeding” (BTB). Frequently, gonadal
steroid preparations, including combined EþP formulations, progestogens, and rarely androgens, are
administered continuously with the goal of establishing amenorrhea; any bleeding unrelated to other
causes is considered to be AUB-I. There are other pharmacological interventions including selective
progesterone receptor modulators and gonadotrophin-releasing hormone agonists and antagonists
that are administered with a goal of attaining amenorrhea but frequently are associated with BTB.
For orally administered agents at least, many episodes of BTB are related to reduced circulating
gonadal steroid levels secondary to compliance issues, resulting in reduced suppression of FSH pro-
duction and subsequent follicular development and increased endogenous estradiol [43]. Other po-
tential causes of reduced circulating levels of estrogens and progestins include the use of
anticonvulsants such as valproic acid [44], antibiotics such as rifampin and griseofulvin [45], cigarette
smoking, and related enhanced hepatic metabolism of gonadal steroids [46]. Valproic acid may also
impact gonadal steroid metabolism by increasing serum androgen levels and otherwise being asso-
ciated with features of PCOS [44].
As many as 55% of women using a 52 mg LNG-IUS can be expected to experience BTB in the first six
months after placement, after which it reduces to about 15e20%. Approximately 20% become amen-
orrheic by the end of the second year, increasing to 50% by year five [47].
Another contributor to AUB-I can be pharmaceuticals used to treat depression [48] or those that interfere
with dopamine metabolism, disordered prolactin release, and resulting disorders of ovulation [49].
An important cause of AUB-I, in particular HMB, is the use of anticoagulant drugs such as warfarin,
heparin, low-molecular-weight heparin, and some of the new orally active anticoagulants. Initially
included in AUB-C, the FIGO Menstrual Disorders Committee (MDC) has determined that the rightful
place for AUB related to these agents is in the AUB-I category.
Not Otherwise Classified (AUB-N)
There are a number of conditions and abnormalities, possible causes AUB, that are either rare or
their role in pathogenesis is not well defined. Examples include arteriovenous malformations [50] and
cesarean scar defects (“Isthmocele”) [51]. In addition, other disorders that have not yet been identified
and can be defined only using biochemical or molecular biological assays may exist. Collectively, these
entities (or future entities) have been placed in a category termed “Not Otherwise Classified” or AUB-N.
As further evidence becomes available, such abnormalities may be allocated a separate category, or
they could be assigned to one of the existing categories in the classification system.
Systematic approach to investigation
Overview
The information obtained by a structured approach to investigation may identify one or more
possible causes of the AUB. When multiple potential causes or contributors are identified or suspected,
it is incumbent on the clinician to thoughtfully integrate the information and identify the most likely
mechanism in a given patient. For girls and women with chronic AUB, these strategies include the
following:
a. Identification of the symptom type of chronic AUBdHMB, irregular uterine bleeding, IMB, or un-
scheduled or BTBdin the context of the use of gonadal steroids or other agents for contraception or
therapy.
b. Determination of the clinical impact of the symptom(s) on the patient such as interference with
lifestyle or the presence of iron deficiency with or without related anemia.
c. Evaluation for the underlying cause(s) of the AUB using a systematic and appropriately compre-
hensive approach based on the PALM-COEIN system for classification of causes. The progress and
results of this investigation may be recorded in an investigational matrix like those shown in
Figures 3 and 5aed [52].
Optimal management of patients with chronic AUB requires a menstrual history obtained with
detail at a level rarely taught in medical school or residency training programs. This is necessary not
only to distinguish among those with ovulatory cycles, ovulatory disorders, and bleeding between
normal periods but also to understand the effect of AUB on the patient's quality of life. This information
is typically followed by available investigative techniques that preferably start with transvaginal ul-
trasonic imaging of the uterus, if possible, during the initial evaluation. In absence of immediate
Figure 3. PALM-COEIN Working Matrix. This matrix can be used to guide and document the process of investigation.
availability of transvaginal ultrasound (TVUS), or where it is not appropriate because of factors such as
virginal status or patient reticence, the clinician arranges for appropriate imaging and laboratory
testing based upon the history and physical examination.
The results of the investigation will allow the clinician to identify one or a combination of causes or
contributors to the abnormal bleeding. This information, together with insight into the patient's
previous history and desires regarding immediate and future pregnancy, will allow for the design of a
menu of appropriate therapeutic options.
When a patient presents with nongestational acute AUB defined as that which, in the opinion of the
clinician, is of sufficient severity to warrant urgent intervention [1], the initial strategy and goals are
different. For such bleeding, the primary aims are threefold, and investigation is critically integrated
with management:
a. Assessment for hemodynamic status and stabilization as appropriate.

b. Identification of the most likely underlying cause(s) including evaluation for the presence of
pregnancy.
c. Initiation of immediate intervention(s) designed to promptly reduce or stop the bleeding.
Once the acute AUB is successfully treated, patient counseling is undertaken based upon previous
history. Those with no prior history of chronic AUB may be considered for expectant management as
long as no clinically significant finding has been obtained; many, if not most, of these patients have
experienced acute bleeding because of a transient ovulatory disorder. However, if chronic AUB is
present, appropriate investigation is indicated to identify the potential causes.
The Menstrual History
The features that distinguish normal uterine bleeding from AUB in the reproductive years have been
modified by FIGO on the basis of a contemporary review of available data, and the use of a form can
facilitate the determination of the status of a given patient (Figure 1). Many aspects of the history are
critical for optimal categorization of the causes of the bleeding. For example, cyclic and predictable
menstruation is usually associated with ovulation, whereas irregular and unpredictable bleeding is a
typical symptom of ovulatory disorders (AUB-O). For women who experience IMB in the context of
predictable cyclic menses, a focal lesion such as an endometrial polyp is often found (AUB-P) [53].
For chronic AUB, it is essential that the health care provider clearly determines the duration of the
clinical problem in months or years as well as the cycle length in days, the predictability of onset of
bleeding, and the duration and rate of the bleeding episodes, including the number of heavy days, and
the passage of clots (some women do not consider the clots to be bleeding). For women with HMB, the
presence of an underlying coagulopathy can be suggested by adding structured questions to the
menstrual history (Figure 4) [24]. For those who are identified to be at high risk with this tool,
appropriate investigations for coagulopathy are warranted, and a referral to a specialist with expertise
in hematology may be required.
Determination of the Extent of Blood Loss and Impact on Quality of Life
It is recommended that the evaluation of AUB symptoms should be based on a patient's reported
heaviness, frequency, regularity, and duration of bleeding [6,54] in conjunction with the perceived
impact on quality of life and general functioning [8,55,56]. In routine clinical practice, attempts at
accurate measurement of menstrual blood loss volume are impractical and, in general, unnecessary.
Although the effect of the bleeding on the levels of iron or hemoglobin are important considerations,
abnormal hemoglobin is not a prerequisite for investigating AUB including HMB. The aspects of AUB,
and particularly HMB, that worry women the most include the psychological irritation associated with
the bleeding and the complex of accompanying symptoms, particularly pelvic pain, the failure to al-
ways contain the gushes of menstrual loss (both during the day and at night), and the modification in
lifestyle behaviors that are necessary to conceal or contain menstrual flow [56,57].
Figure 4. Screening for Coagulopathy.
Work is ongoing to develop a simple structured menstrual questionnaire for use in clinical practice,
which will assist with assessment of blood loss, total menstrual fluid loss, and lifestyle factors and will
be a starting guide to possible underlying causes [58] (Internal Reference Matteson). For the present, it
is recommended that a series of simple questions be asked, which encompass as many of the following
as practicable: Frequency of changing “menstrual protection” items and use of “double” protection,
changing menstrual protection at night, self-consciousness about odor, inability to contain “gushes” of
menstrual flow, embarrassment at being unable to contain “gushes” of flow, and preparations and
rituals to prevent embarrassing episodes [8,57,58].
Pelvic examination
For both acute and chronic AUB, the physical examination may identify potentially relevant pa-
thologies and other features that may influence the investigational and/or treatment plan; however,
most of the clinically significant contributors to the symptoms are not detected because physical ex-
amination does not provide any information about the pathology impacting the endometrial cavity.
Whereas the physical examination is limited to the identification of intracavitary causes of AUB, it is of
great value in evaluation of the cervix, vagina, vulva, perineum, and perianal regions and possible
causes of abnormal bleeding and local tenderness.
Laboratory Assessment
Women with HMB should be, at the minimum, measured for hemoglobin and hematocrit as well as, in
most instances at least, ferritin, total iron, and iron saturation. Testing for coagulation disorders should be
performed in women who are identified by validated instruments such as the questionnaire described
previously (Figure 4) [24e26,59]. Patients determined to be at high risk for coagulopathy on the basis of this
instrument should undergo evaluation, if possible in conjunctionwith a hematologist, where assays may be
obtained for von Willebrand factor, Ristocetin co-factor, and a number of other disorders as appropriate.
Other laboratory investigations are performed as appropriate depending on the history. For example, an
assessment of prolactin and thyroid function should be undertaken in women with ovulatory disorders.
Evaluation of the Uterus
Evaluation of the uterus is an integral component of the evaluation of patients with chronic AUB.
Manual examination is usually inadequate because palpable lesions such as leiomyomas may not
contribute to the bleeding; clinically significant abnormalities are infrequently detected by this pro-
cess. Conceptually, it is important to consider three components when evaluating the uterus: (1)
assessment of the endometrium for the presence of hyperplasia or malignancy, (2) visualization of the
endometrial cavity and cervical canal for localized lesions such as polyps and submucous leiomyomas,
and (3) evaluation of the myometrium for adenomyosis, leiomyomas, and, more rarely, arteriovenous
malformations. The endocervical epithelium and cervical stroma should also be assessed considering
polyps, malignancy, and abnormalities such as the isthmocele, which is sometimes a result of previous
cesarean section. Because it is not necessary to evaluate all components in every patient, it is important
to apply these investigative approaches judiciously considering the age of the patient, existing risk
factors, and the previous response, if any, to medical or surgical interventions.
a. The Role of Ultrasound
Currently initial imaging of the uterus is almost always undertaken using two-dimensional (2-D)
TVUS, a routine component of the investigation in moderate- and high-resource settings. However,
although most primary care and many specialist physicians uncritically accept the printed report
describing the findings as an accurate depiction of the anatomical situation, the quality of the
assessment, and particularly the interpretation, are highly dependent on the skill and experience of the
ultrasound operator.
Several developments have improved our ability to detect and define certain structural lesions;
however, none are more accessible than contrast hysterosonography performed with the simultaneous
injection of sonographic contrast solutions such as saline or gel, a circumstance that facilitates the
evaluation of the endometrial cavity and the relationship of myometrial abnormalities to the endo-
metrium. Direct comparison among TVUS, contrast hysterosonography, and hysteroscopy suggests that
diagnostic hysteroscopy is significantly better than the other two techniques at detecting endometrial
and intracavitary lesions and that contrast hysterosonography is better than conventional TVUS [60,61].
Other advances in sonographic imaging include color-flow Doppler assessment to assist with the
evaluation of the vascular patterns in endometrial and myometrial lesions and 3-D imaging, a tech-
nique that may well largely replace MRI for more detailed evaluation of the uterus. Doppler assessment
is particularly useful in the identification of AV malformations [62], can help distinguish benign polyps
from malignant ones [63,64], and may have some utility in differentiating between leiomyomas and
leiomyosarcomas [65].
b. Evaluation of the Endometrium
Blind endometrial sampling is the standard method by which women are assessed for endometrial
neoplasia; however, there is an emerging role for both sonographic and hysteroscopic imaging. When
atypical endometrial hyperplasia (endometrial intraepithelial neoplasia) or endometrial cancer or
sarcomas are identified, the patient is categorized as having AUB-M.
It is also apparent that there is a relationship between endometritis, most notably chlamydial
infection of the endometrium, and AUB (AUB-E). Consequently, it may be prudent to consider evalu-
ating for the organism in the endometrium in symptomatic patients [66].
i. Sonographic evaluation
The single-layer thickness of the endometrium in ovulatory women fluctuates in from approxi-
mately 2 mm in the early follicular phase to approximately 6 mm in the late luteal phase [67]. At least
in normal-sized uteri, the two adjacent layers of endometriumdin essence, a double thicknessdcan
be readily imaged, a measurement termed the endometrial echo complex (EEC). Consequently, the
menstrual phase EEC is typically approximately 4 mm and increases up to approximately 12 mm in
the late luteal phase. In the presence of ovulatory disorders, absent exposure to progesterone, the
EEC is frequently much greater in thickness, a feature shared by the great majority of instances of
endometrial hyperplasia and endometrial carcinoma. As a result, TVUS may be considered a
component of initial triage of at-risk premenopausal women with AUB [68]. A well-designed study
has suggested that as long as the premenopausal EEC thickness is 12 mm or less (in premenopausal
women), there is very low incidence of endometrial hyperplasia or neoplasia [69].
ii. Endometrial sampling

Histological assessment of the endometrium requires that a sample (curettage or, preferably,
catheter-based biopsy) be obtained to evaluate for endometrial hyperplasia or malignancy. Of-
fice endometrial sampling has a reasonably high accuracy, particularly if an adequate specimen
is obtained for the detection of endometrial carcinomas [70,71], although sensitivity may be as
low as 91% in premenopausal versus postmenopausal women (98% sensitivity) [70]. However,
insufficient tissue obtained for diagnosis has been reported in 4e29.8% of cases [72e75], and
when only premenopausal women are considered, it has been reported to be approximately 25%
[74]. In 10e25% of the patients, the previous “traditional D&C” alone does not uncover existing
endometrial pathology [76], and it is associated with adverse outcomes such as hemorrhage
(0.4% of cases) and uterine perforation (0.6e1.3% of cases) [76]. Up to 50% of polyps are missed by
blind techniques, some of which may include atypical hyperplasia or carcinoma [70]. Conse-
quently, even if satisfactory and reassuring blind endometrial sampling is performed, should
symptoms persist, the ideal approach is hysteroscopy with targeted sampling or excision of
polyps or other identified lesions.
There is inconsistency in the medical literature regarding the appropriate selection criteria for
endometrial sampling in premenopausal women. Guidelines such as those of the New Zealand
Guidelines Group and the UK's National Institute for Health and Care Excellence suggest that
endometrial sampling should be considered in all women with AUB over the age of 45 years
[8,77]. Other investigators have provided more selective criteria considering risk factors for the
presence of unopposed estrogen (such as obesity and chronic anovulation manifesting in AUB-O),
a feature present in the vast majority of cases of endometrial carcinoma and one that places at
risk those below the 45 years threshold. It is apparent that premenopausal individuals with AUB
and BMI of 30 or more have up to fivefold increased risk of having complex and atypical endo-
metrial hyperplasia or cancer compared with women of normal weight [78e81]. Ultrasound
thresholds have also been suggested: those with AUB and EEC greater than 12 mm should be
sampled [69]. A New Zealand group identified the following factors: (1) age over 45 years; (2)
obesity (>90 kg); (3) a history of chronic anovulation, infertility, or diabetes; (4) a family history
of endometrial cancer; and (5) prolonged exposure to unopposed estrogens or tamoxifen [82,83].
iii. Women from families with Lynch syndrome (previously known as hereditary nonpolyposis
colorectal cancer) have a lifetime risk of developing endometrial cancer that may be as high as
60%, with a mean age of diagnosis between 48 and 50 years [84]. Consequently, women with
AUB of any type who are known or suspected to be from affected families should be liberally
investigated with endometrial sampling regardless of age.
c. Assessment for Focal Endometrial and Endocervical Pathology
Accurate structural evaluation of the endometrial cavity and cervical canal requires imaging with
ultrasonographic and/or hysteroscopic techniques. In instances when vaginal access is limited (for
example, virginal women and women who are very reticent about examination), evaluation with MRI
may be the best option.
In skilled hands, TVUS has 96% sensitivity, 86% specificity, 91% positive predictive value, and 94%
negative predictive value in the diagnosis of intrauterine abnormalities causing AUB [85], and the more
recent introduction of high-frequency vaginal probes has further improved image quality and pre-
dictive value [86]. In the presence of an abnormally thick endometrium, when myomas are present
suspiciously close to EEC, or when abnormal bleeding occurs or persists despite a normal TVUS,
contrast hysterosonography or hysteroscopy is indicated. Contrast hysterosonography with saline or gel
infusion sonography is comparable to hysteroscopy in its sensitivity for the diagnosis of intracavitary
polyps and submucous leiomyomas [60,61,87,88]. The major deficiency, compared with hysteroscopy, is
limited evaluation of the endocervical canal and the inability to concurrently remove selected lesions
unless additional instrumentation is performed. Endometrial carcinoma and endometrial hyperplasia,
particularly those arising as a field defect, may not always be clearly recognizable by endoscopy alone,
making catheter-based endometrial sampling a necessary adjunct to targeted biopsy [89].
With modern equipment and at least selective use of local anesthesia, operative hysteroscopy can
also be performed by most gynecologists in the office environment to identify and, if appropriate,
direct the biopsy of focal lesions [90e95]. Patients with tortuous or stenotic cervices may be difficult to
examine using office hysteroscopy; however, usually even difficult cases can be evaluated successfully
and comfortably provided there is adequate local anesthesia [94].
MRI has been shown to be accurate in the evaluation of the endometrial cavity in women with AUB,
particularly in selected patients in whom SIS or hysteroscopy are not feasible [96].
d. Evaluation of the Myometrium
The purpose of myometrial assessment is generally to identify and characterize adenomyosis,

adenomyomas, and leiomyomas as well as other abnormalities such as AV malformations and the
uterine isthmocele that may contribute to the genesis of AUB. For leiomyomas, the number, location,
size(s), and FIGO classification should be determined and documented.
Two-dimensional TVUS (and sometimes abdominal ultrasound) is a useful primary technique for
the detection and evaluation of myomas in the myometrium, although variations in echogenicity and
body habitus can reduce the sensitivity of the examination. Furthermore, 2-D imaging can be chal-
lenging when the aggregate uterine and leiomyoma volume is quite large because it is difficult to
adequately image and track the various lesions identified. In such instances, 3-D ultrasound or MRI is of
additional value.
For the diagnosis of adenomyosis, TVUS with the application of a set of objective criteria for the
diagnosis of adenomyosis has been found to be comparable with MRI, with approximately 80%
sensitivity and similar specificity [15,97]. These criteria include the following: a globular uterine
configuration, poorly defined endometrialemyometrial junction, myometrial echogenic linear stria-
tions, thickening of the myometrium, asymmetrical anterior and posterior myometrial thickness,
irregular myometrial cystic spaces, and a heterogeneous myometrial echotexture. Although there is
evidence suggesting a threshold of three of these criteria for making a diagnosis [16], the ideal number
has not been established. Similar to the case for polyps and leiomyomas, adenomyosis is a disorder that
could benefit from its own sub-classification system [17].
Color-flow Doppler ultrasound is useful in detecting blood flow and, consequently, is valuable for
the detection of arteriovenous malformations; in addition, it may also have a role in detecting atypical
endometrial polyps and malignancies. However, the most important application of color Doppler is in
distinguishing focal adenomyosis from leiomyomas because in the latter, myometrial vessels course
around the lesion, whereas in adenomyosis, the vessel retains its vertical orientation to the endo-
metrial cavity [98,99].
MRI has utility in at least selected women with AUB not only for the detection of adenomyosis [100]
but also to distinguish adenomyomas from leiomyomas. For adenomyosis, although other criteria exist,
a measured “junctional zone” thickness of greater than 12 mm correlates well with a histopathological
diagnosis of adenomyosis [14,101]. There is some evidence that quantified irregularity (thinnest to
thickest 4e6 mm) in MRI- or 3-D ultrasound-determined thickness of the junctional zone provides
additional sensitivity for the diagnosis of adenomyosis [16,102]. MRI may be superior to transvaginal
sonography, contrast hysterosonography, and hysteroscopy for determining the myometrial involve-
ment of submucous leiomyomas [96].
Although the use of myometrial biopsy to distinguish adenomyosis from leiomyomas has been
explored, the results are somewhat disappointing. Whereas transcervical needle biopsy seems to have
high specificity, it has poor sensitivity for the diagnosis of adenomyosis compared with histopatho-
logical examination of hysterectomy specimens [103,104].
Implementation and integration of results
There are a number of practical considerations for clinicians who deal with women with AUB in the
reproductive years. The exact order and comprehensiveness of the investigation may appropriately
vary depending upon the clinical situation. It is also important to remember that the evaluation may
reveal more than one potential contributor to the genesis of the AUB and that, frequently, identified
structural lesions such as adenomyosis, some polyps, and leiomyomas, particularly Type 3, may be
asymptomatic. In these circumstances, clinical judgment should be applied with trials of therapy
utilized, if appropriate and desired by the patient, to address the symptom(s) and, in the process, assist
with the determination of the clinical relevance of potentially asymptomatic findings.
When can the evaluation be abbreviated?
There are a number of situations where all the investigations described above will not be necessary,
at least initially. This requires that the clinician seek to identify individuals at low risk for malignancy or
structural abnormalities. For example, a thin 19-year-old women with apparent AUB-O manifesting in
irregular but light or normal volume menstrual bleeding and a normal physical examination will not
usually require imaging, laboratory assessment, or endometrial sampling. She may be offered expec-
tant management or, for example, cyclically administered combination estrogen and progestogen
containing pills, rings, or patch contraceptive formulations to provide regular and predictable with-
drawal bleeding or, used continuously, for suppression of bleeding as desired. A similar situation exists
when a young, previously untreated patient has HMB and likely AUB-E, understanding that uncommon
features, such as submucous leiomyomas (AUB-Lsm) and adenomyosis (AUB-A) not recognizable by
physical examination, may exist. However, endometrial sampling will be unnecessary if simple medical
therapy is effective and acceptable to the patient, and it may be reasonable to defer additional imaging
evaluation that is pending in response to a trial of therapy. For women with HMB, it is still necessary to
at least measure hemoglobin and hematocrit because although many with “normal bleeding” are
normal in this regard, others may have existing iron deficiency and IDA.
Who should have more extensive and complete evaluation?
A number of features of the initial assessment, including the menstrual history and physical ex-
amination, can be useful in identifying patients who require a more complete evaluation. The first
group comprises those who have an increased risk of endometrial neoplasia. The criteria for routine
endometrial sampling may vary across jurisdictions; however, when ovulatory dysfunction is sug-
gested by the presence of prolonged irregular and unpredictable bleeding in a woman over the age of
40, evaluation of the endometrium is generally necessary. In addition, age is not the only criterion. For
example, an obese 28-year-old women with a BMI of 42 and a long history of apparent AUB-O should
undergo endometrial sampling because she could also have EIN (atypical endometrial hyperplasia) or
endometrial carcinoma. Another group comprises those who have IMB, a typical manifestation of
endometrial polyps. For others, including women who fail initial therapy, further investigation is
almost always warranted.
Case studies
Figure 5a
a) AUB-LSM
This 32-year-old nulliparous patient has HMB; her menstrual pattern suggests ovulation (30-day
cycle; range 27e33 days), with a menstrual duration of 9 days, heavy with clots. Although her
bimanual examination demonstrates a normal-sized uterus, ultrasound and contrast hysterosonography
demonstrate a FIGO Type 2 leiomyoma. Her hemoglobin level was 10.9 gm/dL, and serum ferritin and iron
saturation all suggested iron deficiency. Because the patient wished to preserve fertility, she opted for
hysteroscopic resection of her leiomyoma after treating her anemia and iron deficiency with oral iron.
Figure 5b
b) AUB-LO, -O
This 25-year-old para 0000 presents with a nine-month history of irregular menstrual bleeding
every 14 to 60 days, with variable duration and heaviness of flow for 2 to 11 days. She has a BMI of 33
Figure 5. Examples of documentation of the results of investigation using a PALM-COEIN “Matrix”.
but no other abnormalities on her general examination. Although manual examination of the uterus
was limited, TVUS demonstrates a 2.5-cm diameter FIGO Type 6 leiomyoma. It is correct to assume that
the leiomyoma is not responsible for the AUB and that the symptoms are related to an ovulatory
disorder. The patient's thyroid function was normal; however, her hemoglobin was 9.3 gm/dL, with red
cell indices suggesting IDA. Because she did not wish pregnancy at this time, she selected cyclically
administered combined contraceptive pills, oral iron replacement, and a weight loss program.
Figure 5c
c) AUB-P, -LO
This 38-year-old para 2002 presented with a six-month history of light IMB. Her menses were
unchanged with a cycle length of 31 ± 3 days, and a normal duration of 4 days with normal volume.
Examination demonstrated normal vulva, vagina, and cervix and no lesions. Her manual examination
suggested a slightly enlarged uterine corpus. TVUS demonstrated 3-cm FIGO Type 4 and a 4-cm FIGO
Type 5 leiomyomas; however, contrast hysterosonography revealed a 1.2-cm long by 8-mm wide
endometrial polyp. She underwent hysteroscopic polypectomy, and her symptoms resolved. The
leiomyomas were clinically insignificant.
Figure 5d
d) AUB-A, -C
This 35-year-old nulligravida presented with a lifelong history of HMB. Her menses were always
cyclic and predictable but long and heavy with clots. She has fought anemia all her life. Over the past
several years, she has experienced progressively worsening dysmenorrhea, which extends through the
entire period, and the volume of bleeding and clots is increasing. It is more difficult to maintain her
hemoglobin levels even with 185 mg of elemental iron every day. She has unexplained bruising on her
arms and legs, a lifelong experience; however, more recently, she has been experiencing bleeding with
flossing and brushing her teeth.
Examination demonstrated a normal-appearing woman with some bruising on arms and legs. Her
BMI was 25. The vulva, vagina, and cervix were normal; however, the uterine corpus was symmetrically
enlarged and slightly tender. TVUS revealed a globally enlarged uterine corpus with thickened hetero-
geneous myometrium, a pattern of striae, and a blurred endomyometrial junction. Because she “failed”
the screening test for coagulopathy, blood assays were obtained, revealing evidence of von Willebrand
disease. A hematology consultation was sought. Ultimately, because she did not wish to conceive in the
foreseeable future, she selected a LNG-IUS releasing 20 mg of levonorgestrel per day for therapy.
Summary
The exact usage of the techniques described will be greatly dependent on access to local technologies,
the skills to use and interpret them, and the ways in which this information may influence management.
However, there are few components of a FIGO-based investigation that are unavailable to most clinicians
throughout the world. A structured history, generally simple laboratory tests, and TVUS with and without
contrast can be used to completely evaluate women with chronic AUB. Clinical judgment and trials of
therapy remain as critical components of the investigation and management pathway.
Practice Points
Many terms and definitions that, heretofore, have been used to describe the symptoms of
AUB, and even abnormal bleeding-related diagnoses, have been poorly defined, leading to
inconsistent communication between and among members of the research, clinical, and
patient communities.
The first FIGO system has been designed to create terms and definitions of normal uterine
bleeding and AUB in the reproductive years that minimize ambiguity. Clinicians are
encouraged to use these terms and definitions when evaluating patients.
While seemingly mundane, a meticulously obtained menstrual history, past and present, is
critical to the understanding of both the impact of menstrual symptoms on the quality of life
of the patient and the potential causes of the AUB problem itself.
Many women have excessive menstrual loss that they feel is normal and minimize, whereas
others have comparatively little blood loss that, by virtue of unpredictability, is disruptive.
The clinician should seek to uncover the individual suffering in silence and respect the ca-
pacity of a spectrum of abnormal bleeding patterns to adversely impact the quality of life.
The second FIGO system, called the PALM-COEIN system, is designed to assist clinicians,
educators, as well as basic, translational, and clinical investigators in identifying the potential
causes of AUB in a given patient.
Complete investigation of women with AUB in the reproductive years frequently requires
that the endometrial cavity be evaluated. This is best performed by the clinician using either
diagnostic hysteroscopy or office-based contrast hysterosonography.
Investigation may identify one or more potential “PALM-COEIN” contributors to the patient's
symptoms.
Whereas many of the mechanisms underlying HMB secondary to AUB-E have been deter-
mined, there is currently no available clinical test for this diagnosis. Consequently, AUB-E can
be suspected in any apparently ovulatory individual with HMB and no other identifiable
cause such as a submucous leiomyoma.
All those involveddclinician, trainee, patient, and, if appropriate, investigatordshould un-
derstand that many findings may indeed not contribute to the symptoms in a given patient.
Examples of findings that may have no relevance in the AUB of a given patient include ade-
nomyosis, endometrial polyps, Type 4e8 leiomyomas, and Type 1 von Willebrand disease.
Research Agenda
The two FIGO systems have been designed as both clinical and research tools. All types of
investigators are invited and encouraged to use the system(s) to help them identify homoge-
neous groups of patients to help them advance their own research agendas.
Possible applications include the following:
Determine the role of Type 3 uterine leiomyomas in the genesis of HMB

Distinguish between the endometrial molecular manifestations in women with HMB with and
without adenomyosis and any other absent potential contributor to the symptom such as
coagulopathy or submucous leiomyoma.
Evaluate the impact of tranexamic acid on HMB in women with isolated Type 1, 2, 3, or 4
leiomyomas
Compare AUB-related quality of life in women with AUB-E and AUB-O
Conflict of interest
The author has no disclosures related to the content of this manuscript.
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Best Practice Issue on “Abnormal Uterine Bleeding”

Malcolm Gordon Munro

AAGL Series on AUB in the Reproductive Years View project

STOP-DUB View project

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Contents lists available at ScienceDirect

Best Practice & Research Clinical

Practical aspects of the two FIGO systems for

The PALM-COEIN system for classiﬁcation of causes

Malignancy and Premalignant Conditions (AUB-M)

Coagulopathy (Systemic Disorders of Hemostasis) (AUB-C)

Ovulatory Disorders (AUB-O)

Endometrial Causes (AUB-E)

Not Otherwise Classiﬁed (AUB-N)

Systematic approach to investigation

a. Assessment for hemodynamic status and stabilization as appropriate.

The Menstrual History

Determination of the Extent of Blood Loss and Impact on Quality of Life

Figure 4. Screening for Coagulopathy.

Evaluation of the Uterus

a. The Role of Ultrasound

b. Evaluation of the Endometrium

ii. Endometrial sampling

c. Assessment for Focal Endometrial and Endocervical Pathology

d. Evaluation of the Myometrium

The purpose of myometrial assessment is generally to identify and characterize adenomyosis,

Implementation and integration of results

When can the evaluation be abbreviated?

Who should have more extensive and complete evaluation?

Figure 5. Examples of documentation of the results of investigation using a PALM-COEIN “Matrix”.

Determine the role of Type 3 uterine leiomyomas in the genesis of HMB

The author has no disclosures related to the content of this manuscript.

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