Use of colour and spectral Doppler ultrasound examination in gynaecology

European Journal of Ultrasound 6 (1997) 143 – 163

Invited clinical review

Use of colour and spectral Doppler ultrasound examination in gynaecology Lil Valentin * Department of Obstetrics and Gynaecology, Malmo¨ Uni6ersity Hospital, S-205 02 Malmo¨, Sweden Received 20 June 1997; received in revised form 18 October 1997; accepted 20 October 1997

Abstract Objecti6e: To review and sum up the published literature on gynecological Doppler ultrasound examination. Methods: Publications on gynecological Doppler ultrasound examination already known by the author, publications found in the bibliographic database Medline, and publications found in the reference lists of available studies were read, and relevant information was extracted and summarized. Results: Reference data representative of normal findings at transvaginal color and spectral Doppler ultrasound examination of the uterine and ovarian arteries have been established in healthy pre- and post-menopausal women and in normal early pregnancies. Blood flow velocities in the uterine and ovarian arteries change during the normal menstrual cycle and are very different in pre- and post-menopausal women. Lower blood flow velocities and higher pulsatility index (PI) values have been recorded in the ovarian arteries after the menopause. Uterine artery blood flow velocities increase and uterine artery PI values and resistance index (RI) values decrease with gestational age in the first trimester. There is not yet an established role of the gynecological Doppler ultrasound examination in clinical practice. It remains unclear whether the gynecological Doppler ultrasound examination contributes substantially to the clinical management of early pregnancy complications or infertility problems, to the differential diagnosis of pelvic masses or uterine pathology. Conclusions: Large prospective studies—preferably randomized controled trials — are needed to determine the clinical value of the gynecological Doppler ultrasound examination. © 1997 Elsevier Science Ireland Ltd. Keywords: Ultrasound; Doppler; Color velocity imaging; Transvaginal; Gynecology

1. Introduction * Tel.: +46 40 332094; fax: 46 40 962600; e-mail: [email protected]

The first report on measurements of blood flow velocities in the uterine and ovarian arteries of

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non-pregnant women was published by Taylor et al. (1985). Since then, the gynaecological Doppler ultrasound method has been refined, and attempts have been made to introduce it into clinical gynaecological practice. However, the optimal way of using gynaecological Doppler ultrasound examination in clinical practice is still unknown. Further on, I present a summary of the results of published reports on gynaecological Doppler ultrasound examination. In the following, ‘blood flow velocity waveform index’ refers to any index calculated from a Doppler shift spectrum, e.g. pulsatility index (PI), resistance index (RI), and systolic diastolic ratio (S/D-ratio).

2. Doppler ultrasound examinations of the uterine and ovarian arteries in healthy pre- and post-menopausal women The use of Doppler examination to diagnose pathological conditions in the female pelvis must be based on satisfactory knowledge of the normal uterine and ovarian circulation as measured by Doppler velocimetry in healthy women. My colleagues and I have conducted three studies to establish reference data representative of normal findings at transvaginal colour Doppler and spectral Doppler ultrasound examination of the uterus and ovaries in healthy pre- and postmenopausal women (Sladkevicius et al., 1993, 1994a, 1995a). The first and second studies (Sladkevicius et al., 1993, 1994a) comprised 12 and 11 pre-menopausal women, respectively. All had regular menstrual cycles. In the third study, 144 post-menopausal women were included (Sladkevicius et al., 1995a). The women in the three studies were asymptomatic and gynaecologically healthy. None used any form of hormonal medication. We studied uterine circulation by examining both uterine arteries lateral to the cervix at the level of the internal os. In the pre-menopausal women we studied ovarian circulation by examining arteries in the ovarian hilum (on the surface of the ovary), in the ovarian stroma (any small artery in the ovarian stroma but not near to the surface or to the largest follicle of the ovary), in the wall of the largest follicle of each ovary, and in the wall of

the corpus luteum. In post-menopausal women arteries in the ovarian stroma were examined. Typical colour Doppler images and Doppler shift spectra obtained from uterine and ovarian vessels of healthy pre- and post-menopausal women with a normal uterus and normal ovaries are shown in Figs. 1–4. Colour was visible in all pre-menopausal ovaries at every examination versus 61% of the post-menopausal ovaries. In the pre-menopausal ovaries, usually many colour spots and even lines of colour were seen irrespective of the cycle day (Fig. 2), whereas in the post-menopausal ovaries, only one or two colour spots were detectable (Fig. 4). Assessed subjectively by the examiner, during the luteal phase the ovary harbouring the corpus luteum was much more intensively coloured and contained a greater number of colour spots and colour lines than the contralateral ovary. The colour Doppler images showed the corpus luteum to be surrounded by an intensive colour ring (Fig. 3). The corpus luteum with its colour ring was still visible on the 1st day of menstruation in all women. In half (5/11) of the women, the corpus luteum with its colour ring did not disappear until the 3rd day of menstrual bleeding. PI and time-averaged maximum velocity values recorded from the uterine and ovarian arteries are presented in Figs. 5–7. Uterine artery PI values were similar in pre- and post-menopausal women, whereas time-averaged maximum velocity values tended to be lower in post-menopausal women. PI values were much higher and time-averaged maximum velocity values much lower in the stromal arteries of post-menopausal ovaries than in those of pre-menopausal ovaries. A total of 90% of PI values recorded from the stromal arteries of premenopausal ovaries were B 1.0 compared with 19% of those of post-menopausal ovaries. In premenopausal women, the time-averaged maximum velocity and PI values recorded from the uterine arteries and from the arteries in the dominant ovary changed considerably during the menstrual cycle, the lowest PI values and the highest timeaveraged maximum velocity values being recorded in the luteal phase of the menstrual cycle. In the uterine arteries, low PI values and high time-averaged maximum velocity values were also recorded

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Fig. 1. (a) Colour Doppler image of vessels coursing through the myometrium towards the endometrium. Subendometrial vessels (probably corresponding to spiral arteries and veins) are seen as well (cycle day 11). (b) Doppler shift spectra obtained from a subendometrial artery (cycle day 4). Fig. 2. (a) Colour Doppler image of the vessels in the ovarian stroma (cycle day 4). (b) Typical Doppler shift spectrum obtained from an artery in the ovarian stroma (cycle day 14).

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Fig. 3. (a) Colour Doppler image of the dominant follicle (cycle day 13). (b) Typical Doppler shift spectrum obtained from an artery in the wall of the dominant follicle (cycle day 13). (c) Colour Doppler image of the corpus luteum in the midluteal phase. (d) Typical Doppler shift spectrum obtained from an artery in the wall of the corpus luteum.

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Fig. 4. (a) Colour Doppler image of the vessels in the ovarian stroma of a post-menopausal woman. Compare with Fig. 2 showing the colour Doppler image of the stroma of a pre-menopausal ovary. (b) Typical Doppler shift spectrum obtained from an artery in the ovarian stroma of a post-menopausal woman. Compare with Fig. 2 showing a Doppler shift spectrum obtained from the stroma of a pre-menopausal ovary.

on the 2nd and 3rd days of menstrual bleeding, whereas high PI values were recorded in the periovulatory period and on the 1st day of menstruation. No unequivocal changes in the circulation of the non-dominant ovary were detected during the menstrual cycle. The dramatic increase in blood flow velocity in the vessels of the wall of the dominant follicle after ovulation (Fig. 7) was reflected in the greater colour intensity of the colour ring surrounding the corpus luteum than of that surrounding the dominant follicle (Fig. 3). Our results confirm those of others in that blood flow velocity waveform index values in the uterine arteries and in the arteries of the dominant ovary were lower in the luteal phase than in the follicular phase, in that high PI values were recorded in the uterine arteries in the peri-ovulatory period and on the 1st day of menstrual bleeding, and in that no unequivocal circulatory changes could be detected in the non-dominant ovary during the menstrual

cycle (Goswamy and Steptoe, 1988; Scholtes et al., 1989; Battaglia et al., 1990; Hata et al., 1990; Steer et al., 1990; Collins et al., 1991; Merce´ et al., 1992; Setti et al., 1993). In agreement with Bourne et al. (1991a), Collins et al. (1991) and Campbell et al. (1993) we found more substantial changes to occur in blood flow velocity than in PI during the menstrual cycle. The PI values recorded by other teams in the intra-ovarian arteries of post-menopausal women were much higher than those obtained by us, PI values being 3.1–6.6 in a study by Bourne et al. (1989); and all \ 1.0 in a study by Weiner et al. (1993a). The discrepant results are perhaps to be explained by differences in examination technique and in the sensitivity of the Doppler ultrasound systems used. Our results agree better with those of Karlan et al. (1993), who found 24% of asymptomatic post-menopausal women to have ovarian artery PI values B 1.0.

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Fig. 5. Time averaged maximum velocity (TAMXV) and pulsatility index (PI) in the uterine arteries. In studies I and II (pre-menopausal women), the filled circles represent the dominant uterine artery, and the open squares the nondominant uterine artery; in study III (post-menopausal women), the filled circles represent the right uterine artery and the open squares the left uterine artery. Median, 10th and 90th percentiles are given. Day −4 represents 4 days before follicular rupture; − 3, 3 days before follicular rupture, etc. Day + 1 represents 1 day after follicular rupture; +2, 2 days after follicular rupture, etc. 1B represents the 1st day of menstrual bleeding, 2B the 2nd day, etc.

To sum up, we and others have found substantial changes to occur in the circulation of the uterus and dominant ovary during the normal menstrual cycle (Goswamy and Steptoe 1988; Scholtes et al., 1989; Battaglia et al., 1990; Hata et al., 1990; Steer et al., 1990; Bourne et al., 1991a; Collins et al., 1991; Merce´ et al., 1992, Setti et al., 1993; Sladkevicius et al., 1993, 1994a, 1995a). Moreover, uterine and ovarian perfusion seem to be less pronounced in post-menopausal women than in pre-menopausal women, which empha-

sises the need of separate reference values for the two categories (Sladkevicius et al., 1995a). However, reference data must be established separately for each type of ultrasound system and for each laboratory, because Doppler sensitivity affects colour detection and the type of Doppler shift spectra recorded, different built-in algorithms of the ultrasound systems may yield different blood flow velocity waveform index values, and the examination technique may also affect the results of Doppler ultrasound examinations.

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Fig. 6. Time averaged maximum velocity (TAMXV) and pulsatility index (PI) in arteries of the ovarian stroma. In studies I and II (pre-menopausal women), the filled circles represent the dominant ovary and the open squares the nondominant ovary; in study III (post-menopausal women), the filled circles represent the right ovary and the open squares the left ovary. Median, 10th and 90th percentiles are given. Day − 4 represents 4 days before follicular rupture; −3, 3 days before follicular rupture, etc. Day + 1 represents 1 day after follicular rupture; +2, 2 days after follicular rupture, etc. 1B represents the 1st day of menstrual bleeding, 2B the 2nd day, etc.

3. Doppler ultrasound examinations of the uterine and ovarian arteries of subfertile women Poor uterine blood flow has been suggested to be a cause of infertility (Goswamy et al., 1988). The results of Doppler ultrasound studies indicate uterine and ovarian circulation to be abnormal in subfertile women, higher blood flow velocity waveform index values having been recorded from the uterine and ovarian arteries of subfertile women than of controls (Steer et al., 1994; Tinkanen et al., 1994). Moreover, it was put forward as a possibility that ‘‘spiral artery blood flow

velocity changes may be used to predict implantation success rate, to reveal unexplained infertility problems, and to select patients for correction of endometrial perfusion abnormalities by an appropriate treatment’’ (Kupesic and Kurjak, 1993). However, to my knowledge this has not been proven in any scientific work. According to several studies, uterine artery blood flow velocity is related to the probability of pregnancy in assisted reproductive treatments (Sterzik et al., 1989; Strohmer et al., 1991; Serafini et al., 1994; Steer et al., 1992, 1995a). Uterine artery blood flow velocity waveform index values

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Fig. 7. Time averaged maximum velocity (TAMXV) and pulsatility index (PI) in the wall of the largest follicle of the dominant and non-dominant ovary. The filled circles represent the dominant ovary and the open squares the nondominant ovary. Median, 10th and 90th percentiles are given. Day − 4 represents 4 days before follicular rupture; −3, 3 days before follicular rupture, etc. Day +1 represents 1 day after follicular rupture; + 2, 2 days after follicular rupture, etc. 1B represents the 1st day of menstrual bleeding, 2B the 2nd day, etc.

have been found to be lower in conception cycles than in non-conception cycles (Sterzik et al., 1989; Strohmer et al., 1991; Steer et al., 1992, 1995a), and Steer et al. (1995a) found uterine artery PI to be significantly correlated to biochemical markers of uterine receptivity. Administration of oestradiol to infertile women with decreased diastolic flow in their uterine arteries has been found to increase the diastolic flow and to improve the pregnancy rate after in vitro fertilisation (Goswamy et al., 1988). However, Tekay et al. (1995) and Favre et al. (1993) were unable to confirm a difference in uterine artery blood flow velocity waveform index values between women who conceived after in vitro fertilisation and those who did not.

Higher than normal RI values and PI values in the arteries of the dominant follicle in the natural cycle have been suggested to be related to low response to gonadotrophin treatment (Pellicer et al., 1994). Baber et al. (1988) found RI values in ovarian arteries to be significantly higher in patients who did not conceive after in vitro fertilisation than in those who did, whereas Tekay et al. (1995) found no relation between intra-ovarian blood flow parameters and the outcome of in vitro fertilisation. The vascularisation of the corpus luteum as measured by Doppler velocimetry does not seem to differ between normal menstrual cycles and those with a short luteal phase (Tinkanen, 1994).

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To my knowledge, the clinical value of gynaecological Doppler ultrasound examination in the evaluation and treatment of subfertile women has not been tested in any randomised controlled trial. The clinical role of the gynaecological Doppler ultrasound examination in the management of infertility problems remains uncertain. Therefore, further studies are needed.

4. Doppler ultrasound examination in the differential diagnosis of extra-uterine pelvic tumours A number of reports have been published on transabdominal and transvaginal colour and spectral Doppler ultrasound examinations of tumours in the female pelvis (Bourne et al., 1989; Hata et al., 1989; Kurjak and Zalud, 1990; Kurjak et al., 1989, 1991a; Kawai et al., 1992; Weiner et al., 1992). These studies showed Doppler examination capable of distinguishing benign from malignant masses; colour was often not detected, and arterial Doppler shift spectra were seldom obtained from benign tumours, whereas colour was almost always seen and arterial Doppler shift spectra obtained from malignant masses. Moreover, when a blood flow velocity waveform index value was used to characterise the circulation of the adnexal tumours, there was little or no overlap between benign and malignant tumours, and much lower PI values and RI values were recorded in malignancies. On the basis of findings in the studies cited, colour and spectral Doppler examination should be an excellent tool for discriminating between benign and malignant pelvic masses. However, according to more recently published reports, the blood flow velocity waveform indices recorded from benign and malignant adnexal tumours manifest considerable overlap (Fleischer et al., 1991a,b; Hata et al., 1992; Tekay and Jouppila, 1992a; Jain, 1994), and lately the superiority of Doppler examination as a tool for differentiating between benign and malignant pelvic tumours has been questioned in several publications (Hata et al., 1992; Hamper et al., 1993; Schneider et al., 1993; Bromley et al., 1994. Brown et al., 1994; Carter et al., 1994a; Levine et al., 1994; Salem et

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al., 1994; Valentin et al., 1994; Stein et al., 1995; Tekay and Jouppila, 1992a, 1996a). Some research teams have found the combined use of tumour morphology based on grey-scale imaging and Doppler ultrasound examination to improve the diagnostic accuracy compared with the use of grey-scale imaging alone (Sengoku et al., 1994; Valentin et al., 1994; Franchi et al., 1995; Buy et al., 1996; Valentin, 1997). Others have been unable to confirm this (Strigini et al., 1996). My colleagues and I have conducted three studies to elucidate the capacity of Doppler ultrasound examination to distinguish benign from malignant pelvic masses (Valentin et al., 1994; Sladkevicius et al., 1995b; Valentin, 1997). The results of these studies were consistent: (1) colour Doppler ultrasound examination was helpful only in the differential diagnosis of multilocular solid tumours (i.e. tumours with a septum or septa and solid parts or papillary excrescences, see Fig. 8), but it did not contribute at all to the differential diagnosis of solid tumours (Valentin et al., 1994; Sladkevicius et al., 1995b; Valentin, 1997); (2) blood flow velocity (i.e. highest peak systolic velocity or highest time-averaged maximum velocity recorded from the tumour) was a better discriminator between benign and malignant tumours than PI, considerably higher blood flow velocities being recorded from the malignancies than from the benign tumours (Valentin et al., 1994; Valentin, 1997); (3) the best Doppler variable for discriminating between benign and malignant tumours was the colour content of the tumour scan as rated subjectively on a visual analogue scale, high colour content indicating malignancy and low colour content benignity (Valentin, 1997) (Fig. 9). By using an extremely simple classification system based on the grey-scale ultrasound image of the tumour, whereby all tumours without solid components were classified as benign and all tumours with solid components as malignant, we detected all the malignancies in the two series of tumours with a false positive rate of 27% in the first series and 61% in the second series (Valentin et al., 1994; Valentin, 1997). By using Doppler examination (peak systolic velocity, timeaveraged maximum velocity, PI, total colour content of the tumour scan) to distinguish benign

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Fig. 8. Grey-scale image of a multilocular solid tumour.

from malignant multilocular solid tumours, we still detected all the malignancies in the two series of tumours, but the false positive rate decreased from 27% (when grey-scale ultrasound examination was used alone) to between 17 and 23% in the first study and from 61 to 42% in the second (Valentin et al., 1994; Valentin, 1997). Based on the results of our own studies, we conclude that the degree to which Doppler examination can contribute to the differential diagnosis of pelvic tumours depends on the proportion of multilocular solid tumours among the tumours examined: the greater the proportion of multilocular solid tumours, the greater the potential of the Doppler ultrasound examination to improve the diagnostic accuracy. The improvement consists of a reduction of the number of multilocular solid tumours being falsely classified as malignant. Our finding that blood flow velocity is a better discriminator between benign and malignant pelvic tumours than blood flow velocity waveform index values agrees with those of Pro¨mpeler et al. (1994) and Hata et al. (1995) but is at variance with those of Carter et al. (1994a). The disagreement is probably attributable to differences in examination techniques. In our hands, Doppler ultrasound examination was useless for discrimination between benign and malignant solid tumours irrespective

of which Doppler variable we used, whereas Leeners et al. (1996) found Doppler examination to be particularly useful in the differential diagnosis of solid tumours. The discrepancy is almost certainly to be explained by different definitions of solid tumour having been used in the two studies. In many studies, PI values B 1.0 or RI values B 0.4 in a pelvic mass were taken to indicate malignancy (Fleischer et al., 1991a,b, 1993; Carter et al., 1994a; Weiner et al., 1992, 1993a, 1994). However, we recorded PI values B 1.0 from 90% of normal pre-menopausal ovaries (Figs. 6 and 7), 19% of normal post-menopausal ovaries (Sladkevicius et al., 1995a), 83% of benign uterine leiomyomas (Sladkevicius, 1994), and 78% of benign adnexal masses (Sladkevicius, 1994) compared with 92% of malignant adnexal masses (Sladkevicius, 1994). Thus, in our hands PI values were not suitable for discriminating between benign and malignant pelvic masses. Based on all available information, the ability of gynaecological Doppler examination to contribute substantially to the differential diagnosis of extra-uterine pelvic tumours must be questioned. Thus, the clinical value of colour Doppler examination in the differential diagnosis of pelvic masses is still uncertain.

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Fig. 9. Colour Doppler images of ovarian tumours. (a) Malignant tumour with high colour content. (b) Benign tumour with low colour content.

It is not known whether there exists a relationship between the vascularisation of malignant adnexal tumours as measured by the Doppler technique and the prognosis of the disease. Should such a relationship exist, it might become possible in the future to use Doppler examination of malignant adnexal masses to predict the prognosis and to select the treatment of choice. The role of gynaecological Doppler examination in the diagnosis of recurrent ovarian cancer is unknown, although Doppler examination has been recommended for follow-up of women treated for malignant pelvic tumours (Weiner et al., 1994).

5. The role of gynaecological Doppler ultrasound examination in screening for ovarian cancer Grey-scale sonography has been suggested as a tool for screening of ovarian cancer (Kurjak, 1991). The problem with ultrasound screening for ovarian cancer is that it generates a substantial number of ‘false positive’ findings, i.e. findings of benign pelvic masses (Andolf et al., 1986; Campbell et al., 1989; van Nagell Jr et al., 1990) resulting in ‘unnecessary’ surgery. In an ultrasoundbased screening programme for familial ovarian cancer, the use of Doppler examination as a sec-

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ondary test reduced the number of false positive results without decreasing the sensitivity substantially (Bourne et al., 1993). However, according to the National Institutes of Health in the United States, although Doppler examination can enhance specificity in predicting malignancy in adnexal masses, its use in ovarian cancer screening must still be considered to be investigational (NIH Consensus Development Panel on Ovarian Cancer, 1995). Doppler ultrasound examination might have the potential not only to decrease the number of false positives but also to increase the sensitivity when screening for ovarian cancer. Thus, in 1993, Kurjak and coworkers described the detection of ovarian cancer by colour and pulsed Doppler in morphologically normal ovaries, suggesting that Doppler ultrasound examination might be used to detect occult cancer in ovaries with normal morphology and size at greyscale ultrasound examination (Kurjak et al., 1993a). It must be emphasised that the effectiveness of periodic screening for ovarian cancer has not been established either in large populations of women without familial or genetic risk factors for ovarian carcinoma or in high-risk patients (Droegemueller, 1994). There are no data to show that screening reduces the mortality from ovarian cancer (Westhoff, 1994). Therefore, at present, screening for ovarian cancer should not be carried out outside research protocols (Westhoff, 1994).

6. Gynaecological Doppler ultrasound examination in the diagnosis of adnexal torsion Doppler ultrasound examination does not seem to play a decisive role in the diagnosis of adnexal torsion; grey-scale sonography appears to be more important (Stark and Siegel, 1994). Colour Doppler signals can be detected either peripherally or centrally in a substantial proportion of twisted adnexa (Stark and Siegel, 1994). Doppler findings probably parallel the vascular changes in the adnexa, persistent arterial flow being expected in less complete stages of torsion. Therefore, detection of flow using the Doppler technique does not exclude adnexal torsion.

7. Doppler ultrasound examination in the differential diagnosis of uterine pathology Uterine myomas, irrespective of whether they are small and asymptomatic or large and symptomatic, considerably affect uterine artery blood flow velocity (Sladkevicius et al., 1996), higher blood flow velocities and lower blood flow velocity waveform index values having been recorded in the uterine arteries of uteri with myomas than in those of normal uteri (Kurjak et al., 1992; Weiner et al., 1993b; Sladkevicius et al., 1996). Arteries in uterine fibroids are characterised by low impedance (measured using PI and RI) but high blood flow velocities (Bourne, 1991; Kurjak et al., 1993b). Most uterine myomas have a characteristic appearance at grey-scale ultrasound examination, and ultrasound diagnosis of myomas seldom entails problems of differential diagnosis. However, in rare cases, it may be difficult to discriminate between a uterine myoma and a solid ovarian mass (Fig. 10). Unfortunately, Doppler measurements of blood flow velocity or PI cannot be used in clinical practice to discriminate between myomas and benign or malignant solid adnexal masses, these Doppler variables manifesting substantial overlap between the three tumour types (Sladkevicius et al., 1995b; Valentin, 1997). However, the colour Doppler image of many myomas is typical, a well-defined straight vessel often being seen to follow the outline of the tumour (Fig. 10). Such vessels are rarely seen in solid ovarian tumours (Sladkevicius et al., 1995b). In my opinion, the finding of such typical ‘myoma vessels’ at colour Doppler examination helps more to distinguish between myomas and other solid pelvic tumours than do measurements of blood flow velocity or PI. The possibility of using colour Doppler imagery to discriminate between different kinds of pelvic solid tumours by characterisation of the tumour vessel tree needs further evaluation. There is insufficient data in the published literature to support a role of gynaecological Doppler ultrasound examination in the diagnosis of uterine leiomyosarcoma. Kurjak et al. (1995) recorded lower RI values from ten leiomyosarcomas than

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Fig. 10. Ultrasound images of solid pelvic tumours. (a) Typical grey-scale image of a uterine leiomyoma. (b) Typical grey-scale image of an ovarian fibroma. Note the similarity between the tumour in Fig. 10a and that in Fig. 10b. (c) Typical colour Doppler image of a uterine leiomyoma. Note the well defined straight vessel following the outline of the myoma.

from 1850 benign leiomyomas. On the other hand, Hata et al. (1997) found RI values not to differ between five malignant uterine leiomyosarcomas and 41 benign uterine leiomyomas; instead,

they found blood flow velocities to be significantly higher in the sarcomas. Endometrial thickness as measured by transvaginal grey-scale sonography can reliably dis-

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Fig. 10. (Continued)

criminate between normal and pathological endometrium in women with post-menopausal bleeding (Karlsson et al., 1995). Some research teams found Doppler measurement of uterine artery blood flow velocity to be a better discriminator between benign and malignant and between normal and pathological endometrium than measurement of endometrial thickness using greyscale sonography (Bourne et al., 1991b; Weiner et al., 1993b). Among others, we found colour Doppler ultrasound examination of the uterine arteries—including the endometrial arteries—neither to be superior to grey-scale imaging in the differential diagnosis of endometrial pathology nor to add to the diagnostic accuracy (Carter et al., 1994b; Chan et al., 1994; Sladkevicius et al., 1994b; Tepper et al., 1994; Sheth et al., 1995). There are only a few published reports on Doppler ultrasound examinations of cervix tumours (Enzelberger et al., 1991; Pirhonen et al., 1995). According to one study, the results of Doppler ultrasound examinations of cervix cancers predicted the prognosis of the disease, and it was suggested that Doppler results be used for planning individualised treatment schedules (Pirhonen et al., 1995). However, a clinical role of gynaecological Doppler examination in the diagnosis or management of abnormalities in the uterine cervix has not been established.

8. Circulatory effects of medication on uterine and ovarian circulation The gynaecological Doppler ultrasound examination offers a possibility to non-invasively study the effects of drugs on uterine and ovarian circulation. Oestrogen replacement therapy has been shown to result in decreased uterine artery PI in post-menopausal women (Bourne et al., 1990; deZiegler et al., 1991; Hillard et al., 1992). Some found gestagens to counteract this effect (Hillard et al., 1992), whereas others were unable to confirm such an effect (deZiegler et al., 1994). Lower uterine artery PI values have been recorded in women treated with tamoxifen than in women treated with placebo (Kedar et al., 1994). Treatment of patients with uterine myomas with GnRH-agonists, mifeprostone or leuprolide acetate has been shown to result not only in decreased myoma size or decreased uterine size but also in increased PI values and decreased blood flow velocity in myoma vessels and increased PI values or RI values in the main uterine arteries (Matta et al., 1988; Creighton et al., 1994; Reinsch et al., 1994). We ourselves have found vaginal administration of the prostaglandin E1 analogue Gemeprost to cause a dramatic increase in uterine artery PI possibly secondary to uterine contractions (Valentin et al., 1995).

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9. Doppler ultrasound examinations of the uteroplacental and luteal circulation in normal first trimester pregnancies There is complete consensus in the published literature, that blood flow velocity waveform indices in the uterine arteries and their branches (i.e. the arcuate, radial and spiral arteries) decrease with gestational age in the first trimester (Deutinger et al., 1988; Thaler et al., 1990; Arduini et al., 1991; Jaffe and Warsof, 1991; Jauniaux et al., 1991, 1992; Jurkovic et al., 1991, 1992; Kurjak et al., 1993c), whereas blood flow velocity increases (Jurkovic et al., 1991, 1992) indicating an increase in uterine perfusion (Thaler et al., 1990). However, Doppler examinations of the intervillous space have yielded conflicting results. Some research teams were unable to detect flow in the intervillous space before the second trimester using the Doppler technique and suggested intervillous flow not to be present in the first trimester (Hustin and Schaaps, 1987; Schaaps and Hustin, 1988; Jauniaux et al., 1991, 1992; Meuris et al., 1995); others did record flow from the intervillous space as early as in the first trimester (Kurjak et al., 1991b; Valentin et al., 1996). We detected flow in the intrachorionic area in 83% of women before 8 completed gestational weeks and in 98% of those at 8–11 weeks (Valentin et al., 1996). There are other data, too, to support the existence of intervillous flow before the second trimester (Burchell, 1967; Boyd and Hamilton, 1970). The discrepancy in results of Doppler ultrasound examinations of the intrachorionic area is probably to be explained by differences in examination technique and in the sensitivity of the ultrasound systems used. The corpus luteum remains detectable at ultrasound examination throughout the first trimester (Zalud and Kurjak, 1990; Jurkovic et al., 1992; Salim et al., 1994; Valentin et al., 1996). Using the Doppler technique, neither we nor others found substantial changes to occur in its circulation (as measured by blood flow velocity and/or blood flow velocity waveform index) during the first trimester of normal pregnancy (Jurkovic et al., 1992; Salim et al., 1994; Alcazar et al., 1996; Valentin et al., 1996).

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10. Doppler ultrasound examination in abnormal first trimester pregnancies Blood flow velocity waveform indices in the uterine and subchorionic arteries (the subchorionic arteries presumably representing the spiral arteries) do not seem to differ between normal and abnormal intrauterine first trimester pregnancies (Schaaps and Soyeur, 1989; Stabile et al., 1990; Arduini et al., 1991; Kurjak et al., 1991b; Jaffe and Warsof, 1992; ). However, in some studies subchorionic blood flow was detectable more seldom in abnormal intrauterine pregnancies (missed abortions, blighted ova) than in normal pregnancies (Kurjak et al., 1991b; Jaffe and Warsof, 1992). Jaffe and Warsof detected blood flow in the subchorionic area more often in cases of blighted ova than in cases of missed abortion. This made them suggest that Doppler ultrasound examination might shed light on the pathophysiology of early pregnancy failure (Jaffe and Warsof, 1992; Jaffe, 1993). Schaaps and Soyeur (1989) and Jauniaux et al. (1994) were unable to detect continuous intervillous flow in normal firsttrimester pregnancies compared with in 100 and 70% of missed abortions. Based on these findings and those of histological examinations of abortion material, they suggested premature entry of maternal blood into the intervillous space to be the final mechanism causing abortion (Jauniaux et al., 1994). The observations of our group do not agree, our detection rate of intervillous flow in normal first trimester pregnancies being 92% (Valentin et al., 1996). Luteal flow as measured by Doppler velocimetry does not seem to differ between normal and abnormal pregnancies (Zalud and Kurjak, 1990). Using the Doppler technique, blood flow velocity signals can be detected in 50–95% of extrauterine pregnancies (Taylor et al., 1989; Jurkovic et al., 1992; Pellerito et al., 1992; Tekay and Jouppila, 1992b). Doppler shift spectra recorded from extrauterine pregnancies resemble those obtained from the spiral arteries of normal intrauterine pregnancies (Jurkovic et al., 1992) in that they manifest high blood flow velocities (Taylor et al., 1989) and little variation between systolic and diastolic velocities (Kurjak et al., 1991c;

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Jurkovic et al., 1992; Pellerito et al., 1992; Tekay and Jouppila, 1992b). A relationship seems to exist between serum hCG concentrations and the ability to detect Doppler shift signals from an extrauterine pregnancy (Kurjak et al., 1991c; Pellerito et al., 1992; Tekay and Jouppila, 1992b) and between serum hCG concentrations and blood flow velocity waveform index in arteries supplying an ectopic pregnancy (Tekay and Jouppila, 1992b; Kurjak et al., 1991c). According to some publications, Doppler ultrasound examination of vessels in a mass suspected to be an ectopic pregnancy increases the diagnostic accuracy (Taylor et al., 1989; Pellerito et al., 1992). Doppler ultrasound examination of the main uterine arteries does not seem to help in the differential diagnosis of extrauterine pregnancy, similar uterine artery blood flow velocity waveform indices having been recorded from the ipsiand contralateral side of a tubal pregnancy (Jurkovic et al., 1992; Tekay and Jouppila, 1992b), and similar indices having been recorded from intra- and extra-uterine pregnancies (Jurkovic et al., 1992). Doppler ultrasound examination of the tubal branch of the uterine artery might contribute to the differential diagnosis of extrauterine pregnancy, significantly lower RI values having been obtained from the tubal gestation side than from the contralateral side (Kirschler et al., 1992). In my experience, Doppler ultrasound examination adds little to the differential diagnosis of extrauterine pregnancy, as I find it possible in most cases to correctly diagnose intra- or extrauterine pregnancy using grey-scale imaging alone. This was also the experience of Achiron et al. (1994). The gynaecological Doppler ultrasound examination offers a possibility to non-invasively study uteroplacental circulation in early pregnancy. If—as suggested by Jaffe and Warsof (1992)— some miscarriages are caused by abnormal uterine circulation, then Doppler ultrasound examination would almost certainly be useful in the diagnosis of the abnormality. It would remain, of course, to develop effective treatment. As the vascularisation of ectopic pregnancies seems to be related to the viability of the trophoblast (Kurjak et al., 1991c; Pellerito et al., 1992; Tekay and Jouppila, 1992b),

there is a potential for the Doppler examination to help in the selection of optimal treatment of ectopic pregnancies (e.g. surgery versus conservative treatment). However, large prospective studies are needed to confirm a possible role of Doppler examination in the clinical management of early pregnancy complications.

11. Summary The gynaecological Doppler ultrasound examination offers a possibility to non-invasively study physiological and pathological circulatory changes in the female pelvis and the effect of drugs on uterine and ovarian circulation. However, the gynaecological Doppler ultrasound examination is still a research tool without a scientifically documented role in clinical practice. Even though reference data representative of normal findings at transvaginal colour and spectral Doppler ultrasound examination of the uterus and ovaries have been established (Sladkevicius et al., 1993, 1994a, 1995a; Valentin et al., 1996) it remains unclear whether the gynaecological Doppler ultrasound examination can contribute substantially to the management of early pregnancy complications or infertility problems or to the differential diagnosis of pelvic masses or uterine pathology. Large prospective studies—preferably randomised controlled trials—are needed to determine the clinical value of the gynaecological Doppler ultrasound examination. One of the most serious problems associated with gynaecological Doppler measurements is the difficulty of obtaining reproducible results, a problem only rarely dealt with in the literature (Farquhar et al., 1989; Steer et al., 1995b; Tekay, 1995; Sladkevicius and Valentin, 1995a,b,c; Tekay and Jouppila, 1996b, 1997). Another problem is the dependence of Doppler results on the type of ultrasound system and examination technique used, making it advisable to establish reference data separately for each type of ultrasound system and for each laboratory. Probably, conventional ways of evaluating the information obtained from a gynaecological Doppler ultrasound examination (noting the pres-

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