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It is estimated that worldwide the average current fertility rate is 9. Boivin, Bunting, Collins,Nygren, 2007. Of those couples that then decide to go on and try some form of assisted reproductive technique (ART) only 10-15% of embryos successful implant themselves in the uterus. (Salle et al., 1998). The desire to create the perfect environment within the uterus, to enable a successful embryo implantation is immense, thus encouraging many studies in the subject. Many parameters including endometrial thickness, endometrial volume and vascular indices (VI - vascularisation index, FI - flow index and VFI - vascularisation flow index) from both endometrial and subendometrial areas have been used to determine what is commonly known as uterine receptivity. "The term 'uterine receptivity' refers to a state when endometrium allows a blastocyst to attach, penetrate and induce changes in the stroma which result in embryonic implantation." (Raga, Bonilla-Musoles, Casañ, Klein, & Bonilla, 1999, p.2851). From studies carried out with fertile women with regular menstrual cycles (26-32 day cycles with 3-8 days of menstrual bleeding and only mild menstrual cramping), vascular changes can be noted within the endometrium. (Jokubkiene, Sladkevicius, Rovas, & Valentin, 2006a). The follicular phase of the menstrual cycle experiences the most changes in the endometrium, when vascular indices VI and VFI, and endometrial thickness and volume increase towards the end of the phase approaching ovulation. (Raine-Fenning, Campbell, Clewes, Kendall, & Johnson, 2004; Raine-Fenning, Campbell, Kendall, Clewes, & Johnson, 2004b). The ideal method of establishing endometrial changes occurring throughout the menstrual cycle would be to take an endometrial biopsy specimen, which has proved to be successful in providing the required information from the area. (Raga, et al., 1999).
To assess these changes in women who about to undergo in-vitro fertilisation (IVF), an endometrial biopsy would be too invasive. Fortunately new developments in three-dimensional sonography have enabled it to be the perfect imaging method to assess endometrial and subendometrial receptivity. (Kim et al., 2009). Three-dimensional (3D) ultrasound allows any plane through an organ to be seen and data can be acquired to provide surface rendering or volume calculation. (Alcázar, 2006). Two-dimensional (2D) sonography does not allow the whole organ or area to be looked at and only individual vessels supplying an organ can be assessed. In 3D power doppler ultrasound, the whole vessel flow can be seen to an organ or area, which is called 3D power doppler angiography (3D-PDA). (Raine-Fenning, Campbell, Clewes, Kendall, & Johnson, 2003). Virtual Organ Computer-Aided Analysis (VOCAL) can be used with 3D-PDA to analysis and measure the endometrial blood flow and volume more accurately. (Raine-Fenning, Campbell, Clewes, & Johnson, 2003).
Many studies (see summary table 1 in appendix D) have tried to establish a connection between pregnancy rates and the changes seen in the endometrium using 3D sonography. The first of these was Raga et al., (1999), who demonstrated that when the blood flow measurements were taken on the day of embryo transfer - the probability of conception was connected to the endometrial volume. Women with an endometrial volume >4ml conceived 37% of the time with only 15% with volumes <2ml and no pregnancies <1ml in volume. Unfortunately a further ten studies didn't always agree with these findings. Perhaps the biggest reason for this is in the methodology of the studies. Rather than build upon Raga et al.'s (1999) work, the next three studies all choose a different methodology allowing no comparison. (Schild et al., 2000; Schild et al., 1999; Yaman, Ebner, Sommergruber, Pölz, & Tews, 2000). The factor affecting the methodology so much in all these studies is the day when the 3D ultrasound was performed. Ng, Chan, Tang, Yeung, & Ho (2006) stated that the best time to assess endometrial and subendometrial vascularity was in the late follicular to early luteal phase. None of the studies found performed an ultrasound in the luteal phase of the stimulated cycle during IVF treatment. Two other studies were carried out on the day of embryo transfer, the same as Raga, et al. (1999), and the only agreement between the three studies were that pregnancy was never achieved when the endometrial volume was <1ml. (Kupesic, Bekavac, Bjelos, & Kurjak, 2001; Raga, et al., 1999; Zollner et al., 2003). From Jokubkiene, Sladkevicius, Rovas, & Valentin (2006b) and Raine-Fenning, Campbell, Clewes, et al.'s (2004) work on the assessment of endometrial and subendometrial changes during the normal menstrual cycle, it was established that most fertile women's endometrial volume ranged from approximately 2-8ml. Since subfertile women cause an increase in endometrial volume (Raine-Fenning, Campbell, Kendall, Clewes, & Johnson, 2004a) it was more than likely that the endometrial volume would be >1ml anyway to achieve a pregnancy as this would have been the closest to the norm, hence not revealing anything new. The studies (Mercé, Barco, Bau, & Troyano, 2008; Wu et al., 2003; Yaman, et al., 2000) which carried out the ultrasound on the day of human chorionic gonadotrophin (hCG) administration also revealed the same results concerning endometrial volume, but all the other works came to no conclusion in regards to this.
Table 2 (in appendix D) shows the parameters measured in each of the eleven studies and very few have the same parameters on the same day as the scan. Dorn et al. (2004) and Ng, et al. (2006) both measured subendometrial VI, FI and VFI but their results contradict one another. Järvelä et al. (2005) and Mercé, et al. (2008) measured endometrial VI and again their results failed to agree. None of the results from the studies agree when allowing for the day of scan to be in included in the comparison. The studies are nine years apart and in the requirement of rationalising any clinical trial, the authors should have done extensive research to justify and validate their proposed study. (Piantadosi, 2005). It seems that no conclusion can be attained from the works and makes the reader ask where the justification was in some of the later trials when this knowledge was already surfacing. Doubt in what day to scan the patient has obviously come into question, therefore why wasn't the patient scanned on various days as was done in some the studies relating to the normal menstrual cycles? (Jokubkiene, et al., 2006a, 2006b; Raine-Fenning, Campbell, Clewes, et al., 2004; Raine-Fenning, Campbell, et al., 2004b). Järvelä, et al. (2005) tried to achieve this but only managed to do scans on two occasions in the trial and the scan produced after hCG was carried out on a variety of days in patients proving no consistency. "The day of the ultrasound examination in these studies was chosen for logistic reasons and did not take into consideration the physiological changes of endometrial blood flow throughout the menstrual cycle." (Ng, Chan, Tang, Yeung, & Ho, 2007, p.14). Another reason for the limited scans may be due to the nature of IVF treatment being very sensitive, therefore to ask patients to come in for more scans could have risked the patient's absence from the trial altogether.
The only study to have incorporated a contrast agent (Levovist) into their study was Dorn, et al. (2004). The blood flow indices were shown to be better displayed using contrast in the study with a significant difference (P<0.001 in VI, FI and VFI measurements) between the non-contrasted results. Even though a more accurate picture may have been seen in this trial, again no correlation was made between the results and the pregnancy rate. (Dorn, et al., 2004).
VOCAL rotational software has been in use for more than ten years and was used for the assessment of endometrial volume back in the year 2000. (Rudigoz, Bory, Affif, & Salle, 2000). It was established as a simple and reproducible system to measure endometrial parameters (Salle, Affif, Bory, & Rudigoz, 2000) with more reliable results than other methods. "The rotational technique proved to be superior to the conventional one, and does appear more dependent upon the morphology of an object than its absolute volume." (Raine-Fenning et al., 2003, p.290). Yet only three of the studies used VOCAL, when it was available to all, bar the first couple of trials. This could have changed the results and made them more comparable.
All the studies wanted to try to demonstrate some changes in the endometrium and subendometrium using 3D ultrasound and they all proved that changes do occur and that 3D ultrasound is a reliable method to do this, more so than 2D ultrasound. (Yaman, Jesacher, & Pölz, 2003). Although, their main objective was to link these results to uterine receptivity in order to create the perfect environment for embryos to implant and increase the chances of couples having successful IVF treatment. Unfortunately most of the works contradicted themselves in one way or another and has still left us uncertain of the relationship between uterine receptivity and endometrium and subendometrium changes. The variations in the day of the ultrasound, patient characteristics, ovarian stimulation and techniques used were the likely reasons that the results differed so much. A standard protocol for this 3D examination is required to allow future studies to be able to eventually state whether this procedure helps to increase pregnancy rates in IVF patients. Until then the value of 3D ultrasound in assessing the endometrium is limited for the predication of pregnancy and should be used cautiously. (Alcázar, 2006).