Review

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Pathophysiology of heavy menstrual

bleeding

Heavy menstrual bleeding (HMB) is a common gynecological complaint with multiple Dharani K Hapangama*,1
etiologies and diverse pathophysiological origins. This review discusses HMB with & Judith N Bulmer2
1
reference to the recently proposed PALM-COEIN classification system for abnormal
uterine bleeding, initially describing the endometrial events in normal menstruation
followed by discussion of the perturbations of normal endometrial shedding that can
result in HMB. Our present understanding of the mechanisms of menstrual bleeding
as well as many of the pathological aberrations of HMB is incomplete. Further 2

research into the pathophysiology of HMB is urgently needed, as clear knowledge

of the mechanisms of this disorder will provide new therapeutic targets to formulate
more effective treatments.

Keywords:

In the developed world an average woman
undergoes ∼400 repetitive cycles of monthly
menstrual bleeding with shedding of her
superficial endometrial functional layer. In
as many as 20–30% of women, this bleeding
is excessive and is termed heavy menstrual
bleeding (HMB) [1] . Apart from the physi-
cal symptoms of anemia (fatigue, lethargy
and exertional dyspnea), HMB can interfere
with normal daily life and may affect the
social and emotional well being of women,
reducing their productivity in society. HMB
commonly presents to primary and second-
ary healthcare providers, with over 1.5 mil-
lion women suffering from this problem in
England and Wales alone [1] . It is the fourth
most common reason for secondary gyneco-
logical referrals and each year over 30,000
women in England and Wales undergo surgi-
cal treatment for HMB [1] . The annual cost
to the National Health Service in 2000 was
estimated to be over GB£65 million [2] and
with the spiraling cost of healthcare provi-
sion, it is clear that the current cost of HMB
to women, society and the National Health
Service is huge.
In this review HMB will be discussed with
reference to the recently proposed polyps;
adenomyosis; leiomyoma; malignancy and
hyperplasia; coagulopathy; ovulatory dys-
function; endometrial; iatrogenic and not
yet classified (PALM-COEIN) classification
system for abnormal uterine bleeding (AUB),
approved by the International Federation
of Gynecology and Obstetrics [3] . HMB
can present as a chronic disorder of over
12 months duration or as an acute increase
in bleeding over a short time period. The age
at presentation can range from adolescence
to the perimenopausal phase and HMB
may occur in the context of either ovula-
tory or anovulatory cycles. This review will
briefly describe the endometrial events in
normal menstruation followed by discussion
of the perturbations of normal endometrial
shedding that can result in HMB.
Normal menstruation
The purpose of menstruation is unknown
but it is a phenomenon confined mainly to
the upper order primates and humans [4] ,
part of
suggesting an associated evolutionary advan-

10.2217/whe.15.81 © 2016 Future Medicine Ltd Womens Health (2016) 12(1), 3–13 ISSN 1745-5057 3
Review Hapangama & Bulmer
tage. The morphology of human endometrium, rela-
tively greater quantity of menstrual shedding/bleed-
ing, larger uterine size relative to adult female body
size and the design of the endometrial microvascula-
ture suggest that women have higher resource allo-
cation to endometrial function than many other pri-
mates. The average menstrual cycle length in women
is 28 days and most women have bleeding for approx-
imately 4–5 days associated with shedding of the
superficial stratum functionalis of the endometrium.
The endometrium is under the regulation of ovarian
steroid hormones, mainly estrogen and progesterone
and their involvement in the monthly endometrial
cycle is well established. These ovarian sex steroids
exert their effects on the endometrium via the respec-
tive steroid hormone receptors [5] . Ovarian androgens
and glucocorticoids of adrenal origin may also play a
role in this process, although the actions of androgens
on the endometrium are yet to be elucidated [4] .
After menstrual shedding every cell type of the stra-
tum functionalis (epithelial, stromal and vascular),
under the influence of estrogen, is regenerated from
the cells of the remaining stratum basalis [6] . Estro-
gen, via estrogen receptor (ER), increases the endo-
metrial responsiveness to all ovarian steroid hormones
by upregulating ER, progesterone receptor (PR) and
androgen receptor (AR) the net result being cell pro-
liferation with consequent rebuilding and increasing
thickness of the endometrial functionalis layer [5] .
After ovulation, as the production of progesterone by
the corpus luteum increases, histologically the endome-
trium assumes secretory phase changes and undergoes
differentiation. Progesterone, acting via PR, reduces
endometrial ER, PR and AR expression, and gener-
ally counteracts the estrogen driven mitotic activity of
endometrial cells. As well as secretory changes in the
endometrial glands, the progesterone dominant effects
of the endometrium include predecidualization of the
endometrial stroma which prepares the endometrium
for implantation of the embryo, although decidual-
ization of endometrial stroma is seen even without
embryo implantation. During the secretory phase of
the menstrual cycle the spiral arterioles within the
stratum functionalis grow and acquire muscle and spi-
ral arterioles are easily identified histologically by the
end of the secretory phase.
As the corpus luteum demises at the end of a cycle
where conception has not occurred, the stratum func-
tionalis is shed in response to the plummeting proges-
terone levels. This withdrawal of progesterone with
luteal regression has been postulated to be the trigger
for the initiation of menstrual bleeding [4] ; with the
induction of stromal shrinkage and spiral arteriolar
vasoconstriction with relative hypoxia in the functio-
4 Womens Health (2016) 12(1)
nalis layer followed by the instigation of acute inflam-
matory changes including the influx of large amount
of leucocytes and immune cells [7,8] , launch of the
inflammatory cascade (increase in proinflammatory
cytokines, prostaglandins and destructive enzymes
of the extracellular matrix such as MMPs exclusively
in the endometrial stratum functionalis) [7] and the
activation of stem/progenitor cells that are postulated
to be resident in the endometrial stratum basalis [6] .
The shedding of the ‘old’ stratum functionalis usually
happens over 1–2 days yet the menstrual bleeding con-
tinues during the proliferation and repair of the sur-
face epithelium of the damaged stratum functionalis
which takes several days. The endometrial hemostasis
which is responsible for cessation of menstrual bleed-
ing involves platelet aggregation, fibrin deposition and
thrombus formation [9] .
Studies of myometrium have traditionally been
limited to the pregnant uterus and labor [10] , although
myometrial contractions felt as menstrual period
associated ‘cramps’ are a symptom that is commonly
reported by women during menstruation. This dra-
matic increase in the amplitude (labor like, and
increased from a base line of <30 mmHg up to 50–200
mmHg) of myometrial contractility, particularly seen
in the inner subendometrial zone of the myome-
trium during menstruation, is likely to be induced by
increased endometrial production of prostaglandins
such as PGF2α and PGE2 [11,12] . These contractions
may play a role in emptying the uterine cavity of men-
strual debris and may also play a haemostatic role by
providing a pressure effect on the endometrial vascu-
lature. Although the pivotal role played by myometrial
contractility in preventing uterine bleeding following
parturition is well established [13] , very little is known
of the contribution of myometrial contractility in
regulation of menstrual bleeding.
After menstrual shedding, the subsequent repair
process has been traditionally presumed to be due
to the action of estrogen [4–5,14] . However, the very
early repair process is not necessarily dependent on
estrogen, as the level of estrogen is at a nadir when
the re-epithelialization of the endometrial surface
occurs; a process that is not impaired in the post-
menopausal hypoestrogenic state [5,15] . The activity of
stem progenitor cells, either solely from the resident
endometrial stem progenitor cell pool or from the cir-
culating hematopoietic precursor pool, is involved in
this regeneration process [6,16] . Therefore, a series of
complex, orchestrated interactions between endocrine,
paracrine, immunological and hemostatic factors on
the endometrium results in normal menstrual bleed-
ing and aberrations of each of these characteristics may
result in HMB.
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HMB
Traditionally HMB is defined as bleeding in excess
of 80 ml per menstrual cycle when measured objec-
tively [17] , although among women who present with
the complaint of significant HMB, fewer than 50%
have been objectively shown to have >80 ml of men-
strual loss [18] . HMB is a relatively uncommon com-
plaint in younger women, yet has a prevalence of one
in three women in the perimenopausal period [19] . The
pathophysiology of HMB may be discussed in the con-
text of both ovulatory and anovulatory cycles. Ovula-
tory HMB is heavy, regular menstrual bleeding occur-
ring between 21 and 32 days, whereas in anovulatory
cycles heavy, often prolonged bleeding occurs 35 or
more days apart [4] . Adolescents and young women
presenting with HMB dating from their menarche are
termed as suffering from primary HMB, whereas rela-
tively acute onset HMB occurring in later reproductive
life is referred to as secondary HMB [20] .
According to the Federation of Gynecology and
Obstetrics classification of AUB, nine categories are
listed according to the acronym PALM-COEIN [3] .
The PALM group consists of structural abnormali-
ties that can be visualized using imaging techniques
or diagnosed by histopathology; whereas nonstructural
disorders that cannot be imaged or diagnosed with
histopathology are included in the COEIN group.
Mechanisms of HMB
Any process that interferes with the normal endocrine,
paracrine or hemostatic functions of the endometrium
as well as possibly any interference with myometrial
contractility may cause HMB.
Polyps
Polyps are defined as abnormal outgrowth of hypertro-
phied tissue and in the endometrial cavity can be either
endometrial or myometrial in origin [21] . Myometrial
‘polyps’ are submucosal leiomyomas and will be dis-
cussed in the next section. Endometrial polyps are com-
mon outgrowths of endometrial lining consisting of a
monoclonal overgrowth of endometrial stromal cells
with inclusion of a non-neoplastic glandular compo-
nent [22] . They may be single or multiple and one study
reported endometrial polyps in 28% of women, with
the highest incidence in the fifth decade [21] . The size
can vary from a small rounded protruberance within
the endometrial lining to a large broad based or pedun-
culated lesion that can fill the uterine cavity. Endome-
trial polyps are usually benign but careful histologi-
cal examination is required to exclude the possibility
of focal atypical hyperplasia or even adenocarcinoma,
although these findings are more common in post-
menopausal women [21,23] . Diagnosis of an endometrial
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Pathophysiology of heavy menstrual bleeding Review
polyp may be difficult in a fragmented specimen but
the presence of thick walled vessels, altered fibrous or
collagenous stroma and irregular glands will be help-
ful. Endometrial polyps respond variably to estrogen
and progesterone and lack the cyclical changes seen
in the adjacent endometrium. They may present with
the symptom of an irregular and intermenstrual HMB
pattern. Up to 2% of endometrial polyps may have a
premalignant or malignant potential in premenopasal
women and according to a recent systematic review [23]
this risk is increased when the patient has presented
with bleeding irregularities.
Endometrial stimulation by estrogen is postulated
as the main driving force for endometrial polyp for-
mation and this is supported by the observation that
use of tamoxifen, which acts as an ER agonist on the
endometrium, increases the risk of endometrial pol-
yps [24,25] . In addition, genetic mutations and the over-
expression of endometrial aromatase, which increases
the local estrogenic signal, are also thought to be
involved in the formation of endometrial polyps [24,25] .
Small (<1 cm) benign endometrial polyps often regress
but larger lesions are likely to persist [23,24] .
Endometrial polyps are the commonest endome-
trial pathology associated with tamoxifen treatment,
with an incidence rate of 8–36% [26] ; this frequency is
much higher compared with the incidence of 0–11%
which is seen in untreated women [27] . Compared with
women not taking tamoxifen, these polyps are likely
to be larger, more fibrotic and to more frequently show
mucinous metaplasia. Histology may also identify
hyperplasia with an incidence of malignant transfor-
mation of 3–10.7% in tamoxifen-related endometrial
polyps, a much higher rate than in healthy controls [26] .
The exact mechanism whereby endometrial polyps
cause an increase in menstrual loss is not fully under-
stood. An abnormal microvasculature is a feature of
endometrial polyps with the presence of thick muscu-
lar walled blood vessels being an important diagnostic
feature on histopathological examination and this may
provide some explanation. Incomplete shedding of the
endometrial covering has been described in endometrial
polyps and this may also potentially contribute to HMB.
Myometrial dysfunctions (adenomyosis
& leiomyoma)
Leiomyomas
Leiomyomas, commonly referred to as ‘fibroids’ are
benign neoplasms of the myometrium and are the
commonest tumor in women of reproductive age. As
many are asymptomatic, the prevalence is difficult to
determine. However, after histopathological examina-
tion of hysterectomy samples, leiomyomas were identi-
fied in 77% of uteri [28] . Leiomyomas are monoclonal
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Review Hapangama & Bulmer
arising from a single cell. Various nonrandom chro-
mosomal abnormalities have been reported, including
deletion of portions of 7q, trisomy 12 and rearrange-
ments of 12q15, 6p21 or 10q22 [29] . There is a familial
predisposition and having a first-degree relative with
fibroids increases a woman’s risk at least two-fold [30,31] .
The prevalence of leiomyomas reduces after the
menopause and they are not detected in preadolescent
girls. The incidence increases in reproductive years and
peaks in the fifth decade. Obesity is a risk factor, while
increased parity and cigarette smoking are protective [28] .
Compared with normal myometrium, leiomyomas have
a higher concentration of ER, PR and aromatase [32] and
they grow in response to estrogen and progesterone.
The majority of leiomyomas do not cause clini-
cal symptoms and even when symptoms are present
it is sometimes uncertain whether they are due to the
fibroids [33] . The reason why many fibroids do not cause
symptoms is not known. It is estimated that 20–50%
women with fibroids will have symptoms that can
directly be attributed to the leiomyoma(s) [34] . Various
symptoms have been reported, including AUB, pelvic
pressure (also causing urinary incontinence, dysuria,
urgency and other bladder symptoms), bloating, con-
gestion, heaviness, dyspareunia and constipation. The
commonest symptom is HMB. An ultrasound study
reported that premenopausal women with AUB had a
higher incidence of submucosal leiomyomas (21 vs 1%)
and intramural leiomyomas (58 vs 13%) compared
with asymptomatic women [35] . A more recent US based
study reported that women with leiomyomas were more
likely to report excessive bleeding (46%) than those
with no leiomyoma (28%). Risk of bleeding increased
with size and bleeding symptoms were similar in those
with submucosal and nonsubmucosal leiomyomas [36] .
Several theories have been proposed to account for
the HMB that is seen in association with leiomyo-
mas. These include an increase in the uterine surface
area, increased vascularity and vascular flow into the
uterus, reduction in myometrial contractility particu-
larly of the inner junctional zone, endometrial ulcer-
ation over a submucosal leiomyoma and compression
of the venous plexus within the myometrium leading
to congestion of myometrium and endometrium [11] .
There is limited objective evidence for many of these
suggested pathogenetic mechanisms. Location has
been suggested to influence symptoms, with submu-
cosal leiomyomas having a greater association with
HMB, although objective evidence for this is limited;
there is no consistent relationship between the size and
location of fibroids and HMB [37,38] .
Early studies revealed that the myometrium in leio-
myomatous uteri showed an increase in the venous
plexus, especially at the edge of the leiomyomas [39] .
6 Womens Health (2016) 12(1)
Early studies also noted an increased vascular supply
to leiomyomas; fibroids are very vascular, contain-
ing thick walled muscular vessels. This dysregulation
of normal vascular function in leiomyomas may be
attributed to abnormalities in expression of angiogenic
growth factors and their receptors [39,40] . In a recent
study, blood flow and angiogenic gene expression was
investigated in fibroid, perifibroid and distant myome-
trium. Blood flow in tissue around leiomyomas was
higher than within the leiomyoma, although there was
heterogeneity. There was no difference in angiogenic
gene expression between perifibroid and distant myo-
metrium but expression of nine angiogenesis related
genes differed significantly between fibroid and distant
myometrium and two genes were significantly dif-
ferent between fibroid and perifibroid myometrium.
However, there was no correlation between blood flow
and any clinical or molecular parameter [41] .
The presence of leiomyomas may also affect the
composition of the overlying endometrium. When
endometrial leucocytes in endometrium near to leio-
myomas was compared with distant endometrium, the
number of uterine natural killer cells was reduced in
endometrium overlying leiomyomas during the mid
and late secretory phases, while macrophages were
increased in the same area throughout the menstrual
cycle [42] . Both uterine natural killer cells and macro-
phages are potential producers of angiogenic growth
factors [43,44] which may influence vessels within the
endometrium overlying leiomyomas.
Despite advances in understanding of the molecular
changes in leiomyomas and associated myometrium
and endometrium, it remains unclear why clinical
symptoms are so varied. HMB is seen in some women
with leiomyomas but it does not correlate clearly with
the size or location of fibroids or with the expression of
angiogenic growth factors or blood flow.
Adenomyosis
Adenomyosis is a common disorder that is charac-
terized by the presence of endometrial glands and
stroma within the myometrium, usually surrounded
by hypertrophied myometrial smooth muscle [45–47] .
Until recently the diagnosis depended on examina-
tion of hysterectomy specimens and the reported
prevalence varied from 5 to 70%; this variation is
partly related to the number of histological sections
examined, with the incidence of adenomyotic foci
increasing as more sections are examined in hyster-
ectomy specimens [45] . Variations in prevalence may
also be explained by inconsistent histological defini-
tions of adenomyosis, with some specifying a mini-
mum depth based on myometrial thickness, while
others make the diagnosis based on microscopic fields
future science group

beneath the endometrial–myometrial interface, with
variations from one high power field to two low power
fields [46,47] . Diagnosis can now also be made using
imaging techniques such as MRI or transvaginal ultra-
sound. A recent ultrasound study of 985 symptomatic
women attending a gynecology clinic noted adenomy-
osis in 20.9%, with good correlation between ultra-
sound and histological diagnosis in the 45 women who
subsequently had a hysterectomy [48] . Adenomyosis is
commonest in women of late reproductive age and the
majority of women with this condition are parous [48] .
Approximately one-third of women with adeno-
myosis are asymptomatic. The commonest symptom
is HMB, with other symptoms and signs including
dysmenorrhea, an enlarged tender uterus, dyspareu-
nia and metrorrhagia [45,46] . A study of hysterectomy
specimens has suggested that the extent and spread of
adenomyosis may relate to the clinical symptoms: the
degree of penetration of adenomyosis into the myome-
trium did not affect symptoms but spread of adenomy-
osis correlated with both pelvic pain and dysmenorrhea
but not with HMB or dyspareunia [49] . The symptoms
reported by women with adenomyosis are nonspecific
and as there is often co-existent uterine pathology such
as leiomyomas, it is uncertain whether the symptoms
can be solely attributed to the adenomyosis.
The cause of HMB in adenomyosis is unknown.
In common with leiomyoma, adenomyosis can affect
normal myometrial contractility and this may con-
tribute to the HMB [11] . Although diagnosis of super-
ficial adenomyosis (within one low power field of the
stratum basalis) is disputed, this has been reported to
have an increased association with HMB compared
with deeper adenomyosis [50] . Superficial adenomyosis
with associated myometrial hypertrophy may lead to
compression of the overlying endometrium, resulting
in heavy bleeding similar to the effects of fibroids caus-
ing HMB [51] . The proportion of endometrial glands
within adenomyosis has also been reported to be asso-
ciated with HMB [46,50] . In contrast, a further study
that related HMB to increasing depth of myometrial
penetration did not find any association of HMB and
superficial adenomyosis or with glandular density
within foci [46,50,52] . Adenomyosis is often associated
with other uterine pathology, including endometrial
polyps, leiomyomas and hyperplasia and these may
also be associated with HMB [51] .
Although the majority of women with adenomyo-
sis are parous, adenomyosis may be associated in some
cases with infertility. In a group of women who had
bowel resection for endometriosis, women who did not
conceive spontaneously or after IVF were significantly
more likely to have adenomyosis [53] . The explanation is
uncertain and has been related to abnormal uterotubal
future science group
Pathophysiology of heavy menstrual bleeding Review
transport in diffuse adenomyosis [54] . However, endo-
metrial leucocyte populations are also altered in women
with adenomyosis, with reports of increased endome-
trial macrophages and uterine natural killer (NK) cells
in luteal phase endometrium of women with recurrent
implantation failure and adenomyosis diagnosed by
pelvic MRI [55] .
The pathogenesis of adenomyosis is uncertain and
various explanations have been suggested. The most
popular hypothesis is that endometrium invaginates
into myometrium from the stratum basalis during peri-
ods of regeneration and healing. This could occur due
to trauma such as pelvic surgery or after repeated sharp
curettage following failed pregnancy that disrupts the
endomyometrial border [56] . Adenomyosis is influenced
by steroid hormones, although reports of expression of
ER, PR and AR vary. It has been reported that foci
of adenomyosis express higher levels of ER than the
corresponding eutopic endometrium [51] , suggesting a
high estrogen responsiveness in adenomyotic lesions
resulting in mitosis. However, there are other reports
suggesting that the expression of ER in adenomyosis is
lower than in adjacent endometrium [57] . Adenomyosis
tissue also express aromatase, leading to local produc-
tion of estrogen that may contribute to further growth
stimulation [45] .
An alternative suggestion is that adenomyosis devel-
ops within the myometrium from Mullerian remnants.
This is supported by studies of eutopic endometrium
and adenomyomatous endometrium which show dis-
tinct differences. Compared with eutopic endome-
trium, the endometrium within foci of adenomyosis
did not respond to hormone changes, rarely showed
secretory changes, did not exhibit cyclical changes
in the apoptosis regulatory protein Bcl-2 and showed
altered expression of cytokines and growth factors [58] .
More recently, it has been proposed that adenomyosis
arises from bone marrow derived stem cells that are
displaced through the vasculature or from stem cells
within the stratum basalis of endometrium. Although
still largely speculative, this has also been proposed as a
pathogenetic mechanism in endometriosis [59,60] .
It is not known why some women develop adeno-
myosis while others do not. There is a familial predis-
position and several studies have investigated genetic
abnormalities in adenomyosis. Various chromosomal
and genetic abnormalities have been reported in ade-
nomyosis but results have been variable and studies
are limited compared with those for endometriosis [61] .
There is an association between adenomyosis and
endometriosis; in an MRI study of women with deeply
infiltrating endometriosis, an irregular junctional zone
was observed in 39.9% of women with endometriosis
compared with 22.5% in the reference group [62] .
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Review Hapangama & Bulmer
Endometrium in adenomyosis may also display evi-
dence of increased invasiveness; stromal cells from
adenomyosis exhibit greater invasiveness compared
with normal stromal cells when grown on collagen or
in co-culture with myocytes from both normal uteri
and those affected by adenomyosis [62,63] .
Despite its prevalence in women of reproduc-
tive age, our understanding of adenomyosis remains
incomplete. The pathogenesis remains unclear but the
detection of stem cells in endometrium has opened up
new possibilities. Many cases are asymptomatic and
there are conflicting data regarding the relationship of
depth and extent of adenomyosis to clinical symptoms,
including HMB. Recent research points to distinct
endometrial abnormalities in adenomyosis, including
potentially altered local immune responses, increased
capacity for invasion and altered expression of steroid
hormone receptors.
Malignancy & hyperplasia
Estrogen, via its cognate receptors ERα (ESR1) and
ERβ (ESR2), signals normal endometrial epithelial
and stromal cell proliferation and hence when present
in excess estrogen can promote endometrial tumorigen-
esis [5] . Conversely progesterone is the natural tumor
suppressor for endometrium, counteracting almost all
the pro-proliferative actions of estrogen, arresting the
cell cycle, inhibiting inflammation [5] ; and promoting
differentiation and apoptosis of the glandular epithe-
lium. Therefore any condition that alters the balance
between estrogen and progesterone, either factors caus-
ing excessive, prolonged estrogenic stimulation or pre-
venting the counteracting effects of progesterone will
promote excessive endometrial growth with potential
development of endometrial hyperplasia (EH) and
carcinogenesis [4,5] .
EH is histologically defined as the abnormal over-
growth of endometrial glands in relation to the endo-
metrial stroma [64] . Several classification schemes have
been proposed and reproducibility is variable [64] . The
WHO (2003) classification includes six categories:
benign cycling endometrium, simple hyperplasia with-
out cytological atypia, complex hyperplasia without
cytological atypia, simple hyperplasia with cytological
atypia, complex hyperplasia with cytological atypia
and carcinoma. This classification led to confusion and
diagnostic difficulty and interobserver agreement was
poor, leading to other classifications being proposed,
although interobserver agreement remained relatively
low [64] . More recently the WHO has simplified the
classification of EH to hyperplasia without atypia
(including simple and complex hyperplasia) and atypi-
cal hyperplasia/endometrioid intraepithelial neopla-
sia [65] . These categories are based on the recognition
8 Womens Health (2016) 12(1)
that hyperplasia without cytological atypia is not asso-
ciated with genetic changes, whereas hyperplasia with
cytological atypia is a known precursor of endometrial
cancer (EC) and exhibits many of the mutations typical
of invasive endometrioid adenocarcinoma [64] . Unop-
posed estrogen stimulation, usually associated with
anovulation or occasional ovulation in premenopausal
women, is a common cause of EH which may be seen
in 20% of women with polycystic ovarian syndrome
(PCOS) with oligomenorrhea, and when present with
cytological atypia may carry approximately a 30% risk
of developing into or co-existing with EC [66] . Fur-
ther risk factors include obesity, nulliparity, infertility,
unopposed estrogen therapy, selective ER modulators,
diabetes and Lynch syndrome [64] . The mechanisms
by which EH induces HMB are not fully under-
stood. The plausible explanations include lack of the
usual reduction in progesterone to initiate shedding
of the thick and excessive endometrial tissues; ongo-
ing proliferative activity in the endometrium even at
the time of shedding and possibly generous blood flow
that is established to support the enhanced endome-
trial growth; all of which may cause prolonged, heavy
bleeding as well as incomplete cessation of bleeding.
Endometrial carcinoma is the commonest gyneco-
logical malignancy in the western world. Two types
of EC have been described. Type 1 tumors are usually
endometrioid in type and arise on a background of EH
associated with excessive unopposed estrogen secretion,
often with cytological atypia. These tumors are seen
in association with obesity and PCOS, as well as other
causes of excessive estrogen. In contrast, type 2 tumors
arise on a background of atrophic endometrium and are
not estrogen dependent tumors. These tumors include
uterine serous carcinoma and clear cell carcinoma and
typically have an adverse prognosis. Despite the differ-
ent associations with hyperplastic and atrophic endo-
metrium, mixed endometrial and serous/clear cell
carcinomas are not uncommon [67] and recent molec-
ular studies have suggested that the classification of
endometrial carcinomas is more complex [68] .
Most women presenting with EC are postmeno-
pausal [69] . EC is rarely seen in premenopausal women,
particularly in women below the age of 40 years, and
hence EC is a rare cause of HMB. The carcinogenesis
process is common in highly regenerative tissues and yet
the large number of repetitive regeneration cycles that
the endometrium endures does not appear to increase
the potential for endometrial carcinogenesis. However,
EC is a hormonally driven disease and the continuous,
unopposed effect of the mitotic action of estrogen is
thought to be the primary oncogenic promoter in at
least 80% of endometrial cancers [5] . Therefore, condi-
tions that dysregulate the sequential exposure to pro-
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gesterone of the estrogen primed endometrium, such
as obesity, PCOS, diabetes, estrogen secreting ovarian
tumors and tamoxifen use, among others, will increase
the risk of EC [69,70] . The usual pattern of the bleeding
associated with EC is irregular and continuous rather
than regular HMB and is thought to be secondary to
disruption of endometrial vessels due to invasion by
malignant cells and abnormal neovasculogenesis [37] .
Coagulopathy
Disruption of the endometrial vasculature at menstrual
shedding is the reason for initiation of menstrual blood
loss. Spurting of blood from gaping exposed vessels
has been observed at hysteroscopic examination of the
menstrual endometrium. The cessation of this bleeding
requires platelet aggregation and clot formation; dam-
age to endothelial cells causes secretion of von Wille-
brand factor which initiates both events. The deposition
of thrombin adds strength to the clot and seals the vas-
cular lumen preventing continued blood loss, followed
by fibrinolysis of the clot and sealing of the open end of
the vessel by PAI-1, urokinase and tissue plasminogen
activators (uPAs and tPAs) [9] ; this process is likely to be
required for the end of menstrual blood loss. Conversion
of plasminogen to plasmin by PAs initiates fibrinolysis
in the clot and this process is inhibited by PAI-1. The
equilibrium between activation and inhibition of the
fibrinolytic system plays a major role in the maintenance
of the intravascular clot. Increased endothelial cell tPA
activity may be associated with the dissolution of the
clot found within 24 h of menstruation [9] .
Leucocytes are a prominent component of endome-
trial stroma throughout the menstrual cycle but num-
bers increase dramatically in the mid and late secretory
phase so that in premenstrual endometrium >30% of
endometrial stromal cells are leucocytes [71] . Infiltration
of stromal leucocytes is a feature of late secretory phase
and premenstrual endometrium. These leucocytes pro-
duce a variety of cytokines, chemokines and proteases
that may play a role in initial disruption of the integrity
of the stratum functionalis tissue including blood ves-
sels. The vasoactive prostaglandins that are produced in
the menstrual endometrium also induce vasculogenesis
and epithelial repair via VEGF [4,37] .
The overall prevalence of a laboratory diagnosis of von
Willebrand disease in women presenting with HMB has
been reported to be as high as 13% [72] . Abnormal plate-
let aggregation has also been reported to be common
and these two conditions should be ruled out before
embarking on investigations for other haemostatic dis-
orders in women presenting with primary HMB [9] .
Other conditions such as disorders of deficiency in clot-
ting factors (inherited or acquired hemophilia A and B,
chronic liver disease, vitamin K deficiency and factor
future science group
Pathophysiology of heavy menstrual bleeding Review
VIII inhibitor); disorders of fibrinolysis and thrombo-
cytopenic disorders can in theory cause HMB but are
extremely rare [9] . Platelet function disorders (PFDs),
a heterogeneous group of inherited, qualitative platelet
defects have emerged as an important cause of HMB,
particularly in adolescents [27] . Women with PFDs and
HMB have been reported to be a clinically distinctive
subgroup of women with HMB, with significantly high
incidences of blood group O and the δ-storage pool defi-
ciency with a PFD diagnosed well after menarche. High
false negative standard platelet function study results are
reported therefore additional diagnostic strategies, such
as electron microscopy to detect significantly reduced
platelet δ-granule numbers should be considered [27] .
A decrease in clot strength and integrity due to the
breakdown of fibrin results in an increased blood loss
during menstruation. Plasminogen activators are fibri-
nolytic in that they induce lysis or dissolution of blood
clots and endometrial and menstrual effluent levels of
plasminogen activators are increased in women with
excessive menstrual blood loss [73] .
Ovulatory dysfunction (hormonal causes
of HMB)
Normal menstrual bleeding depends on the sequential
exposure of the estrogen-primed endometrium to estro-
gen and progesterone, followed by withdrawal of pro-
gesterone at the end of the menstrual cycle. Any endo-
crine irregularity that prevents these sequential events
may potentially result in HMB.
Polycystic ovarian syndrome is a common gyneco-
logical condition presenting with anovulatory cycles,
obesity, features of excessive androgens and HMB.
Androgens are converted into estrones in peripheral
tissue, resulting in prolonged periods of excessive and
unopposed estrogen action on endometrium during the
anovulatory cycle. Anovulatory PCOS endometrium is
thick prior to the start of bleeding and also lacks the
drop in progesterone which is the trigger for the normal
but highly orchestrated cellular events associated with
menstrual shedding [74] .
A further increasingly common condition that inter-
feres with normal hormonal equilibrium in the endo-
metrium is obesity. The conversion of androstenedione
secreted by the adrenal gland into estrone by aromatase
in adipose tissue provides an important source of addi-
tional estrogen for the endometrium [75] . This results in
excessive estrogen driven endometrial growth and often
produces HMB associated with shedding of the thick
stratum functionalis.
Endometrial causes of HMB
According to hysteroscopic observations, menstrual
shedding of the endometrium does not occur as an
www.futuremedicine.com 9
Review Hapangama & Bulmer
orderly process; rather there is patchy loss of the
superficial functionalis layer [76] . There are focal
islands of epithelial denudation, stromal breakdown
and loss of vascular integrity, which cause isolated
areas of bleeding, while simultaneous tissue regenera-
tion is initiated in other areas. With this seemingly
chaotic process of contrasting changes that occur in
different areas of the endometrium during menstrua-
tion, it is not surprising that aberrations are wide-
spread. However, consistent HMB with every men-
ses is only reported in up to one in five women [1] ,
suggesting that in healthy women a tight regulation
of this process exists, whereas in persistent HMB,
abnormalities in the endometrial progenitor zone in
the stratum basalis may produce an abnormal stratum
functionalis and abnormal regeneration process.
Regulation of menstrual shedding and cessation of
menstrual bleeding is not fully understood. The previ-
ously proposed theory that re-epithelialization of the
luminal epithelial surface is the primary factor in ces-
sation of bleeding [73] is not supported by the histologi-
cal observations that complete re-epithelialization is
frequently seen on days 1 and 2 of the menses, despite
continued menstrual bleeding. The stratum basalis
of the endometrium maintains tissue integrity during
menstrual breakdown of the stratum functionalis [5] .
The differences between the cells in the two function-
ally and possibly phenotypically different layers, are
only beginning to be understood [6] .
Angiogenesis is development of new microvessels
from existing blood vessels. Human endometrium is
one of the very few adult organs where regular physi-
ological angiogenesis occurs; in the basalis layer during
menstruation and in the stratum functionalis and sub-
epithelial capillary plexus during the proliferative and
early secretory phases. Mechanisms of regulation of
endometrial vascular growth remain to be fully deter-
mined. VEGF produced by intravascular neutrophils
has been suggested to play a role in the development of
these vessels by intussusception and elongation in the
endometrium [77] . Abnormal or incomplete angiogen-
esis, resulting in abnormal blood vessels with fragile
vessel walls may cause HMB and several studies have
suggested that abnormal endometrial vessel number,
structure or function may play a role in HMB. Increased
blood flow has been suggested [78] and reduced vascu-
lar smooth muscle proliferation and lower expression of
myosin heavy chain [79,80] may reflect altered endome-
trial vascular development in HMB. A recent study has
reported that, although vessel number did not differ
between control and HMB, there was altered expres-
sion of vascular smooth muscle differentiation markers
in HMB, again suggesting altered endometrial vascular
development which could impact on function [81] .
10 Womens Health (2016) 12(1)
Iatrogenic
Agents such as tamoxifen that have an estrogenic effect
can induce endometrial growth and may be associ-
ated with HMB. However, women on progestogenic
hormonal therapy such as the contraceptive progesto-
gen only pill, implant or Depot may also experience
paradoxical HMB, which is thought to be secondary
to the abnormal vasculogenesis associated with pro-
gestogen action [37] . Although progestogens are a com-
mon treatment for HMB, bleeding irregularities are a
common reason for discontinuing progestogens, with
2% of women on Depot injections of medroxyproges-
terone actetae suffering excessive bleeding [37] . By con-
trast, preoperative treatment with the PR modulator,
ssoprisnil (with antiprogestogenic properties), is asso-
ciated with development of aggregates of thin walled
vessels as well as and thick walled muscular vessels in
endometrium, suggesting that progesterone may have
an inhibitory effect on endometrial vasculogenesis, and
therefore should reduce HMB [82] .
Administration of a foreign object into the uterine
cavity, such as inert copper contraceptive devices, is a
well-established cause of increased menstrual loss and
is possibly due to interference with normal endometrial
development and myometrial contractility.
Not yet classified
The PALM-COEIN classification has allowed this
category to include some rare uterine abnormalities
of HMB and any potential future entities which can
either cause or contribute to HMB. This includes some
poorly defined entities such as chronic endometritis,
arteriovenous malformations and myometrial hyper-
trophy [3] . This category also includes rare conditions
such as the glycolipid storage disorder Gaucher disease,
in which HMB is a common symptom [83] .
Conclusion
HMB is a common gynecological complaint with
multiple etiologies and diverse pathophysiological ori-
gins. Our present understanding of the mechanisms of
menstrual bleeding as well as many of the pathologi-
cal aberrations of HMB is incomplete. Further research
into the pathophysiology of HMB is urgently needed,
as clear knowledge of the mechanisms of the disorder
will provide new therapeutic targets to formulate more
effective treatments.
Future perspective
There is an increasing interest to find novel, non-
surgical and fertility sparing management options for
HMB. The future perspective therefore includes the
development of therapies directed towards new avenues
such as endometrial vasculature, myometrium and
future science group

endometrial stem cells. Improving the basic scientific
knowledge in these areas of pathophysiology of HMB
in particular is warranted for timely discoveries to be
made for the benefit of millions of women suffering
with this distressing condition.
Acknowledgements
Executive summary
Heavy menstrual bleeding (HMB) is a common gynecological complaint with multiple etiologies and diverse
pathophysiological origins.
Our current understanding of the mechanisms of menstrual bleeding as well as many of the pathological
aberrations of HMB is incomplete.
Further research into the pathophysiology of HMB is urgently needed, as clear knowledge of the mechanisms
of the disorder will provide new therapeutic targets to formulate more effective treatments.
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