Human Reproduction, Vol. 15, (Suppl. 3), pp. 57-66, 2000
The structure of endometrial microvessels
M.Hickey13 and I.S.Fraser2
imperial College School of Medicine at St Mary's, Department of Obstetrics and Gynaecology, Norfolk
Place, London W2 1PG and 2Sydney Centre for Reproductive Health Research, Family Planning NSW
and Department of Obstetrics and Gynaecology, University of Sydney, NSW 2006, Australia
3
To whom correspondence should be addressed at: Imperial College School of Medicine at St Mary's,
Department of Obstetrics and Gynaecology, Norfolk Place, London W2 1PG, UK.
E-mail: [email protected]
Recent studies have provided substantial evidence to highlight abnormalities in the structure
of endometrial microvessels in users of progestogen-only contraception. Structural changes
alone are unlikely to lead to breakthrough
bleeding, but appear to be associated with a
reduction in vessel integrity, and may reflect
alterations in the control and growth of endometrial microvessels in those exposed to exogenous progestogens. In users of low-dose
progestogens, immunohistochemical studies
have demonstrated changes in superficial endometrial vascular morphology, density and in
endometrial migratory cell populations. In
Norplant users the endometrial endothelial
basal lamina is deficient in the initial months of
exposure, when bleeding problems are most
common. The basal lamina refers to the very
thin structure consisting mostly of collagen IV
and laminin seen underlying endothelial and
epithelial cells at the electron microscope level.
In addition, hysteroscopic studies have demonstrated increased fragility of superficial vessels.
Changes in endometrial microvascular anatomy
associated with normal menstruation have been
reviewed, and are compared with those seen
following contraceptive steroid exposure. Likely
mechanisms of breakthrough bleeding such as
increased superficial vascular fragility and the
possible alterations in endometrial vascular
structure leading to this are discussed.
Key words: breakthrough bleeding/endometrium/
microvasculature/progestogens
© European Society of Human Reproduction and Embryology
Introduction
Uterine bleeding requires the breakdown of endometrial blood vessels and the overlying epithelium.
Bleeding that is irregular or prolonged suggests
that the normal mechanisms which maintain tight
control over vascular breakdown and repair have
been disrupted. The depth of evidence implicating
alterations in structure and function of endometrial
microvessels in different types of abnormal endometrial bleeding has increased enormously since
it was first seriously considered in 1979 (Fraser
and Diczfalusy, 1980). Bleeding that markedly
differs in quantity, duration and appearance from
normal menstrual bleeding suggests that different
blood vessels may be the source. Circumstantial
evidence suggests that endometrial capillaries and
venules are the source of breakthrough bleeding
(BTB). This is based upon the observations that
spiral arteriole development is reduced under progestogenic influence, with more capillaries and
venules seen (Hourihan et al, 1986, 1991); that
progestogen-related bleeding is generally light and
prolonged — suggesting a small vessel source
(Fraser et al, 1996); and that small superficial
vessels have been seen to bleed at hysteroscopy in
users of progestogen-only contraception (Hickey
et al, 1996a,b).
The aims of this paper are to outline the structure
of endometrial microvessels, to discuss how this
structure is altered by exogenous sex steroids,
particularly progestogens, and to relate these
changes to the possible mechanism of BTB with
these preparations.
57
M.Hickey and I.S.Fraser
VASCULATURE OF PRIMATE ENDOMETRIUM
FUNCTIONALIS
ENDOMETRIUM
GERMINALIS
MYOMETRIUM
Figure 1. Vasculature of primate endometrium. Adapted from Kaiserman-Abramof and Padykula, 1989.
Normal anatomy of the endometrial
vasculature
Arterial blood reaches the uterus via the uterine
and ovarian arteries. These vessels form the arcuate
arteries in the myometrium (see figure 1). Radial
arteries arise from the arcuate arteries at 90°
towards the endometrium. After crossing the endomyometrial junction, small basal arteries arise from
the radial arteries and supply the basal endometrium and larger spiral arterioles which run towards
the endometrial surface (functional layer). The
spiral arterioles are thought to be sensitive to
oestrogen and progesterone (Perrot-Applanat et al.,
1988), but the mechanism of sex steroid control
of the endometrial microvasculature is less well
understood.
Capillaries arising from the spiral arterioles form
a subepithelial plexus which empties into a venous
plexus within the functional layer. The spiral arterioles are thought to be acutely sensitive to oestrogen
and progesterone, but the mechanism of sex steroid
control of the endometrial microvasculature is
poorly understood. These veins subsequently drain
into the inner myometrium. Endometrial microvessels consist only of endothelial cells (EC) linked
by tight junctions, their associated basal lamina
and surrounding pericytes.
Endometrial endothelial basal lamina (BL) is a
specialized form of extracellular matrix, which
contributes to vessel growth, differentiation and
vessel permeability. Vascular BL is a complex
structure composed of several macromolecules,
58
which interact to form the heterogeneous structure,
which can be defined as BL. The BL also provides
a sheet-like structure to which endothelial cells
can closely attach (Bulletti et al., 1988). Because
BL is distributed across many cells, changes in its
integrity or composition will modify the behaviour
of other cell groups. Absence or disruption of the
BL could thus contribute to endometrial vascular
fragility and BTB.
Pericytes are associated with all vascular capillaries and post-capillary venules. Differences in
pericyte morphology and distribution among vascular beds suggest tissue-specific functions. Pericytes
may contribute towards the regulation of local
blood flow, vessel formation and cellular differentiation (Hirschi and D'Amore, 1996). Physical contact between endothelial cells and pericytes,
mediated by cell adhesion molecules, integrins
and gap junctions is likely to influence vascular
function in the endometrium.
Endometrial lymphatics
The endometrial lymphatic system has been much
less extensively studied than the vascular system.
This is partly due to the technical difficulties
involved in examining this system. Consequently,
our understanding of the role and actions of the
endometrial lymphatics is incomplete.
The work of Casley-Smith and Florey (1961)
has been used as a basis for establishing the
morphological criteria for the identification of
lymphatic vessels as opposed to blood vessels. At
Structure of endometrial microvessels
the ultrastructural level, the lymphatic vessel wall
appears substantially thinner than that of the corresponding sized blood vessels. The endothelial cells
are less tightly attached and gaps sometimes exist
between adjacent cells. The basal lamina of the
lymphatic is mostly irregular and fragmented, and
may be absent, whereas in blood vessels it is
usually clearly demarcated. However, lymphatics
may be difficult to differentiate, and the absence
of erythrocytes within the vessel does not indicate
that the vessel is a lymphatic. At the light microscope level, differences between these vessels are
even more subtle and the lymphatic vessels may
be seen to have substantially thinner endothelium.
These similarities in appearance have obvious
implications for studies of endometrial blood vessels. However, recent observations in mature nonpathological tissues have suggested that the VEGF
receptor flt-4 may act as a lymphatic marker (Nojiri
and Ohhashi, 1999).
A detailed light microscopic, ultrastructural and
three-dimensional study of the endometrial lymphatic system, in normal cycling women was performed by Blackwell and Fraser (1981). This study
showed that approximately two-thirds of normal
human endometrium has a recognizable lymphatic
system, with 1-20 vessels per square millimetre,
mostly concentrated in the deeper portions of the
tissue. There was no obvious correlation between
the presence of lymphatics and the stage of the
menstrual cycle, or the position of lymphatic vessels and that of other endometrial structures such
as glands and blood vessels.
Blackwell and Fraser (1981) suggest that endometrial lymphatics may play a role in endometrial
regression seen preceding normal menstruation
(Markee, 1950) and following sex steroid exposure,
and in endometrial remodelling.
Endometrial vascular changes during the
normal menstrual cycle
Most of the data describing the structure of endometrial microvessels is based on endometrial
biopsy specimens and on in-vivo data from the
1940s by Markee using endometrial explants
placed in the anterior chamber of the eye in the
rhesus monkey and observed under the influence
of oestrogen and progesterone. The physical loca-
tion of the endometrium makes in-vivo studies
difficult in the human, and it remains unclear how
much information can be realistically extrapolated
from non-human and biopsy studies.
The late pre-ovulatory phase is accompanied by a
5-fold increase in the length of the spiral arterioles,
leading to vascular coiling. Distal spiral arterioles
connect to the sub-epithelial capillary plexus. During the secretory phase, the spiral arterioles increase
in size and tortuosity, and the subepithelial capillaries dilate (Markee, 1940).
Pre-menstrually, the endometrial stroma rapidly
regresses and spiral arterioles coil. Menstrual
bleeding is preceded by vascular stasis, vasoconstriction with brief relaxation of arterioles leading
to bleeding (Markee, 1940; Christiaens et al.,
1982). Bleeding also occurs via gaps in vessel walls
and epithelium, rupturing haematomata, diapedesis
from capillaries and directly from endometrial
veins.
Mechanisms of vascular breakdown
Menstruation is preceded by a fall in circulating
progesterone and the activation of a range of local
factors and mechanisms able to disturb small vessel
structure and induce vascular breakdown. These
factors include: (i) Prostaglandins (Cameron,
1991); (ii) Macrophages and other migratory leukocytes (Finn, 1986; Bulmer et al., 1987, 1991); (iii)
Plasminogen activators (Koh et al., 1992); (iv)
Cytokines (Tabibzadeh and Sun, 1992); (v) Lysosomes (Henzl et al., 1972); (vi) Matrix metalloproteinases (MMP, Hampton and Salamonsen,
1994); and (vii) Apoptosis (Tabibzadeh et al.,
1995).
Recent research has not been able to demonstrate
close endometrial and vascular morphological correlations with specific abnormalities of menstrual
bleeding, but has pointed to an increasing number
of molecular mechanisms that may be involved in
the occurrence of normal and abnormal uterine
bleeding. These molecules have complex interactions, and the precise sequence of events culminating in endometrial vascular breakdown and repair
is still under investigation. Endometrial destruction
and regeneration are largely under the control of
these local factors, although the initial trigger
comes from falling oestradiol and progesterone
59
M.Hickey and I.S.Fraser
concentrations following luteolysis. Lysosomes
release hydrolytic enzymes in pre-menstrual endometrium that could contribute to tissue breakdown,
bleeding, and remodelling. (Henzl et al., 1972;
Christiaens et al., 1982). Lysosomes activate in
response to falling progesterone, but it is unclear
whether they have a primary or secondary role in
the onset of endometrial vascular breakdown
(Fraser et al., 1996). Increasing evidence suggests
that certain matrix metalloproteinases are the
agents responsible for extracellular matrix and
vascular breakdown in normal, and perhaps also
abnormal, menstrual bleeding (Hampton and
Salamonsen, 1994; Vincent et al, 1999). These
enzymes may modify microvascular structure by
removing supporting materials from the intercellular space and by damaging basal lamina.
Endometrial leukocytes are known to be
involved in tissue destruction and regeneration/by
the production of a range of molecules capable of
damaging vessels as well as other tissue components. Menstruation is preceded by a marked
increase in endometrial stromal granulated lymphocytes, T lymphocytes and macrophages. Polymorphonuclear leukocytes only appear in uterine
tissues at the onset of tissue breakdown (Kamat
and Issacson, 1987; Bulmer et al., 1988) and are
often located near blood vessels in the endometrium
where they may influence vascular permeability
and integrity. This influx of leukocytes into the
endometrium is clearly influenced by changes in
ovarian sex steroid production, and small populations of these cells have varying oestrogen and/or
progesterone receptor positivity (Tabibzadeh and
Satyaswaroop, 1989). The adhesion molecules
intracellular adhesion molecule (ICAM)-l and vascular cell adhesion molecule (VCAM) are known
to be involved in the migration of leukocytes from
the circulation, through vessel walls and into the
tissues (Lessey and Arnold, 1998; Searle et al.,
1999).
Evidence for the role of prostaglandins in the
initiation of bleeding (Karim, 1983; Cameron et al.,
1991), and the control of endometrial blood flow
(Einer-Jensen, 1973) has been substantial. Prostaglandins can cause premature bleeding when
injected into the endometrial cavity in women
(Toppozoda et al., 1980), and induce bleeding in
60
vitro in the hamster cheek explant (Abel et al.,
1982). Withdrawal of progesterone at the end
of the menstrual cycle may promote increased
prostaglandin production, producing the characteristic vasospasm that precedes vasodilatation (via
prostaglandin F 2a ). This may also account for the
common phenomenon of dysmenorrhoea during
the initial days of menstrual bleeding. Prostaglandin release may further increase in response
to the tissue destruction of endometrial ischaemia
and necrosis (Smith, 1990) creating a positive
feedback of vascular damage and endometrial
breakdown.
Mechanism of haemostasis and vascular
repair
In Markee's observations of endometrial explants,
vasoconstriction of spiral arterioles limits blood
loss in the early phase of normal menstruation.
Haemostatic plug formation occurs in the first 24 h,
but these plugs are small, transient, intravascular
and are rarely seen more than 20 h after the
onset of menstruation (Christiaens et al., 1982). In
contrast to haemostatic mechanisms in other body
tissues, menstrual blood does not show persistent
clotting (Sixma and Webster, 1977). There is early
intravascular coagulation associated with major
anticoagulation effects within the tissue and uterine
lumen. Coagulation factors are reduced in menstrual blood, and there is greatly increased activity
of thrombolytic endometrial tissue plasminogen
activator (tPA) as well as plasmin and a2 antiplasmin (Rees et al., 1985). In collected menstrual
blood, platelets are reduced and dysfunctional
(Rees, 1990), suggesting that the normal clotting
mechanisms have been 'disabled' by menstrual
fluid. In the late secretory and menstrual phase
there are much reduced levels of von Willebrand
factor (vWF), a substance which is crucial for
platelet adherence to damaged vessels, suggesting
impaired haemostasis (Au and Rogers, 1993).
Endometrial repair commences during early
menstruation (Christiaens et al., 1982), and epithelial repair is complete by day 4-5 of menstruation
(Ferenczy etal., 1979). Angiogenesis is an essential
component of endometrial renewal. The agents
controlling endometrial angiogenesis are still under
investigation, but this process appears to be con-
Structure of endometrial microvessels
trolled by a variety of angiogenic and antiangiogenic stimuli (Gargett et al, 1999). Peptide and
non-peptide angiogenic factors interact during
endometrial renewal, including epidermal growth
factor (EGF), transforming growth factors (e.g.
TGF-P), platelet-derived epidermal growth factor
(PD-EGF), tumour necrosis growth factors and
vascular endothelial growth factor (VEGF; Smith,
1998). These growth factors may act to control
endometrial proliferation and differentiation. It is
unclear whether the overall control of this process
is mediated by oestrogen and progesterone, and
recent evidence suggests that endometrial vascular
growth may be largely locally determined (Rogers
et al, 1998).
VEGF is a fundamental regulator of normal
and abnormal angiogenesis, and is necessary for
cyclical endometrial blood vessel proliferation and
in pathological angiogenesis in the female reproductive tract (see Ferrara, 1999 for review). VEGF
is a secreted peptide, and the receptors for VEGF
are localized predominantly on vascular endothelial
cells (Millauer et al, 1993; Neufleld et al, 1994).
VEGF also acts to increase vascular permeability,
which may be of importance in the degradation
of the extracellular matrix during angiogenesis
(Charnock-Jones et al, 1993). Furthermore, VEGF
also modulates the expression of a number of
proteolytic enzymes involved in angiogenesis
(Pepper et al, 1991).
Changes in endometrial microvessels in
response to exogenous sex steroids
The prevailing clinical interest in endometrial vascular changes in response to exogenous sex steroids
arises from the common problem of irregular
bleeding associated with steroid contraceptives and
hormone replacement therapy. Alterations in the
integrity of endothelial cells, their junctions or the
surrounding basal lamina and pericytes could all
compromise microvascular stability and promote
vascular fragility.
Endothelial cell junctions
The role of tight junctions between adjacent endothelial cells in controlling endometrial bleeding is
unclear. In decidua, endothelial cell tight junctions
have not been noted to provide much strength in
bonding adjacent cells together (Parr et al, 1986).
Little is known about the role of endometrial
tight junctions during the normal menstrual cycle.
Adherens junctions appear to provide the bonding
strength in epithelium, but these junctions are not
present in endothelium. Ultrastructural studies have
shown that patchy microvascular fragmentation
accompanies menstruation, although in some areas
vessels appear normal right into menstruation
(Roberts et al, 1992). However, there is little
recent information on the ultrastructure of EC
junctions
following
progestogen
exposure
(Blackwell and Fraser, 1988). The identification of
a marker for endometrial endothelial tight junctions
might provide further information on changes in
these junctions, and further ultrastructural studies
are needed.
Exogenous sex steroids appear to influence vascular structure, growth and blood flow in the
human endometrium, but accurate in-vivo work is
hampered by the physical location of the endometrium and the size of superficial microvessels.
Long-term low-dose levonorgestrel leads to a
reduction in endometrial arteriole numbers and
size, and a change in vascular morphology with a
decrease in arteriole spiralling, increased gaps
between endothelial cells and haemostatic plugs
(Hourihan et al, 1990, 1991). Ultrastructural studies by Johannisson et al. (1982) observed contracted endothelial cells and an increase in
plasmalemmal vesicles, implying a loss of microvascular integrity.
Endometrial microvascular density
During the normal menstrual cycle, endometrial
vascular density does '• not significantly change,
despite periodic angiogenesis (Shaw et al, 1981;
Johannisson et al, 1982; Rogers et al, 1993;
Grimwood et al, 1995; Song et al, 1995). However, an increase in endometrial microvascular
density has been observed following 3-12 months
of exposure to the low-dose long-acting levonorgestrel contraceptive implant system, Norplant
(Rogers et al, 1993; Hickey et al, 1999a). In
women exposed to high and medium dose progestogens a decrease in endometrial vascular density
has been observed (Song et al, 1995), while in
those treated with danazol or the GnRH agonist,
goserelin, or following the menopause, endometrial
61
M.Hickey and I.S.Fraser
vascular density is constant (Hickey et al, 1996b).
It is difficult to reconcile these observations, but
they suggest that some exogenous sex steroids, or
different local steroid concentrations, may disrupt
the normal tightly controlled relationship between
the growth of endothelial cells and capillaries
and that of surrounding glandular and cellular
components of the endometrium.
The origin of this increased vascular density in
Norplant implant users is unclear, and there is
no evidence that low-dose levonorgestrel directly
stimulates angiogenesis, as judged by changes in
endothelial cell proliferation indices (Goodger and
Rogers, 1994; Subakir et al, 1995). However,
superficial vessels with a neovascular appearance
have frequently been seen at hysteroscopy in
progestogen users (Hickey et al, 1996b). It is
possible that abnormal endometrial angiogenesis
may occur by a different mechanism from that
observed in other tissues. Endothelial cell proliferation is only one feature of angiogenesis, and the
absence of increased endothelial cell proliferation
indices does not mean that vascular growth is not
occurring by other mechanisms. An increase in
vascular density could also occur secondary to
diminished programmed cell death (apoptosis).
Endometrial vascular basal lamina
A reduction in immunostaining for the endometrial
basal lamina components collagen, laminin and
heparan sulphate proteoglycan (HSPG) has been
seen in the initial months of progestogen exposure,
when bleeding problems are most common (Hickey
et al., 1999b). This finding was not confirmed in
longer-term Norplant users (Palmer et al., 1996).
Alterations in vascular basal lamina are known
to contribute to vascular fragility in other organ
systems. In diabetes mellitus there is a characteristic thickening of the BL, but with a loss of
functional capacity and 'leakiness' leading to retinal vascular fragility (Martin et al., 1988). In some
tumours and inflammatory conditions characterised
by vascular fragility the BL is absent or disrupted
(Barsky et al, 1983).
Basal lamina components may be reduced
because they are not being formed or are being
broken down. Recent data suggesting that MMP
activity may be increased in Norplant endometrium
62
(Vincent et al, 1999), may account for this breakdown of the ECM.
Endometrial vascular morphology
Changed vessel morphology alone cannot account
for bleeding, but it may be associated with altered
vascular control and function following exogenous
sex steroid exposure.
Dilated superficial endometrial vessels have been
identified by several authors in endometrial biopsies from steroid-exposed endometrium (Maqueo,
1980; Hourihan et al, 1986; Song et al, 1995).
Dilated vessels that are superficial, thin-walled and
with abnormal morphology may be more fragile.
Using a hysteroscopic measurement technique, it
has been established that mean superficial vascular
diameter is greater in low dose progestogen users
compared to regularly cycling women during the
secretory phase of the menstrual cycle, and that
there is a distinct phenomenon of dilated superficial
vessels which bleed on contact (Hickey et al,
1998). Preliminary three-dimensional studies using
CD34 as a marker of endothelial cells have used
image analysis to demonstrate the same dilated
vessels join with normal sized capillaries and with
solid columns of endothelial cells which do not
appear to have a lumen. These findings suggest
major disturbance of endometrial angiogenesis processes in the presence of continuous progestogen
exposure.
In-vitro measurement of endometrial
microvessels
Apparent dilatation of the superficial endometrial
vessels has been noted in biopsy specimens following oestrogen and progestogen exposure (Ober,
1970; Ludwig, 1990), but few authors have been
able to provide precise measurements of these
vessels. Peek et al measured the combined luminal
and endothelial cell area in biopsies from the
functional layer of the endometrium on days 2022 in women with regular menstrual cycles who
were not exposed to sex steroids (Peek et al,
1992). The mean area of these vessels was 204
(im2, and the mean diameter 16.2 |im. Wide variations were observed between vessels. Following
exposure to short-duration and high-dose oral
levonorgestrel (0.75 mg; suitable for emergency
Structure of endometrial microvessels
contraception), there was no significant change in
vascular diameter (mean 15.8 |im).
In-vivo measurement of endometrial
microvessels
It is difficult to assess vascular dilatation invitro since these vessels rapidly collapse. Using a
hysteroscopic technique which corrects for image
magnification and distortion, Hickey et al. found
that mean superficial vascular diameter was greater
in users of low-dose levonorgestrel contraceptive
implants (Norplant) compared to women with
spontaneous ovulatory menorrhagia (Hickey et al.,
1998). Vascular diameter was 120 ± 11.6 |im
(mean ± SEM) compared to 74 ± 7.2 (im in those
with menorrhagia. This study also confirmed the
presence of scattered dilated vessels (up to 777
urn diameter) on the endometrial surface in some
Norplant users.
The wide variation between these in-vitro and
in-vivo measurements emphasizes the dynamic
nature of vascular function and morphology, and
the limitations of studies confined only to processed
biopsy specimens.
Why are these vessels enlarged or dilated?
Because of aberrant angiogenesis ?
The abnormal vascular morphology and increased
microvascular density in progestogen-exposed
endometrium strongly suggest that endometrial
angiogenesis is disrupted by prolonged exposure
to exogenous progestogens. The observation that
growth of endometrial capillary endothelial cells
exposed to levonorgestrel or 3-keto-desogestrel,
but not progesterone or medroxyprogesterone acetate, in culture is markedly inhibited, may also be
an indicator of impaired angiogenic mechanisms
(Peek et al., 1995; Rodriguez-Manzaneque et al.,
2000).
Because of altered vascular perfusion ?
Preliminary studies using laser-Doppler to directly
measure superficial endometrial vascular perfusion
suggest that LNG from Norplant markedly reduces
perfusion in some users (Hickey et al., 2000).
Vascular dilatation may be a reaction to reduced
perfusion. Vasomotion describes the spontaneous
and rhythmic dilation and constriction of microves-
sels. Normal vasomotion is profoundly altered by
low-dose progestogens, with an almost total loss
of short-term variability. Again, this implies that
the control of endometrial vascular function is
altered following exogenous sex steroid exposure.
As a direct effect of vasoactive mediators
VEGF is expressed in the endometrium following
progestogen exposure (Lau et al., 1999). VEGF
can directly increase vascular permeability and
may lead to dilatation. Hypoxia is a major stimulant
of VEGF up-regulation. Changes in endometrial
oxygenation are likely to accompany changes in
vascular perfusion. Oxygen tension in superficial
endometrial vessels or surrounding tissues has not
yet been assessed. These effects may also be
influenced by the local release of vasoconstrictor
substances, such as endothelins, and lead to further
alterations in local flow and dilatation.
Increased vascular fragility
Hysteroscopic studies in Norplant users have demonstrated a number of superficial vascular changes
which are consistent with increased endometrial
vascular fragility (Hickey et al., 1996). These
include: (i) Abnormal vascular morphology with
arborization and mosaic patterns; (ii) Dilated vessels on the endometrial surface (see above); (iii)
Contact bleeding from dilated vessels; (iv) Profuse
subepithelial haemorrhages (petechiae and
ecchymoses). These changes have not been
observed in regularly cycling women who have
not been exposed to sex steroid hormones
(M.Hickey et al., unpublished data).
Summary
There is growing evidence that structural changes
in small and dilated endometrial microvessels are
the source of BTB in progestogen-only users.
Changes in these vessels may contribute to
increased vascular fragility. These include
increased vessel numbers, reduced vascular basal
lamina components, altered vessel morphology
with marked dilatation, and an influx of vasoactive
factors and proteases promoting vascular
breakdown.
However, few of these changes have been directly linked with bleeding episodes, suggesting that
intermediate factors act between vessel breakdown
63
M.Hickey and LS.Fraser
and vaginal bleeding. Since the epithelium must
also be breached before endometrial bleeding is
seen by the patient, the role of epithelial integrity
in containing bleeding from damaged vessels needs
further investigation.
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