Professional Documents
Culture Documents
Middle East Fertility Society Journal
Middle East Fertility Society Journal
Original Article
a r t i c l e i n f o a b s t r a c t
Article history: Introduction: The study aims to evaluate the effect of obesity on the endometrium in women with poly-
Received 6 February 2018 cystic ovarian disease (PCOD) through evaluation of endometrial and subendometrial vascularity by two-
Revised 4 April 2018 dimensional (2D) ultrasound, Doppler and three dimensional power Doppler (3DPD).
Accepted 17 April 2018
Methods: A prospective case-control study, conducted in a tertiary University hospital between February
Available online 27 April 2018
2016 and December 2016. The study included 50 women with PCOD and 50 fertile regular menstruating
women divided according to their body mass index (BMI) into normal weight and overweight/obese
Keywords:
groups. Endometrial thickness and pattern combined with Doppler examination of the uterine vessels
Obesity
Polycystic ovarian disease
for measurement of Resistance index (RI) and pulsatility index (PI) were assessed. Evaluation of endome-
Endometrium trial and subendometrial blood flow was performed by 3DPD using Virtual organ computer-aided anal-
Doppler ysis program.
VOCAL Results: No significant difference in the endometrial pattern or thickness between all study groups.
Infertility Endometrial volume was significantly lower in the overweight/obese PCOD women and overall in the
PCOD women compared to the control group (p < 0.01). Uterine artery RI was significantly higher in
the PCOD women compared to the control group (p = 0.004), but no difference in uterine PI. Vascular
indices of endometrial and subendometrial blood flow were significantly lower in the overweight/obese
PCOD women than the normal weight PCOD women.
Conclusions: The endometrium is negatively affected by obesity in women with PCOD. Additionally,
PCOD women had lower endometrial and subendometrial blood flow than non-PCOD women.
Therefore, overweight/obese PCOD women should be encouraged to reduce their body weight in order
to improve the endometrial receptivity.
Ó 2018 Middle East Fertility Society. Production and hosting by Elsevier B.V. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
https://doi.org/10.1016/j.mefs.2018.04.006
1110-5690/Ó 2018 Middle East Fertility Society. Production and hosting by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
E.R. Othman et al. / Middle East Fertility Society Journal 23 (2018) 324–330 325
clinical pregnancy and miscarriage rates were comparable Group A: Women with PCOD who are overweight/obese with
between all BMI subgroups [5]. BMI 25 kg/m2.
Ultrasonographic findings indicating changed endometrial Group B: Women with PCOD who are normal weight with BMI
receptivity have not yet been agreed. The different ultrasound < 25 kg/m2.
parameters of endometrial receptivity include endometrial thick- Group C: Fertile regularly menstruating women who are over-
ness, endometrial pattern, endometrial volume and Doppler stud- weight/obese with BMI 25 kg/m2.
ies of uterine vessels and the endometrium. Three-dimensional Group D: Fertile regularly menstruating women who are nor-
Power Doppler (3DPD) assessment is applied for the study of dif- mal weight with BMI < 25 kg/m2.
ferent variables endometrial-subendometrial perfusion that is also
The participants were scheduled to be evaluated on two visits
used as receptivity markers [8].
after the onset of spontaneous or progesterone-induced menses.
The current study aims to determine the effect of obesity on the
The first one was dated to be between the 12th–14th days (preovu-
endometrium in women with PCOD, and compare them to the
latory), while the second was between the 20th–22nd days (mid-
endometrium of fertile regular menstruating women as controls,
luteal). All participants were examined by the same sonographer,
using ultrasonographic endometrial and subendometrial vascular-
who had no clinical information about the patients, using a
ity parameters.
SonoAce X8 machine (Medison, Korea) with transvaginal volumet-
ric probe with 4–8 MHz frequency (using an average 6.5 MHz).
2. Materials and methods At each visit, after asking the patients for emptying their blad-
der, preliminary transvaginal sonography (TVS) was done for eval-
2.1. Study type, setting and duration uation of endometrial thickness and pattern. Endometrial
thickness was measured as the distance between the echogenic
The study was a prospective pilot case-control study conducted interfaces of the endometrium and the myometrium through the
in a tertiary University hospital between February and December central longitudinal axis of the uterine body, at the junction
2016. The study was registered at Clinical Trials. Gov between the upper one-third and lower two-thirds of the endome-
(NCT02694419). trial cavity. The endometrial pattern was classified to a triple or
non-triple layer. A triple layer endometrium appears as a hypere-
2.2. Study population chogenic outer lines and central hyperechogenic line with a hypoe-
chogenic region between them. A non-triple layer appears as
All infertile women attended the infertility clinic in the afore- homogenous endometrial pattern characterized by either hypere-
mentioned hospital during the study period were clinically evalu- chogenic or isoechogenic endometrium.
ated, and those who were diagnosed as PCOD according to Then, Color Doppler ultrasound was used to demonstrate the
Rotterdam criteria (presence of two out of the following three cri- main ascending branches of left and right uterine arteries as they
teria: oligomenorrhea (absence of menses for 35–182 days) or cross over the hypogastric vessels just before they enter the uterus
amenorrhea (absence of menses for >182 days), signs or symptoms at the uterine-cervical junction. These vessels were then examined
of hyperandrogenism (acne, hirsutism), ultrasound showing poly- by pulsed-wave Doppler, which used to generate a consistent
cystic ovaries) [9] were invited to participate in the study. The waveform over five consecutive cardiac cycles. The wave forms
study was approved from the Assiut Medical School Ethical Review were analyzed to obtain the resistance index (RI) and the pulsatil-
Board and a written informed consent was obtained from all study ity index (PI) from three similar consecutive waveforms. The for-
participants. mulas used for PI and RI were PI = (S D)/mean and RI = (S D)/
All included women were between 18 and 40 years old with S respectively, when S is the peak Doppler frequency shift and D
basal serum follicle stimulating hormone (FSH < 10 mIU/mL) level is the minimum. The average value of the bilateral uterine arteries
tested on day 3 of a spontaneous or induced cycle. We excluded is calculated for each index. Mean values of bilateral uterine RI and
women known to have Diabetes mellitus, hypertension, cardiovas- PI were used for statistical analysis.
cular diseases, women used ovulation induction drugs or hormonal The US scanner was then switched to the 3DPD mode. The ultra-
contraception in the preceded 3 months, those had previous sound probe was kept steady, and the patient was asked to lie sta-
laparoscopic ovarian drilling and women with any uterine abnor- tic on the bed during the volume acquisition. A three-dimensional
malities as congenital anomalies, endometrial lesions, adeno- data set was acquired using the medium-speed sweep mode, and
myosis, fibroids and intrauterine adhesions. Moreover, women the sweep angle was set to 90° to ensure that the complete
refused to participate in the study were also excluded. endometrial cavity is obtained.
Age matched fertile women with regular menstruation and at The built-in VOCAL (virtual organ computer aided analysis)
least previous one spontaneous pregnancy had approached to par- imaging program for the 3DPD histogram analysis was used to cal-
ticipate in the study as a control group at the time of recruitment. culate the endometrial volume and vascularity indices within the
endometrium. VOCAL displays sequential parallel slices of 3D anat-
2.3. Intervention omy to facilitate more precise volume analysis of irregularly
shaped structures. During the analysis and calculations, the man-
The following data were collected at inclusion; age, duration of ual mode of the VOCAL Contour Editor was used to cover the whole
infertility, previous infertility treatment, any used medication and three-dimensional volume of the endometrium with a 30° rotation
previous operations. Menstrual history was taken including the step. Hence, six contour planes were analyzed for the endome-
regularity of the cycle, and the date of first day of last menstrual trium of each patient to cover 180°. The subendometrium was
period. Body weight and height of each woman was obtained to set through the application of ‘‘shell-imaging”, which allows the
calculate the BMI before allocation. user to generate a variable contour that parallels the originally
One-hundred participants had stratified into four groups (25 defined contour (Fig. 1).
women in each group) depending upon their BMI and the presence In the present study, the subendometrial region was considered
or absence of PCOD. BMI was measured in kg/m2 and categorized to be within 2 mm outside of the originally defined myometrial-
according to WHO categories; 18.5 to <25 as normal weight, 25 endometrial contour ‘outside shell’. There is no consensus
to <30 as overweight, and 30 as obese [10]. regarding what size of shell should be used, but blood flow and
326 E.R. Othman et al. / Middle East Fertility Society Journal 23 (2018) 324–330
vascularity within 2 mm of the myometrial-endometrial border fertile regularly menstruating women with matched age were
has been shown to be reduced in patients with PCOD [11]. recruited as a control group (25 overweight/obese women ‘Group
The following indices were obtained: Vascularization index C’, and 25 normal weight women ‘Group D’).
(VI): the ratio of the number of color voxels to the number of all As regard to PCOD patients; the mean BMI for women in group
the voxels represents the presence of blood vessels (vascularity) A was 30.42 ± 3.15 kg/m2, while the mean BMI for women in group
in the endometrium and is expressed as a percentage of the B was 23.35 ± 1.51 kg/m2. No statistical difference between both
endometrial volume. Flow index (FI): the mean power Doppler sig- groups as regards mean duration of infertility; 3.53 ± 2.74 years
nal intensity inside the endometrium is used to express the aver- for group A and 3.72 ± 3.53 years for group B (P = 0.796) (Table 1).
age intensity of flow. Vascularization flow index (VFI): calculated There was significant difference in the endometrial volume
by multiplying VI and FI, it reflects a combination of vascularity between both groups both in the preovulatory and midluteal phase
and flow intensity (Fig. 2). (P = 0.001, 0.000 respectively). Additionally, 3DPD indices shown
significant difference between both groups regarding VI and FI in
2.4. Statistical analysis both phases being higher in group B, while there was no significant
difference regarding VFI.
All data were analyzed using SPSS software Chicago, IL, USA, There was no statistical difference between the two groups
version 21. Qualitative data were expressed as frequency and per- regarding endometrial thickness (8.06 ± 1.40 cm in group A versus
centage. Fisher’s exact test was used to examine the relation 7.74 ± 1.76 cm in group B preovulatory and 9.16 ± 1.99 cm in group
between qualitative variables. Quantitative data were presented A versus 9.26 ± 2.15 cm in group B midluteal), endometrial pattern
in terms of, mean and standard deviation. For quantitative data, (triple layer in 76% of patients in group A versus 72% of patients in
comparison between two groups was done using Mann-Whitney group B preovulatory and 16% in group A versus 4% in group B mid-
test. Spearman correlation analysis between the ultrasonographic luteal) and uterine artery Doppler indices (Table 2).
and Doppler parameters with BMI was done. Level of significance When comparing obese women in group A and C, we found that
‘‘P” value was evaluated, where P value <0.05 is considered of sig- the mean BMI for women in group C was 30.65 ± 3.47 kg/m2 with
nificant value. no statistical difference between both groups. No statistical differ-
ence between both groups regarding endometrial (8.06 ± 1.40 cm
3. Results in group A versus 9.10 ± 2.33 cm in group B preovulatory and 9.1
6 ± 1.99 cm in group A versus 10.25 ± 4.07 cm in group B mid-
One hundred and seventy-nine infertile women were evaluated luteal), endometrial pattern (triple layer in 76% of patients in both
during the study period, of them 66 (36.9%) women were diag- group A & C preovulatory and 16% in group A versus 8% in group B
nosed to have PCOD according to Rotterdam criteria. Sixteen midluteal).
women were excluded for various exclusion criteria ends in 50 There was a significant difference in the endometrial volume
PCOD patients included in the study group (25 overweight/obese between both groups both in the preovulatory and midluteal phase
women ‘Group A’, 25 normal weight women ‘Group B’). Fifty (P = 0.002, 0.000 respectively) being more in fertile obese women.
E.R. Othman et al. / Middle East Fertility Society Journal 23 (2018) 324–330 327
Fig. 2. 3-Dimensional power Doppler histogram showing endometrial and subendometrial vascularity with measurement of vascular indices.
Table 1
The basal criteria of the study participants.
# § $
Group A Group B P-value Group C P-value Group D P-value
(n = 25) (n = 25) (n = 25) (n = 25)
Age, years 26.24 ± 1.78 25.08 ± 2.16 0.146 25.48 ± 2.32 0.074 25.52 ± 1.15 0.573
BMI, kg/m2 30.42 ± 3.15 23.35 ± 1.51 0.000* 30.65 ± 3.47 0.823 23.02 ± 2.66 0.274
Nullipara 12 (48%) 10 (40) 0.325 – – – –
Type of infertility: Primary 12 (48%) 10 (40) 0.325 – – – –
Secondary 13 (52%) 15 (60)
Duration of infertility 3.53 ± 2.74 3.72 ± 3.53 0.796 – – – –
History of oligomenorrhea 25 (100%) 24 (96%) 0.312 – – – –
History of hirsutism 9 (36%) 8 (32%) 0.765 – – – –
There was a significant difference between both groups regarding women; whether they were fertile or PCOD (group B&D) in any
the uterine artery RI being higher in PCOD obese women than fer- ultrasonographic or Doppler endometrial parameters except RI in
tile obese women, while PI didn’t show significant difference. the midluteal phase (P = 0.001).
Moreover, all 3DPD indices were significantly higher in fertile The results of Spearman correlation analysis between BMI and
obese women than PCOD obese women in both preovulatory and different ultrasonographic and Doppler parameters were shown
midluteal phase except VFI in the midluteal phase (P = 0.123) in Table 3. There was a significant strong negative correlation
(Table 2). between endometrial thickness and BMI in both preovulatory
Both fertile groups (C&D) showed no significant difference in (r = 0.762, P = 0.000) and midluteal phases (r = 0.737,
any of the ultrasonographic or Doppler endometrial parameters P = 0.000) (Fig. 3). Also, there was a significant mild negative
in either preovulatory or midluteal phases of the menstrual cycle. correlation between VFI of the endometrium and subendometrial
Additionally, no significant difference between normal weight and BMI in the midluteal phase (r = 0.260, P = 0.009) (Fig. 4).
328 E.R. Othman et al. / Middle East Fertility Society Journal 23 (2018) 324–330
Table 2
Ultrasonographic and Doppler endometrial characteristics in the study groups.
# § $
Group A Group B P-value Group C P-value Group D P-value
(n = 25) (n = 25) (n = 25) (n = 25)
Endometrial thickness, mm
Preovulatory 8.06 ± 1.40 7.74 ± 1.76 0.299 9.10 ± 2.33 0.053 8.38 ± 1.15 0.055
Midluteal 9.16 ± 1.99 9.26 ± 2.15 0.734 10.25 ± 4.07 0.19 9.12 ± 1.30 0.768
Endometrial pattern
Triple-layer (n, %)
Preovulatory 19 (76%) 18 (72%) 0.747 19 (76%) – 19 (76%) 0.747
Midluteal 4 (16%) 1 (4%) 0.346 2 (8%) 0.663 3 (12%) 0.602
All values are expressed as mean ± SD, RI; resistance index, PI; pulsatility index, VI; vascularization index, FI; flow index, VFI; vascularization flow index.
*
Statistical significant difference.
#
P-value between group A and group B.
§
P-value between group A and group C.
$
P-value between group B and group D.
Table 3
Correlation analysis between ultrasonographic and Doppler endometrial parameters
4. Discussion
with BMI of the study participants.
In our study, the endometrial thickness and pattern have been BMI correlated negatively with the endometrial thickness
shown not to be affected by body weight in patients with PCOD. (r = 0.762).
This was consistent with the results reported by Zeng et al. [5], that Endometrial volume in our results was significantly lower with
endometrial thickness and pattern had no significant difference higher BMI in women with PCOD (P = 0.000). Endometrial volume
according to the BMI. However, our study showed that higher was also significantly lower in the PCOD women compared to con-
trol women (P = 0.000). This is consistent with the results of Moh- Conflict of interest
sen et al. study [11] regarding endometrial volume, which was sig-
nificantly lower in the PCOD women than the control women who The authors declare that they have no conflict of interest.
were all overweight or obese.
In the current study, using the uterine artery Doppler, RI was References
found to be increased in women with PCOD when compared to
the control group. However, the results showed that overweight/ [1] C.L. Ogden, M.D. Carroll, L.R. Curtin, et al., Prevalence of overweight and obesity
in the United States. 1999–2004, JAMA 295 (2006) 1549.
obesity had no significant effect on RI in all groups. The increased [2] J.W. van der Steeg, P. Steures, M.J. Eijkemans, et al., Obesity affects
RI in PCOD women than in the control women was consistent with spontaneous pregnancy chances in subfertile ovulatory women, Hum.
the results of Mohsen et al. study [11]. Reprod. 23 (2008) 324.
[3] H. Teede, A. Deeks, L. Moran, Polycystic ovary syndrome: a complex condition
There were no significant differences in PI among all the study with psychological, reproductive and metabolic manifestations that impacts
groups, which were inconsistent with previous studies, reported a on health across the lifespan, BMC Med. 8 (2010) 41.
higher uterine artery PI in women with PCOD than in normal [4] R. Azziz, K.S. Woods, R. Reyna, et al., The prevalence and features of the
polycystic ovary syndrome in an unselected population, J. Clin. Endocrinol.
women [11,19,20]. Chien et al. reported that the subendometrial
Metab. 89 (2004) 2745.
flow could affect the pregnancy and implantation, whereas there [5] X. Zeng, H. Pang, X. Li, et al., Impact of obesity on endometrial blood flow in
was no relationship with uterine artery RI and PI [21]. This proba- women without polycystic ovarian syndrome during intracytoplasmic sperm
bly reflects the limitation of pulsed-wave Doppler analysis, which injection, Reprod. Biol. Endocrinol. 11 (2013) 57.
[6] L.C. Giudice, Endometrium in PCOS: implantation and predisposition to
selects a portion of the uterine artery, presuming it to reflect the endocrine CA, Best Pract. Res. Clin. Endocrinol. Metab. 20 (2006) 235.
downstream endometrial blood flow. [7] J. Bellver, M.A. Melo, E. Bosch, et al., Obesity and poor reproductive outcome:
Lam and coworkers were first to use quantitative 3DPD angiog- the potential role of the endometrium, Fertil. Steril. 88 (2007) 446.
[8] M. Choudhary, J. Chowdhary, M.L. Swarankar, et al., Predictive value of
raphy to evaluate endometrial and subendometrial blood flow in subendometrial–endometrial blood flow assessment by transvaginal 3D power
women with PCOD as defined by Rotterdam criteria [22]. doppler on the day of HCG on clinical outcome of IVF cycles, Int. J. Res. Med.
Assessment of the endometrial receptivity by 3DPD study of Sci. 3 (2015) 3114.
[9] Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group,
subendometrial-endometrial blood flow is a simple, non-invasive Revised 2003 consensus on diagnostic criteria and long term health risks
method especially if the primary ultrasound markers of endome- related to polycystic ovary syndrome, Fertil. Steril. 81 (2004) 19.
trial receptivity are poor (ET < 7.0 mm, hyperechoic or presence [10] WHO ‘Obesity: Preventing and managing the Global Epidemic’. Report of a
WHO Consultation on Obesity, Geneva.
of subendometrial calcification) [8]. [11] I.A. Mohsen, E. Elkattan, H. Nabil, et al., Effect of metformin treatment on
In the present study, endometrial and subendometrial blood endometrial vascular indices in anovulatory obese/overweight women with
flow was studied by 3DPD. VI and FI were shown to be significantly polycystic ovarian syndrome using three-dimensional power doppler
ultrasonography, J. Clin. Ultrasound 41 (2013) 275.
lower in overweight/obese PCOD women than normal weight
[12] C.J. Brewer, A.H. Balen, The adverse effects of obesity on conception and
PCOD women, while VFI was not significantly different. implantation, Reproduction 140 (2010) 347.
Also, our results showed that VI and FI were significantly lower [13] E.H.Y. Ng, C.C.W. Chan, O.S. Tang, et al., Endometrial and subendometrial blood
in the overweight/obese PCOD women than fertile overweight/ flow measured by three-dimensional power Doppler ultrasound in patients
with small intramural uterine fibroids during IVF treatment, Hum. Reprod. 20
obese women. VFI was significantly lower in the PCOD over- (2005) 501.
weight/obese women during the preovulatory phase than the over- [14] N. Raine-Fenning, B. Campbell, N. Kendall, et al., Endometrial and
weight/obese fertile women. This was consistent with Mohsen subendometrial perfusion are impaired in women with unexplained
subfertility, Hum. Reprod. 19 (2004) 2605.
et al. results that stated significant lower values of VI, FI, and VFI [15] C.T. Erel, L.M. Senturk, The impact of body mass index on assisted
in overweight/obese PCOD women than fertile overweight/obese reproduction, Curr. Opin. Obstet. Gynecol. 21 (2009) 228.
women during both preovulatory and midluteal phases of men- [16] B. Carrington, G. Sacks, L. Regan, Recurrent miscarriage: pathophysiology and
outcome, Curr. Opin. Obstet. Gynecol. 17 (2005) 591.
strual cycle [11]. [17] E.D. Levens, M.C. Skarulis, Assessing the role of endometrial alteration among
Our results showed that there was no significant difference in obese patients undergoing assisted reproduction, Fertil. Steril. 89 (2008) 1606.
the endometrial and subendometrial blood flow parameters when [18] G.G. Gosman, H.I. Katcher, R.S. Legro, Obesity and the role of gut and adipose
hormones in female reproduction, Hum. Reprod. Update 12 (2006) 585.
comparing normal weight PCOD women with fertile normal [19] S. Ajossa, S. Guerriero, A.M. Paoletti, et al., Reproductive endocrinology:
weight women. Also there was no significant difference in all US uterine perfusion and hormonal pattern in patients with polycystic ovary
and Doppler endometrial parameters when comparing over- syndrome, J. Assist. Reprod. Genet. 18 (2001) 436.
[20] C. Chekir, M. Nakatsuka, Y. Kamada, et al., Impaired uterine perfusion
weight/obese fertile women to normal weight fertile women.
associated with metabolic disorders in women with polycystic ovary
In conclusion, the current study suggests that the endometrium syndrome, Acta Obstet. Gynecol. Scand. 84 (2005) 189.
is negatively affected by the increased body weight and obesity in [21] L. Chien, W. Lee, H. Au, et al., Assessment of changes in utero-ovarian arterial
PCOD women. Additionally, PCOD women had lower endometrial impedance during the peri-implantation period by Doppler sonography in
women undergoing assisted reproduction, Ultrasound Obstet. Gynecol. 23
and subendometrial blood flow than non-PCOD women. The (2004) 496.
endometrial and subendometrial blood flow may be a cause of sub- [22] P. Lam, I. Johnson, N. Raine-Fenning, Endometrial blood flow is impaired in
fertility and recurrent miscarriage in women with PCOD. So PCOD women with polycystic ovarian syndrome who are clinically hyperandrogenic,
Ultrasound Obstet. Gynecol. 34 (2009) 326.
women who are overweight or obese should be encouraged to
reduce their body weight in order to improve not only ovulation
but also endometrial receptivity.