Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China
1 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, The University of Hong Kong, 6/F, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong. Email: nghye{at}hkucc.hku.hk
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Abstract |
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Key words: endometrial and subendometrial blood flow/natural cycles/stimulation/three-dimensional power Doppler
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Introduction |
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In a review of natural cycle IVF (Pelinck et al., 2002), implantation rates ranged from 0 to 33.0% in natural cycles but were only 79% in stimulated cycles. We previously reported an implantation rate of 50% in 32 natural IVF cycles performed in 19 patients (Ng et al., 2001
). It is possible that the endometrium in natural cycles is more receptive when compared with that in stimulated cycles. High serum estradiol (E2) concentrations resulting from excessive ovarian response adversely affect the outcomes of assisted reproduction cycles (Forman et al., 1988
; Simón et al., 1995
, 1998
; Check et al., 2000
; Ng et al., 2000
) but did not impair oocyte and embryo quality (Ng et al., 2003
). Reduced implantation in these cycles might be related to suboptimal endometrial perfusion (Basir et al., 2001a
; Ng et al., 2004
) and abnormal endometrial morphometry (Basir et al., 2001b
).
Angiogenesis plays a critical role in various female reproductive processes such as development of a dominant follicle, formation of a corpus luteum, growth of endometrium and implantation (Abulafia and Sherer, 2000; Smith, 2001
). A good blood supply towards the endometrium is usually considered to be an essential requirement for normal implantation. Endometrial microvascular blood flow determined by an intrauterine laser Doppler technique in the early luteal phase of the cycle preceding an IVF cycle has been shown to be predictive of pregnancy and superior to other conventional parameters predicting endometrial receptivity (Jinno et al., 2001
). Endometrial blood flow can be non-invasively evaluated by colour and power Doppler ultrasound. Power Doppler imaging is more sensitive than colour Doppler imaging at detecting low velocity flow and hence improves the visualization of small vessels (Guerriero et al., 1999
). In combination with three-dimensional (3D) ultrasound, power Doppler provides a unique tool with which to examine the blood supply towards the whole endometrium and the subendometrial region (Schild et al., 2000
; Kupesic et al., 2001
; Wu et al., 2003
; Raine-Fenning et al., 2004
; Ng et al., 2004
).
The above findings in excessive responders prompted us to investigate whether there is any change in endometrial and subendometrial blood flow following ovarian stimulation. The aim of this study was to compare endometrial and subendometrial blood flow measured by 3D power Doppler ultrasound between stimulated and natural cycles in the same patients.
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Materials and methods |
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Stimulated cycles
All patients received a long protocol of pituitary down-regulation as previously described (Ng et al., 2000). In short, all women were pre-treated with buserelin (Suprecur; Hoechst, Germany) nasal spray 150 mg four times a day from the mid-luteal phase of the cycle preceding the treatment cycle and received hMG (Pergonal; Serono, Switzerland) for ovarian stimulation. hCG (Profasi; Serono) was given i.m. when the leading follicle reached 18 mm in diameter and there were at least three follicles of
16 mm in diameter. Serum E2 concentration was measured on the day of hCG administration.
Natural cycles
Patients who did not achieve pregnancy in the stimulated IVF cycle and had frozen embryos would undergo FET 2 months after the stimulated cycle. Patients attended the clinic daily from 18 days before the next expected period for the determination of serum E2 and LH concentrations until LH surge, which was defined as the day on which the LH level was >20 IU/l and double the average of the LH levels over the past 3 days. The transfer was performed on the third day after the LH surge.
Serum E2 and LH concentrations were measured using commercially available kits (Automated Chemiluminescence System; Bay Corporation, USA). The sensitivity of the E2 assay was 36.7 pmol/l and the intra- and inter-assay coefficients of variation were 8.1 and 8.7% respectively. The sensitivity of the LH assay was 0.07 IU/l and the intra- and inter-assay coefficients of variation were 4.5 and 5.2% respectively.
Ultrasound markers of endometrial receptivity
The details of ultrasound measurement and 3D data analysis were as previously described (Ng et al., 2004; Raine-Fenning et al., 2004
). All ultrasound measurements were performed by E.H.Y.N. on hCG+2 (prior to transvaginal ultrasound-guided oocyte retrieval) in stimulated cycles and LH+1 in natural cycles using Voluson 730® (Kretz, Zipf, Austria) at
08:0010:00 after they had emptied the bladder. The results of the ultrasound assessment did not affect subsequent clinical management.
The maximum thickness of the endometrium on both sides of the midline was measured in a longitudinal plan. The endometrial pattern visualized was designated as a multilayered or a non-multilayered endometrium (Sher et al., 1991). A multilayered endometrium presented as a triple-line pattern in which hyperechogenic outer lines and a well-defined central echogenic line were seen with hypoechogenic or black areas seen between these lines. A non-multilayered endometrium consisted of homogeneous endometrial patterns characterized by either hyperechogenic or isoechogenic endometrium. Using colour Doppler in the two-dimensional (2D) mode, flow velocity waveforms were obtained from the ascending main branch of the uterine artery on the right and left side of the cervix in a longitudinal plane before it entered the uterus. The gate of the Doppler was positioned when the vessel with good colour signals was identified on the screen. The pulsatility index (PI) and resistance index (RI) of the uterine arteries were calculated electronically when similar consecutive waveforms of good quality were obtained (Basir et al., 2001a
). The intra-observer coefficient of variation was 5.6% for endometrial thickness, 9.6% for PI and 4.1% for RI.
The ultrasound machine was then switched to the 3D mode with power Doppler. The setting conditions for this study were: Frequency: Mid; Dynamic set: 2; Balance: G > 140; Smooth: 5/5; Ensemble: 12; Line Density: 7; power Doppler Map: 5; and the setting condition for the sub-power Doppler mode was: Gain: 6.0; Balance: 140; Quality: normal; Wall Motion Filter: low1; Velocity range: 0.9 kHz. The resultant truncated sector covering the endometrial cavity in a longitudinal plane of the uterus was adjusted and moved and the sweep angle was set to 90° to ensure that a complete uterine volume encompassing the entire subendometrium was obtained. The patient and the 3D transvaginal probe remained as still as possible during the volume acquisition. A 3D dataset was then acquired using the medium speed sweep mode. The resultant multi-planar display was examined to ensure that the area of interest had been captured in its entirety. If the volume was complete without power Doppler artefact, the dataset was stored for later analysis by E.H.Y.N.
The built-in VOCAL® (virtual organ computer aided analysis) Imaging Program for the 3D power Doppler histogram analysis was used to analyse with computer algorithms to calculate the endometrial volume and indices of blood flow within the endometrium. Vascularization index (VI) measuring the ratio of the number of colour voxels to the number of all the voxels is thought to represent the presence of blood vessels (vascularity) in the endometrium and is expressed as a percentage (%) of the endometrial volume. Flow index (FI), the mean power Doppler signal intensity inside the endometrium, is thought to express the average intensity of flow. Vascularization flow index (VFI), calculated by multiplying VI and FI, is a combination of vascularity and flow intensity (Pairleitner et al., 1999). During the analysis and calculation, the manual mode of the VOCAL Contour Editor was used to cover the whole 3D volume of the endometrium with a 15° rotation step. Hence, 12 contour planes were analysed for the endometrium of each patient to cover 180°. Following assessment of the endometrium itself, the subendometrium was examined through the application of shell-imaging, which allows the user to generate a variable contour that parallels the originally defined surface contour. In the present study, the subendometrial region was considered to be within 1 mm of the originally defined myometrialendometrial contour (Ng et al., 2004
). VI, FI and VFI of the subendometrial region were obtained accordingly.
To assess the reliability of 3D scanning and data acquisition, 15 patients undergoing stimulated IVF and FET cycles were scanned twice and each 3D dataset was analysed twice using VOCAL. The mean intraclass correlation coefficient (ICC) with 95% confidence interval (CI) was calculated by the one-way random effects model (Järvelä et al., 2003; Raine-Fenning et al., 2003
). The mean (95% CI) ICC for 3D scanning of endometrium volume, VI, FI and VFI were 0.9509 (0.8591, 0.9838), 0.9896 (0.9689, 0.9966), 0.8957 (0.7157, 0.9649) and 0.9916 (0.9750, 0.9973) respectively. The mean (95% CI) ICC for data acquisition of endometrium volume, VI, FI and VFI were 0.9923 (0.9746, 0.9917), 0.9827 (0.9437, 0.9949), 0.9884 (0.9619, 0.9966) and 0.9852 (0.9517, 0.9957) respectively.
Statistical analysis
The primary outcome measures were endometrial and subendometrial VI, FI and VFI. Continuous variables were not normally distributed and were given as median (range), unless indicated. Statistical comparison was carried out by Wilcoxon signed ranks test and Fisher's Exact tests, where appropriate. The change in endometrial and subendometrial blood flow between stimulated and natural cycles was expressed by the difference of the flow indices between stimulated and natural cycles divided by the flow indices in the stimulated cycle.
Correlation between parameters in stimulated cycles and corresponding parameters in natural cycles was assessed by the Spearman rank method. Correlation between 2D colour Doppler flow indices of uterine vessels and 3D power Doppler flow indices of endometrial and subendometrial regions was examined separately in stimulated cycles and in natural cycles. Two-tailed P<0.05 was taken as significant.
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Results |
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Table I summarizes serum E2 concentrations and various ultrasound markers of endometrial receptivity during stimulated and natural cycles. Endometrial thickness and volume were significantly higher in stimulated cycles than in natural cycles while endometrial and subendometrial VI/FI/VFI were significantly lower in stimulated cycles. There were no differences in endometrial pattern, uterine PI and RI between stimulated and natural cycles.
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Endometrial thickness, endometrial volume, uterine PI/RI and endometrial and subendometrial VI/VFI in stimulated cycles were significantly correlated with corresponding parameters in natural cycles (Table II). No correlation was found between endometrial and subendometrial FI in stimulated cycles and those in natural cycles. Neither in stimulated cycles nor in natural cycles could a correlation be demonstrated between uterine PI and RI and any endometrial and subendometrial 3D power Doppler flow indices and between serum E2 concentration and any ultrasound marker of endometrial receptivity.
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Discussion |
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To the best of our knowledge, this is the first study comparing endometrial and subendometrial blood flow measured by 3D power Doppler ultrasound between stimulated and natural cycles in the same patients undergoing IVF treatment. Those taking CC in the FET cycles were excluded because of supraphysiological levels of serum E2 in some patients following clomiphene citrate and the anti-estrogenic effects of clomiphene citrate on the endometrial development (Massai et al., 1993; Nakamura et al., 1997
). Our results showed that endometrial and subendometrial 3D power Doppler flow indices were significantly lower in stimulated cycles than in natural cycles and were reduced in
60% of patients after ovarian stimulation. The decrease was mainly observed in endometrial and subendometrial VI and VFI while the decrease in endometrial and subendometrial FI was
5% only. Because of the small number of subjects in the present study, the decrease in endometrial and subendometrial 3D power Doppler flow indices was not further examined in different subgroups such as male factors of infertility versus non-male causes. Endometrial and subendometrial 3D power indices in the stimulated cycle were only moderately correlated with that in the natural cycle, while endometrial thickness and volume in the stimulated cycle were highly correlated with corresponding parameters in the natural cycle. The implication of such decreases in endometrial and subendometrial 3D power Doppler flow indices in relation to implantation remains uncertain as the thresholds for these indices are not yet well defined and may be different in stimulated and natural cycles.
There was a huge range in the magnitude of decrease in these blood flow indices after stimulation, which was not related to serum E2 concentrations in stimulated cycles. We did not observe any correlation between serum E2 concentration and endometrial and subendometrial 3D power Doppler flow indices in stimulated and natural cycles. The reduction in endometrial and subendometrial 3D power Doppler flow indices after ovarian stimulation shown in this study also appeared to be contradictory to the potent angiogenic and vasodilatation effects of E2 (Losordo and Isner, 2001). Little information is available regarding the exact mechanisms by which this steroid exerts its function on the process of both physiological and pathological angiogenesis (Kapiteijn et al., 2001
). The number of stromal blood vessels per mm2 was found to be similar between natural cycles and stimulated cycles with serum E2 <20 000 pmol/l, although it was markedly higher in those with serum E2
20 000 pmol/l (Basir et al., 2001b
). However, there was a significant reduction in progesterone and estrogen receptors in the glands and stroma of stimulated endometrium when compared with that of natural cycles (Hadi et al., 1994
; Bourgain et al., 2002
). The mechanisms and control of angiogenesis in the endometrium are far from being fully understood (Smith, 2001
) and supraphysiological E2 concentration may have opposite effects on endometrial angiogenesis.
Absent endometrial or subendometrial flow detected by colour or power Doppler in 2D ultrasound is associated with no pregnancy (Zaidi et al., 1995; Battaglia et al., 1997
) or much reduced pregnancy rate (Chien et al., 2002
; Maugey-Laulon et al., 2002
). We observed absent endometrial and subendometrial blood flow in four patients in the stimulated cycle but three of them showed return of blood flow in the natural cycle. Therefore, patients having absent endometrial and subendometrial blood flow in the stimulated cycle may be advised to cryopreserve all embryos for subsequent transfer in natural cycles. Presence of endometrial and subendometrial blood flow can be confirmed by repeating 3D ultrasound examination in natural cycles. For those with persistent absent endometrial and subendometrial blood flow in natural cycles, therapeutic agents such as aspirin (Rubinstein et al., 1999
) or sildenafil (Sher and Fisch, 2000
) may be used to improve the blood flow towards the endometrium.
Blood flow in the uterine blood vessels assessed by colour Doppler ultrasound is usually expressed as downstream impedance to flow and is assumed in many studies to reflect the actual blood flow to the endometrium, although the major compartment of the uterus is the myometrium and there is collateral circulation between uterine and ovarian vessels. The chances of pregnancies were noted to be maximal when uterine PI was in the range of 2.002.99 (Steer et al., 1992). However, we could not demonstrate here any correlation between uterine Doppler flow indices and endometrial and subendometrial blood flow measured by 3D power Doppler in both stimulated and natural cycles. This implied that blood flow towards the endometrium could not be assessed by uterine Doppler flow indices. No attempt was made in the comparison of endometrial and subendometrial blood flow between patients with uterine PI <3.0 and
3.0 because uterine PI was
3.0 in two patients in stimulated cycles and in one patient in natural cycles.
We did not observe any difference in uterine PI and RI between stimulated and natural cycles in this study. This suggested that serum E2 exerted the maximum vasodilatation effect on uterine vessels in the natural cycle and further increase in serum E2 concentration during stimulated cycles would not lead to significant change in downstream impedance to flow in uterine vessels. This finding differed from the observation of our previous study (Basir et al., 2002). It was uncertain whether this difference was related to the different timing of ultrasound examinations. We performed ultrasound examinations on hCG+4 in stimulated cycles and LH+3 in natural cycles in the previous study (Basir et al., 2002
) but changed to hCG+2 in stimulated cycles and LH+1 in natural cycles for logistic reasons.
In conclusion, endometrial and subendometrial 3D power Doppler flow indices in the stimulated cycle were significantly lower than that in the natural cycle and were only moderately correlated with those in the natural cycle.
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Acknowledgements |
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References |
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Submitted on March 15, 2004; accepted on June 2, 2004.