Human Reproduction Vol.19, No.2 pp. 330±338, 2004 DOI: 10.

1093/humrep/deh056

Quantifying the changes in endometrial vascularity

throughout the normal menstrual cycle with three-
dimensional power Doppler angiography

N.J.Raine-Fenning1, B.K.Campbell, N.R.Kendall, J.S.Clewes and I.R.Johnson

Academic Division of Reproductive Medicine, School of Human Development, University of Nottingham, UK
1
To whom correspondence should be addressed at: Academic Division of Reproductive Medicine, D Floor, East Block, Queens
Medical Centre, Nottingham NG7 2UH, UK. E-mail: nick.fenning@nottingham.ac.uk

BACKGROUND: We used three-dimensional power Doppler angiography (3D-PDA) to examine the periodic
changes in endometrial and subendometrial vascularity during the normal menstrual cycle in 27 women without
obvious menstrual dysfunction or subfertility. METHODS: 3D-PDA was performed on alternate days from day 3 of
the cycle until ovulation and then every 4 days until menses. Virtual organ computer-aided analysis and shell-ima-
ging were used to de®ne and to quantify the power Doppler signal within the endometrial and subendometrial
regions producing indices of their relative vascularity. RESULTS: Both the endometrial and subendometrial vascu-
larization index (VI) and vascularization ¯ow index (VFI) increased during the proliferative phase, peaking ~3 days
prior to ovulation (P < 0.001) before decreasing to a nadir 5 days post-ovulation (P < 0.001). Thereafter, both vascu-
lar indices gradually increased during the transition from early to mid-secretory phase. The ¯ow index (FI) showed
a similar pattern but with a longer nadir post-ovulation. Smoking was associated with a signi®cantly lower VI and
VFI. The FI was signi®cantly lower in women aged >31 years and signi®cantly higher in parous patients.
CONCLUSIONS: Endometrial vascularity, as assessed by 3D-PDA, varies signi®cantly during the menstrual cycle
and is characterized by a pre-ovulatory peak and post-ovulatory nadir during the peri-implantation window.

Key words: endometrium/menstrual cycle/power Doppler/subendometrial vascularity/three-dimensional ultrasound

Introduction 1998; Aardema et al., 2001; Carbillon et al., 2001a). A better

Each month, the human endometrium undergoes a series of
distinct cyclical changes in preparation to receive the devel-
oping blastocyst. Such changes necessitate well-controlled,
dynamic remodelling of the endometrial microvasculature
through the processes of angiogenesis and arteriogenesis
(Smith, 2000; Rogers and Abberton, 2003). Dysregulation of
endometrial blood ¯ow has been associated with several
menstrual disorders including dysmenorrhoea, menorrhagia,
intermenstrual bleeding and endometriosis (Jaffe, 2000; Smith,
2001). An adequate blood supply also appears to be an
important determinant of endometrial receptivity during assis-
ted conception treatment (Friedler et al., 1996; Carbillon et al.,
2001b), and it is possible that a cohort of women with
unexplained infertility have decreased uterine and endometrial
perfusion (Goswamy et al., 1988; Kurjak et al., 1991).
Following implantation, the endometrial vasculature under-
goes considerable change in association with the trophoblastic
invasion of the spiral arteries, and suboptimal responses have
been associated with recurrent miscarriage (Jirous et al., 2001;
Habara et al., 2002), preterm delivery (Strigini et al., 1995),
intrauterine growth restriction and pre-eclampsia (Kurdi et al.,
330 Human Reproduction vol. 19 no. 2 ã European Society of Human Reproduction and Embryology 2004; all rights reserved
understanding of endometrial blood ¯ow during the menstrual
cycle is clearly of paramount importance in terms of both
physiological and pathophysiological change and may permit
the de®nition of new aetiologies or facilitate assessment of
future therapeutic treatments.
Ultrasound has been used to record endometrial develop-
ment non-invasively and, whilst the characteristic architec-
tural variations in appearance and thickness have been well
described (Randall et al., 1989; Bakos et al., 1993, 1994),
there is much less information available on how endometrial
blood ¯ow changes during the menstrual cycle. Of the
studies examining uterine perfusion during the menstrual
cycle, the majority have applied pulsed wave Doppler and
subsequent waveform analysis of gated signals returning
from speci®c sections of the uterine vessels (Steer et al.,
1990; Kupesic and Kurjak, 1993; Sladkevicius et al., 1993;
Achiron et al., 1995; Bourne et al., 1996). These studies
differ quite considerably in design both in terms of their
patient populations and with respect to the vessels assessed,
with most concentrating on the uterine artery rather than its
downstream branches. Those studies that have reported upon

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blood ¯ow within subendometrial vessels (Kupesic and
Kurjak, 1993; Sladkevicius et al., 1993; Achiron et al.,
1995; Tan et al., 1996) are limited by their selection of
individual vessels and the assumption that they are repre-
sentative of the subendometrium as a whole (Hoskins, 1990).
This has to be questioned in the light of recent work during
controlled ovarian stimulation treatment that has demon-
strated differential ¯ow rates with greater impedance to ¯ow
in spiral arteries located in the posterior aspect of the uterus
(Hsieh et al., 2000). In addition, accurate and reliable
measurement of blood ¯ow velocities within any vessel
requires angle correction and the generation of a well-
de®ned, measurable waveform, both of which are dif®cult in
spiral arteries due to their inherently low ¯ow rates and
tortuous nature (Nelson and Pretorius, 1988; Vieli, 1990).
Power Doppler is better suited to the study of the
subendometrial vasculature as it is more sensitive to these
lower velocities and is essentially angle independent (Rubin
et al., 1994). Blood ¯ow and vessel patterns are demonstrated
by encoding the power in the Doppler signal rather than its
mean frequency shift (Rubin, 1999). In combination with
three-dimensional ultrasound, power Doppler provides a
unique tool with which to examine the uterine blood supply
as a whole as opposed to analysis of individual vessels or two-
dimensional planes (Downey et al., 2000). Following data
acquisition, the power Doppler signal can be quanti®ed within
any three-dimensional area, thereby permitting investigation of
regional uterine blood ¯ow. This technique has been used in the
clinical setting to predict the response to controlled ovarian
stimulation and subsequent outcome of assisted reproduction
treatment (Schild et al., 2000; Kupesic et al., 2001; Kupesic
and Kurjak, 2002; Wu et al., 2003).
Having demonstrated our own inter-observer reliability and
validity of data acquisition and measurement with this
technique (Raine-Fenning et al., 2002a), the aim of this study
was to use `three-dimensional power Doppler angiography' to
quantify the changes in endometrial blood ¯ow that occur
throughout the menstrual cycle.
Materials and methods
Experimental design
This was a prospective, longitudinal observational study. Patients
were asked to call on the ®rst day of menstruation to book an
appointment for day 3 of the menstrual cycle. They were then seen on
an alternate day basis until the collapse of a dominant follicle was
noted on ultrasound following a peak in serum LH, thereby signifying
ovulation. Thereafter, patients were seen every 4 days until the next
menstrual period. A transvaginal ultrasound scan was conducted and
blood was taken for serology at each visit. We requested that patients
serially attended at the same time of the day if at all possible.
Patient selection
The inclusion criteria were aimed at selecting a control population of
women without menstrual dysfunction or obvious subfertility. Thirty
women of reproductive age were recruited. The exclusion criteria
were: (i) an irregular menstrual cycle; (ii) current hormonal
contraception; (iii) intrauterine contraceptive device in situ; (iv)
tubal sterilization; (v) a menstrual disorder necessitating any form of
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Quantifying normal endometrial vascularity with 3D
treatment; and (vi) history of endometriosis, infertility, pelvic
in¯ammatory disease, recurrent miscarriage or polycystic ovarian
disease
We did not specify an upper or lower age limit and did not limit the
study to parous women because we wanted to investigate the effects of
age and parity. In view of the evidence of a circadian rhythm in uterine
blood ¯ow (Zaidi et al., 1995), we attempted to keep the time of
assessment similar in each woman whenever possible, and data
acquisition was largely undertaken between 07.00 and 13.00 hours.
Approval was given by the local ethical committee, and subsequent
recruitment was facilitated through local and regional advertisements.
Patients were not ®nancially rewarded for their participation in the
study but did receive a small remuneration to cover travel and parking
costs. Patients were interviewed by a clinician (N.J.R.F.) to determine
their eligibility, outline the study and obtain written consent before
enrolment.
Data acquisition
All data were acquired with a Voluson 530DÔ machine (GE Kretz,
Zipf, Austria) and a 7.5 MHz transvaginal probe. The ultrasound scans
were conducted by one of two observers (N.J.R.F. and J.S.C.) whose
inter-observer reliability of data acquisition had been established in
preliminary work (Raine-Fenning et al., 2002a). Each patient was
scanned in a supine position with knees ¯exed and hips abducted. The
pelvis was examined in detail to exclude obvious ovarian or uterine
pathology. Power Doppler ultrasound was then applied using pre-
determined settings derived from preliminary work, and these were
kept constant for every patient: pulse repetition frequency 1.0, power
4.0, colour gain 38.4, wall motion ®lter 75, rise 0.2, persistence 0.8,
reject 82 and with the central frequency set to mid. These settings were
found to offer the best compromise between small vessel detection and
Doppler artefact (Raine-Fenning et al., 2002b). A longitudinal view of
the uterus and endometrial cavity was obtained and the volume mode
entered. The resultant truncated sector de®ning the area of interest was
then moved and adjusted, and the sweep angle set to 90° to ensure that
a complete uterine volume encompassing the entire subendometrium
was obtained. The patient was asked to remain as still as possible and
every effort was made by the ultrasonographer to limit inappropriate
movements of the transducer. A three-dimensional data set was then
acquired using the medium speed sweep mode. The resultant
multiplanar display was examined to ensure that the area of interest
had been captured in its entirety. Particular attention was given to the
coronal image in the C plane, speci®c to three-dimensional ultrasound,
which provides more spatial information than the transverse or
longitudinal image. If the volume was complete with no power
Doppler artefact, the data set was stored to a magnetic optical disk. If
there was apparent artefact, such as typical `¯ash' artefacts seen with
bowel movements or the patient coughing, the data set was reacquired
until a satisfactory image was obtained.
Standardization of the ultrasound settings was ensured by using the
same pre-de®ned probe programme without adjustment once the
programme had been loaded. Prior to each acquisition, the power
Doppler settings were checked to ensure they had not changed during
manipulation of the volume sector, which can lead to an automatic
increase or decrease in the settings with larger and smaller volumes,
respectively. At the end of the scan session, the acquired volumes were
reloaded from the magnetic optical disk and sent to a personal
computer via a dedicated DICOM link (Digital Imaging and
Communications in Medicine) (Mildenberger et al., 2002). 3D
ViewÔ software (GE Kretz) was used by the personal computer to
receive and store the volume data sets and for the subsequent analysis
of the endometrial data.
331
 N.J.Raine-Fenning et al.

Table I. Power Doppler quanti®cation

Vascular index Description

Vascularization VI Colour values/(colour values + grey-scale

index values)
Flow index FI Weighted colour values/colour values
Vascularization VFI Weighted colour values/(colour values +
¯ow index grey-scale values)

The three-dimensional indices of vascularity are shown together with

statistical and descriptive versions of the algorithms used to derive them.
1P
00 1P
00 1P
00
hc…c† c
hc…c† c
hc…c†
cˆ1
VI ˆ 1P
FI ˆ cˆ1 VFI ˆ cˆ1
00 P
100 P
100 P
100 P
100
hg…g† ‡ hc…c† hc…c† hg…g† ‡ hc…c†
gˆ1 cˆ0 cˆ1 gˆ1 cˆ0

Figure 1. Virtual organ computer-aided analysis (VOCALÔ). This
®gure shows a typical multiplanar display of the uterus following
three-dimensional power Doppler data acquisition. The longitudinal
and transverse views are show in the upper right and left images,
respectively, and the third view, the coronal plane, can be seen in
the lower left image. The myometrial±endometrial border has been
manually delineated, and the subendometrium de®ned through the
process of shell-imaging, whereby a second contour or `shell' is
applied that exactly mirrors the originally de®ned surface contour.
The resultant three-dimensional model can be seen in the lower left
image.
Data analysis
Data assessment was undertaken by one observer (J.S.C.) to limit bias.
Three-dimensional endometrial volumetric and vascular measure-
ments were undertaken with the virtual organ computer-aided analysis
imaging program (VOCALÔ) within 3D ViewÔ. VOCAL allows the
user to de®ne the volume of interest manually with a standard
computer mouse as the data set is rotated about a central axis, and we
have previously described the application of this technique for
endometrial volume measurements (Raine-Fenning et al., 2002c). For
the purpose of this study, all measurements were conducted manually
in plane C (coronal image) as this plane was rotated about plane A
(longitudinal image) using the 9° rotation step (see Figure 1). Because
the data set is rotated through 180°, the 9° rotation step makes 20
planes available to calculate each individual volume and represents
the best compromise between reliability, validity and time to de®ne
the initial volume (Raine-Fenning et al., 2003). Once the endometrium
had been de®ned, the power Doppler signal within it was quanti®ed
through the `histogram facility', which employs speci®c mathematical
algorithms to generate three indices of vascularity (Pairleitner et al.,
1999). These indices are representative of either the percentage of
power Doppler data within the de®ned volume (the VI; vascularization
index), the signal intensity of the power Doppler information (the FI;
¯ow index) or a combination of both factors (the VFI; vascular ¯ow
index) (see Table I for a full de®nition of each index) and have been
suggested as representative of vascularity and ¯ow intensity (Jarvela
et al., 2003).
Following assessment of the endometrium itself, the subendome-
trium was examined through the application of `shell-imaging', which
allows the user to generate a variable contour that parallels the
originally de®ned surface contour. For the purpose of this study, we
used shell-imaging to de®ne a three-dimensional region within 5 mm
of the originally de®ned myometrial±endometrial contour and then
quanti®ed the power Doppler signal within this subendometrial region
(see Figure 1). This is an arbitrary distance but one that re¯ects the
inner third of the myometrium and the region supplied by the radial
arteries (Bulletti et al., 1985).
332
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g = grey-scale value in ultrasound image normalized to 0... 100; c = colour
value in ultrasound image normalized to 0... 100; low intensity = 0; high
intensity = 100; hg(x) = frequency of grey value x in ultrasound image;
hc(x) = frequency of color value x in ultrasound image.
Having con®rmed our own inter-observer reliability of both
acquisition and quanti®cation of three-dimensional power Doppler
data from the endometrium (Raine-Fenning et al., 2002a), we acquired
a single data set from each patient at every visit, and a single observer
subsequently conducted two serial measurements of all resultant data
sets. The mean of these two measurements is shown in the Results.
Hormonal analysis
Blood was centrifuged, and plasma was separated and stored at ±20 °C
until assayed. Steroid hormone measurements were made by
radioimmunoassay as previously described, with minor modi®cations.
Plasma estradiol concentrations were determined following extraction
with diethyl ether (Glasier et al., 1989) and utilized estradiol-6-O-
carboxymethyloximino-2-[125I]histamine as tracer (IM135,
Amersham Pharmacia Biotech UK Ltd, Bucks, UK) with an antibody
raised against estradiol-6-carboxymethyloximino-bovine serum albu-
min (BSA) (UCB A901 Biogenesis Ltd, Poole, UK) (Campbell et al.,
1994). The sensitivity, and intra- and inter-assay coef®cients of
variation were 50 pmol/l, 10.6% and 13.5%, respectively. Plasma
progesterone concentrations were determined by direct immunoassay
using [125I]11-progesterone glucuronide (Amersham Pharmacia
Biotech) (Yong et al., 1992) as label, and rabbit antiprogesterone
11-hemisuccinate BSA antiserum (SAPU R7044X) (Souza et al.,
1997). The sensitivity, and intra- and inter-assay coef®cients of
variation were 175 pmol/l, 8.6% and 14.5%, respectively. Human LH
was determined using reagents supplied by the National Institute of
Diabetes and Digestive and Kidney diseases (NIDDK). NIDDK-hLH-
I-SIAFP-1 (Potency 4500 IU/mg) was labelled with 125I using the
chloramine-T method as previously described (Campbell et al., 1990).
The antiserum used was NIDDK-anti-hLH-3, which was used
according to the supplier's instructions at a ®nal dilution of
1:600 000. The reference preparation was LER 907, which had a
potency of 277 IU/mg. The sensitivity, and intra- and inter-assay
coef®cients of variation were 1.3 IU/l, 6.6% and 12.8% respectively.
Statistical analysis
Statistical analysis was undertaken using SPSS version 10.1.4 using
the repeated measures general linear model to determine differences
with time.
 Quantifying normal endometrial vascularity with 3D

Table II. Subgroup analysis of the effect of compounding factors on endometrial and subendometrial vascularity
Smoking status Parity Body mass index Age

Never Current Nulliparous Parous <24 >24 <31 >31

Number 19 8 9 18 13 14 14 13
Mean 0 14.07 0 2.22 21.74 27.34 25.86 36.54
SEM 0 1.42 0 0.21 0.43 0.67 0.84 1.05
Min 0 6 0 1 19.6 24.3 20 31
Max 0 20 0 3 23.8 32 30 42
Endometrium
VI 0.747 0.476 0.566 0.667 0.622 0.601 0.752 0.47
(0.137) (0.12) (0.174) (0.115) (0.126) (0.142) (0.118) (0.16)
FI 30.903 31.523 29.875 32.551 31.412 31.013 31.762 30.664
(0.911) (0.797) (1.155) (0.762) (0.835) (0.943) (0.783) (1.063)
VFI 0.313 0.179 0.203 0.289 0.242 0.251 0.288 0.204
(0.059) (0.052) (0.075) (0.05) (0.054) (0.061) (0.051) (0.069)
Subendometrium
VI 3.867 1.526*** 2.436 2.958 2.709 2.685 3.128 2.265
(0.418) (0.365) (0.53) (0.349) (0.383) (0.433) (0.359) (0.487)
FI 37.414 36.529 35.251 38.692** 37.509 36.434 38.199 35.744*
(0.651) (0.569) (0.826) (0.545) (0.597) (0.674) (0.56) (0.759)
VFI 1.581 0.618*** 0.975 1.224 1.094 1.105 1.298 0.901
(0.173) (0.151) (0.219) (0.145) (0.158) (0.179) (0.149) (0.202)

The mean and SEM are shown for each variable together with the maximum (Max) and minimum (Min) values.
*P < 0.05; **P < 0.01; ***P < 0.001.

Results appreciated graphically (see Figure 3). The initial increases in

Of 49 patients interviewed, 37 met the recruitment criteria and
entered the study. This number of patients was required to ful®l
our aim to study 30 patients as, of these remaining 37 patients,
seven were immediately excluded on their ®rst ultrasound
examination due to pelvic pathology including leiomoyomata
(three patients), ovaries with a polycystic appearance (two
patients), endometriosis and an endometrial polyp. Three
further patients were lost during the study as two failed to
produce a dominant follicle and one had ®ndings consistent
with luteinized unruptured follicle syndrome, resulting in a
®nal study group of 27 patients. This group had a mean age of
31 years (range 20±42 years), a median parity of one, with nine
nulliparous and 18 parous women, and contained eight current
smokers. All nine nulliparous women were under 31 years of
age, whilst of the 18 parous women, ®ve were under 31 and the
remaining 13 were aged 31 or more. The median duration of
the menstrual cycle overall was 28 days divided equally
between the follicular and luteal phases (see Table II).
VI, FI and VFI paralleled the increase in estradiol during the
follicular phase, but there was a loss of this relationship after
ovulation. However, all three indices began to increase again as
the serum progesterone levels increased during the luteal
phase.
Subgroup analysis
Whilst there were no differences between the groups in terms
of the endometrial vascular indices, several factors were found
to exert signi®cant effects on subendometrial vascularity (see
Table II). Smoking was associated with a signi®cantly lower VI
and VFI but not FI in the subendometrium. The subendometrial
FI was signi®cantly lower in the group of women aged 31 or
more and signi®cantly higher in parous patients. Of those
patients that had conceived previously, all had gone on to have
a live birth so we could not examine the effect of gravidity
separately.

Endometrial vascularity Discussion

Both endometrial and subendometrial indices of vascularity
demonstrated signi®cant changes with time (P < 0.001) (see
Figure 2). Both the VI and VFI increased from the mid-
follicular phase, peaking ~3 days prior to ovulation. Thereafter,
there was a decrease in both of these indices, reaching a nadir 5
days post-ovulation before a gradual increase during the
transition from the early to mid-luteal phase. The FI showed a
similar pattern but with a more pronounced fall in the late
follicular phase and an earlier post-ovulatory nadir.
Relationship to sex steroid pro®les
The changes in all three vascular indices closely paralleled
those seen in serum estradiol and progesterone during certain
aspects of the menstrual cycle. These relationships are best
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This is the ®rst study to use three-dimensional power Doppler
angiography to describe the periodic changes in endometrial
and subendometrial blood ¯ow that occur during the normal
menstrual cycle. The vascular indices generated through the
quanti®cation of the power Doppler signal, thought to represent
the degree of vascularity and perfusion within these three-
dimensionally de®ned areas (Pairleitner et al., 1999; Jarvela
et al., 2003), demonstrated a distinct pre-ovulatory peak and
peri-implantation nadir. These ®ndings are contrary to the
current consensus derived from conventional pulsed wave
Doppler studies which suggest that both uterine and endome-
trial blood ¯ow increase steadily throughout the menstrual
cycle, reaching a peak in the luteal phase (Goswamy and
Steptoe, 1988; Scholtes et al., 1989; Battaglia et al., 1990;
333
 N.J.Raine-Fenning et al.
Figure 2. Temporal variation in the three-dimensional power
Doppler indices throughout the menstrual cycle relative to ovulation
de®ned as day zero and indicated by the central vertical line. The
lower darker line marked by triangular points represents data from
the endometrium, and the lighter line above marked by circular
points represents data from the subendometrium. The central point
represents the mean value, and the error bars a single standard error.
Steer et al., 1990; Santolaya-Forgas, 1992; Sladkevicius et al.,
1993; Bourne et al., 1996; Tan et al., 1996; Zaidi, 2000).
Whilst our results differ considerably from this pattern, they
must be considered in terms of the technique applied to assess
blood ¯ow and against what is known of changes in the uterine
vasculature through histological studies.
Assessment of blood ¯ow
The majority of studies examining uterine perfusion during the
normal menstrual cycle have used two-dimensional ultrasound
334
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Figure 3. The relationship between the subendometrial ¯ow index
and both serum estradiol (A) and serum progesterone (B)
throughout the menstrual cycle. The central broken line indicates
ovulation, de®ned as day zero.
and pulsed wave Doppler to determine blood ¯ow velocity and
impedance to ¯ow within the uterine artery (Goswamy and
Steptoe, 1988; Scholtes et al., 1989; Battaglia et al., 1990;
Steer et al., 1990; Santolaya-Forgas, 1992; Sladkevicius et al.,
1993; Bourne et al., 1996; Tan et al., 1996; Zaidi, 2000).
Almost all report a gradual yet continuous increase in blood
¯ow velocity in association with a reduction in the resistance to
¯ow from the early follicular phase maximal at the time of
implantation. Several groups also noted a temporary increase in
resistance to ¯ow in association with a concomitant reduction
in velocity during the peri-ovulatory period (Scholtes et al.,
1989; Steer et al., 1990; Collins et al., 1991; Sladkevicius et al.,
1993) that has been attributed to a physical vascular obstruction
induced by a transient increase in myometrial basal tone and
uterine contractility (Lyons et al., 1991; de Ziegler et al.,
2001). Myometrial contractions, however, are intermittent and
occur less frequently with time from ovulation (Bulletti et al.,
2000; de Ziegler et al., 2001), and are unlikely to explain the
sustained fall in endometrial blood ¯ow seen in this study.
The majority of these studies assume that blood ¯ow within
the uterine arteries is representative of regional uterine and
endometrial perfusion. This is supported by studies that have
looked at blood ¯ow characteristics within vessels at the
subendometrial level and report similar patterns of ¯ow to
those seen in the uterine arteries (Sladkevicius et al., 1993,
1994; Achiron et al., 1995; Bourne et al., 1996). Nevertheless,
analysis is still generally restricted to a single vessel and
complicated by the tortuous nature of the vessels and low

velocity ¯ow pro®les. Power Doppler is more sensitive to these
lower velocities and, in combination with three-dimensional
ultrasound, provides information from the endometrium or
subendometrial region as a whole, thereby giving an impres-
sion of perfusion. Indeed, our ®ndings are much more in
keeping with studies that have been designed speci®cally to
examine perfusion within the human endometrium during the
menstrual cycle.
Fraser et al. (1987) measured endometrial blood ¯ow across
the menstrual cycle by observing the clearance of radiolabelled
xenon133 following its instillation into the uterine cavity. They
demonstrated a similar pattern to that observed in this study,
with a signi®cant elevation in the middle to late follicular phase
(days 10±12), followed by a substantial fall and a subsequent
slow rise during the luteal phase (days 21±26) that was
maintained until menstruation. More recently, Gannon et al.
(1997) used an intrauterine laser Doppler technique to assess
the weekly variation in red blood cell ¯ux within the
subendometrium during the menstrual cycle. They found that
the mean endometrial microvascular perfusion varied through-
out the cycle, with two distinct and signi®cantly increased
episodes of perfusion during the follicular and luteal phases of
the cycle. Whilst they also noted the highest ¯ow during the
proliferative phase, contrary to our ®ndings and those of Fraser
et al. (1987), this peak (days 6±9) and the second luteal peak
(days 17±22) both occurred at an earlier stage of the menstrual
cycle. The discrepancies most probably re¯ect measurement
technique, with both three-dimensional power Doppler ultra-
sound and xenon clearance being more representative of
overall uterine and endometrial ¯ow. Laser Doppler ¯uxmetry
provides more information about small segments of the
endometrium, as it measures the passage of red blood cells
through a sphere of 1 mm diameter (Johansson et al., 1991;
Mayrovitz, 1992). It may not, therefore, be truly representative
of the entire endometrium, although Gannon et al. (1997) did
show minimal regional variation throughout the uterus.
Not all data relating to changes in uterine blood ¯ow are
derived from work in humans. Animal studies also suggest that
a decrease in uterine ¯ow may occur following ovulation in
cows (Ford et al., 1979; Waite et al., 1990), ewes (Greiss and
Anderson, 1969) and sows (Ford and Christenson, 1979).
Waite et al. (1990) demonstrated an increased uterine arterial
smooth muscle tone and lower uterine artery ¯ow rate in
association with the reversal in estrogen to progesterone ratio
that occurs during the luteal phase of the cycle following
oestrus in the cow. Ford et al. (1979) reported the same
relationship between uterine blood ¯ow and the ratio of
estradiol to progesterone during the oestrous cycle of non-
pregnant cows. More recently, Zhang et al. (1995) used a
hydrogen gas clearance technique to demonstrate that myo-
metrial blood ¯ow was signi®cantly greater than endometrial
¯ow in ovariectomized rats and that uterine blood ¯ow
increased in response to boluses of 17b-estradiol.
Histological changes in uterine vascularity
The highest rate of endometrial cell proliferation does occur
during the early proliferative phase of endometrial growth and
is maximal around days 8±10 in the upper one-third of the
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Quantifying normal endometrial vascularity with 3D
functionalis layer (Ferenczy et al., 1979). Signi®cant dilatation
of the vessels within the subepithelial capillary plexus occurs
during the post-ovulatory phase, leading to oedema appearing
in the stroma at the time of the expected implantation (Peek
et al., 1992). It is possible therefore that the power Doppler
signal falls at this time as a result of an increase in the distance
between individual vessels and a resultant decrease in
microvessel spatial density (Gannon et al., 1997). However,
whilst there is evidence of a reduction in endometrial capillary
spatial density following ovulation, it tends to occur during the
latter part of the luteal phase as the endometrium becomes
progressively oedematous (Johannisson et al., 1987; Hourihan
et al., 1991). Nevertheless, implantation itself is characterized
by an in¯ammatory-like response associated with increased
vascular permeability and vasodilatation, and these processes
could theoretically affect the power Doppler signal. Similarly,
during the late luteal phase, we may have seen an increase in
the power Doppler signal due to an increase in endometrial
vascular density associated with the progressive coiling of the
spiral arteries or endometrial compaction characteristic of the
late luteal phase (Shaw and Roche, 1980).
Relationship to sex steroids
Our three vascular indices closely paralleled the changes seen
in serum estradiol and progesterone throughout the menstrual
cycle (see Figure 3). Both endometrial and subendometrial
vascularity demonstrated a signi®cant elevation in the middle
to late follicular phase as the estrogen to progesterone ratio
increased. Animal work has shown that the increase in uterine
blood ¯ow during this phase is due to a vasodilatatory response
that is reproduced by exogenous 17b-estradiol administration
via a nitric oxide-mediated mechanism (Vagnoni et al., 1998).
This relationship was maintained thereafter, with all three
indices of vascularity reaching maximum values around the
time of the estradiol peak before falling in parallel with the
reduction in the circulating estradiol to progesterone ratio to
reach a nadir in the early post-ovulatory period. Goswamy and
Steptoe (1988) described a similar pattern but in terms of an
increase in the resistance to ¯ow in association with this post-
ovulatory fall in estradiol. Whilst other groups have described
the subsequent loss of the relationship with estradiol at this
point (Fraser et al., 1987), the indices of vascularity then began
to rise again, closely following, although lagging behind, the
post-ovulatory increase in progesterone. The vascular indices,
however, continued to rise even as the progesterone levels fell
during the late luteal phase, reaching some of the highest
values throughout the whole menstrual cycle just prior to
menstruation. This may simply re¯ect tissue density and the
increased coiling of spiral arteries as discussed above, but may
also relate to the increasing role of the renin±angiotensin
system in menstrual regulation (Johnson, 1980).
Subgroup analysis
Whilst cigarette smoking is associated with endothelial
dysfunction (Neunteu¯ et al., 2000) and an increase arterial
wall stiffness (Caro et al., 1987), its effect on uterine blood
¯ow is less clear. Different groups have suggested that smoking
is associated with either an increase (Nordenvall et al., 1991) or
335
 N.J.Raine-Fenning et al.
a decrease (Castro et al., 1993) in the systolic to diastolic ratio
of the uterine artery, whilst most report no effect at all (Morrow
et al., 1988; Newnham et al., 1990; Bruner and Forouzan,
1991; Kimya et al., 1998). In this study, smoking was
speci®cally associated with a reduction in the VI and VFI,
but not the FI.
Contrary to this were the isolated ®ndings of a lower FI in
the group of women aged 31 or more and a higher FI in parous
patients. Seventy-two percent of parous women (13 of 18) were
actually aged 31 or more, suggesting that the effect of age
outweighs the positive effect of parity. Whilst both ®ndings
may have been expected and can be explained physiologically,
there is a surprising paucity of work addressing either issue. A
reduction in uterine blood ¯ow with age has been described,
but only during the post-menopausal period where there is a
clear correlation between years since the menopause and the
resistance to ¯ow within the uterine, radial and spiral arteries
(Kurjak and Kupesic, 1995). Three-dimensional power
Doppler angiography has been used to demonstrate a reduction
in ovarian stromal vascularity with age in both women of
reproductive age (Kupesic et al., 2003) and older peri-
menopausal women (Pan et al., 2002), but there are no data
on uterine vascularity addressing the effect of age or parity.
The numbers involved, however, are small, and larger studies
dedicated to factors that may in¯uence endometrial blood ¯ow
are warranted.
Arguably one of the most important ®ndings from our
subgroup analysis was that these differences were observed
within the subendometrium only and not within the endome-
trium. This serves to remind us that the myometrium and
endometrium have separate and discrete vascular beds and
should therefore be considered independently (Ramsey, 1977;
Rogers and Gannon, 1981). Shell-imaging permits such
discriminatory analysis and provides a novel technique with
which to examine regional blood ¯ow within any given organ
or tissue.
This study has demonstrated distinct changes in vascularity
during the normal menstrual cycle, as assessed by three-
dimensional power Doppler, characterized by a pre-ovulatory
peak and a post-ovulatory fall that reaches a nadir at the time of
implantation. The changes parallel those seen in serum
estradiol during the follicular phase and serum progesterone
during the luteal phase. Indices of subendometrial vascularity
are signi®cantly lower in smokers and women aged 31 or more,
but are increased in parous women. Three-dimensional power
Doppler angiography offers a new tool with which to
investigate endometrial perfusion and could potentially be
used to de®ne pathophysiological change associated with
certain disease processes and to quantify the effect of various
treatment modalities on these.
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Submitted on June 26, 2003; accepted on October 6, 2003