Ultrasound diagnosis of polycystic ovary syndrome

4 Ultrasound diagnosis of polycystic ovary syndrome AMMA KYEI-MENSAH JAMAL ZAIDI STUART CAMPBELL

Sixty years after the classic description by Stein and Leventhal, every aspect of the polycystic ovary syndrome (PCOS) still fuels lively debate because of the marked heterogeneity of its clinical and endocrine features. The importance of the ultrasonographic ovarian appearance as a diagnostic criterion for the polycystic ovary (PCO) is also a source of argument and by no means universally acknowledged. Informed opinion is currently polarized between two diagnostic approaches to PCOS. One is primarily based on ovarian ultrasonographic appearances, usually as defined by Adams et al (1985), and combined with certain characteristic symptoms (Conway et al, 1989). In the alternative approach, detection of hyperandrogenic chronic anovulation (HCA) alone is considered sufficient for diagnosis (Yen, 1991) regardless of the ovarian scan appearances. In this chapter, the role of ultrasound (US) in the diagnosis of PCO and the insights that have been gained into the clinical and epidemiological aspects of PCOS using US will be reviewed. The potential contributions of recent advances in US technology, such as three-dimensional ultrasonography and colour Doppler imaging, to a deeper understanding of the underlying pathogenic mechanism of PCOS will also be discussed. DIAGNOSTIC METHODS: HISTOPATHOLOGY AND RADIOIMMUNOASSAY

Traditionally, the diagnosis of PCOS has rested primarily on the typical appearance of bilateral sclerocystic ovaries in women presenting with anovulation, hirsutism or both. Histological examination of the ovary obtained by laparoscopic or open biopsy provides a definitive morphological diagnosis of PCO, but to obtain this 'gold standard' routinely would be invasive and clinically impractical. Hughesdon (1982) studied 34 fullthickness Stein-Leventhal ovarian wedges and 30 age-matched controls and demonstrated that Stein-Leventhal ovaries have an average crossBailli~re's Clinical Endocrinology and Metabolism-249 Vol 10, No. 2, April 1996 ISBN 0-7020-2100-8 0950-351X/96/020249 + 14 $12.00/00

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sectional area about twice that of controls and contain double the number of primary, secondary, small tertiary and subsequently atretic follicles, together with thickening of the tunica and increased ovarian stroma. In the 1970s, the advent of radioimmunoassay techniques caused a shift away from the histological diagnosis of PCO to the use of biochemical markers, for example raised serum concentrations of luteinizing hormone (LH), testosterone and/or androstenedione and abnormalities of oestrogen secretion, particularly oestrone (Yen, 1980). No consensus emerged on a definitive biochemical definition, however, although detection of HCA is the favoured method of diagnosis among clinicians who remain unimpressed by the ovarian ultrasonographic features of PCO. DEVELOPMENT OF US CRITERIA: HISTORICAL PERSPECTIVE The ideal diagnostic imaging technique should produce clear images that correspond closely to the characteristic histopathological changes. It is interesting to observe that successive technological advances in the field of radiological imaging caused changes of emphasis regarding the importance of total ovarian size, follicle number and stromal features in the US diagnosis of PCO. Takahashi et al (1994) carried out a comparative histological and transvaginal ultrasound (TVS) study of ovarian morphology in 32 PCOS patients, with 20 ovulatory women serving as controls. The number, size and position of small cysts on TVS correlated with the histopathological findings (which were identical to those described by Hughesdon), and Takahashi et al concluded that ovarian US appearance was specific enough to allow a histopathological diagnosis of PCO without biopsy. Thirty years ago, the X-ray technique of pelvic pneumography was used to visualize the ovaries (Edwards et al, 1961). The ovarian outline was well described, but pneumography provided no information about the internal architecture of the ovary. Early ovarian US images produced by static Bscanners clearly demonstrated ovarian enlargement but could not visualize small cysts of less than 1 cm in diameter. The development of highresolution, real-time sector scanners with abdominal transducers greatly improved the accuracy of US texture evaluation of the ovary because, for the first time, these cysts could be clearly outlined (Swanson et al, 1981; Orsini et al, 1985). In early US studies of PCO, the main diagnostic criterion was ovarian enlargement. Indeed, some authors regarded this as an absolute prerequisite for the condition (Parisi et al, 1982). The typical PCO was said to be 2-5 times larger than a normal ovary, which has a volume of 4-7 ml (Sample et al, 1977; Orsini et al, 1985). A mean ovarian surface area of 17 cm 2 (Parisi et al, 1982) and a mean ovarian volume of about 12 ml (Swanson et al, 1981) were quoted for a typical PCO. The importance of ovarian size as an ultrasonographic criterion of PCO lessened as various groups (Hann et al, 1984; Nicolini et al, 1985; Orsini et al, 1985) showed that about one-third of patients with PCOS had ovaries of normal volume. This is because the

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patients in these later studies exhibited a wide range of clinical symptoms and endocrine abnormalities, whereas Swanson et al (1981) and Parisi et al (1982) included patients with enlarged ovaries and classic Stein-Leventhal syndrome respectively, who therefore represented only the extreme end of the clinical spectrum. It is clear that the heterogeneity of PCOS also extends to its ultrasonographic features, and the description of a wide variety of US follicular patterns has increased scepticism in those who prefer clinical and endocrine diagnostic criteria for this condition. Swanson et al (1981) described two patterns of follicular distribution in PCO, which, with slight modifications, are still recognized today. The characteristic multiple cysts measured 2-6 mm in diameter and were either uniform in size and arranged in a 'necklace' distribution around the periphery of the ovary, or were of variable size and scattered throughout the ovarian parenchyma. Stroma features were not included in the diagnosis at this stage. The presence of increased numbers of cysts has become the most important US criterion of PCO, particularly when the ovary is of normal size (Franks, 1989). Yeh et al (1987) studied 68 patients with a clinical diagnosis of PCO and found that in 75% of cases, the ovaries contained more than five follicles measuring 5-8 mm in diameter on each side. In contrast, the ovalies of normal women contained no more than three follicles on each side. Paradoxically, US patterns of PCO have been described in which the characteristic cysts have been absent (Hann et al, 1984; Orsini et al, 1985). Harm et al (1984) performed transabdominal scans on 28 patients with endocrine profiles consistent with PCOS and described three morphological patterns: ovaries with multiple discrete cysts of less than 1 cm diameter (39%), diffusely hypoechoic ovaries with no discernible cysts (25%) and ovaries with a texture isoechoic with the uterus and no cysts (7%). Despite these US appearances, no histopathological differences were found between the cystic and hypoechoic ovaries. Multiple cysts can therefore be present but may not always be visualized with US. The paradox of a 'solid' PCO was further developed by Orsini et al (1985), who described four US ovarian patterns in PCO: enlarged cystic, enlarged solid, normal-sized cystic and normal-sized solid. There are several possible explanations: a solid ovarian pattern could be attributable to technical limitations of the scan equipment or attenuation of the US beam by intervening structures. If the cysts were truly absent, this appearance could represent an extreme of the histological spectrum. However, the most likely cause is thickening of the ovarian capsule or stromal hyperplasia. Adams et al (1985) refined the US diagnosis of PCO to include follicular number and stromal characteristics. The typical polycystic pattern was defined by the presence of 10 or more cysts measuring 2-8 mm in diameter arranged peripherally around a dense core of stroma or scattered through an increased amount of stroma (Figure 1). An important distinction was made from the multifollicular ovary, characteristic of normal puberty or recovering weight-related amenorrhoea, in which there is no increase in the stroma.

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Figure 1. Trmlsvaginal ultrasound image of a PCO showing the classical 'necklace' mrangement of follicles.

Recognition of stromal hyperechogenicity occurred at a time of growing interest in the physiological ovarian mechanisms regulated by the thecal interstitial cells (Erickson et al, 1985). Realization of their pivotal role in ovarian function has ensured that the ovarian stroma will be a focus of continued efforts to determine the pathogenic basis of PCOS. US occupies a central role as a non-invasive diagnostic tool in gynaecology, although considerable expertise is required for accurate diagnostic scanning of the ovaries. Hull (1989) found that transabdominal ultrasonography was inadequate for the diagnosis of PCO in about 40% of cases, although overall diagnostic accuracy improved to about 95% using the transvaginal approach. Ultrasonic assessment and image resolution of the pelvic organs has been markedly improved by the development of highfrequency endovaginal US transducers, which can be placed in close proximity to the pelvic organs. The artefactual echoes resulting from intervening tissues and distortion of the pelvic anatomy by a full bladder are also minimized. The greater clarity of TVS images has prompted further modification of Adams' criteria for the diagnosis of PCO, which were obtained with an abdominal transducer. Fox et al (1991) suggest that at least 15 cysts of 2-10 mm diameter arranged around a prominent, highly echogenic stroma are now required for this diagnosis. US AND THE CLINICAL FEATURES OF PCOS Various combinations of US, clinical and endocrine criteria have been evaluated for their diagnostic potential in PCOS. Ovarian appearance

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correlates strongly with menstrual history (Poison et al, 1988), and about 85% of oligomenorrhoeic women (Adams et al, 1986; Polson et al, 1988) and 26% of amenorrhoeic women (Adams et al, 1986) have PCO. In studies involving oligoamenorrhoeic patients, ultrasonography can therefore be used as a reference test against which to evaluate other diagnostic criteria (Conway et al, 1989; Fox et al, 1991). Using this approach, demonstration of oestrogenization by the simple progestogen challenge test proved to be an accurate diagnostic marker for PCO, particularly in the presence of hirsutism (Fox et al, 1991). Adams et al (1986) studied 173 patients with US evidence of PCO and found at least one additional endocrine abnormality suggestive of PCOS in over 90% of cases, confirming the specificity of the US findings. Nevertheless, the detection of a single endocrine marker, such as a raised serum LH concentration or serum testosterone concentration, is not reliable for diagnosis because these findings are not consistent and are present in only 40% and about 25% of patients respectively (Conway et al, 1989; Balen et al, 1995). Investigative studies based on specific endocrine or clinical criteria tend to highlight inviduals at the extremes of the clinical spectrum of PCOS. In contrast, US studies are not always necessarily 'symptom-led' and therefore may describe a far broader population of patients with PCOS (Conway et al, 1989) and yield valuable information on the background prevalence of the disorder. Polson et al (1988) detected PCO in 22% of 257 volunteers, none of whom had complained of any gynaecological problems. Depite this, a striking correlation existed between clinical features and ultrasonographic appearance. Seventy-five per cent of the women with PCO had irregular menses, whereas only 1 out of the 115 women with normal ovaries had abnormal cycles. Overall, 94% of the normal women with PCO had at least one symptom that was recognizable as a clinical marker of PCOS. Ultrasound assessment of ovarian morphology is now an essential part of the pre-treatment work-up of infertile patients. Patients with PCOS are more sensitive to ovarian stimulation than are their normal counterparts, whether undergoing ovulation induction therapy for anovulatory infertility (Schenker and Weinstein, !978) or superovulation therapy for assisted conception (MacDougall et al, 1993). MacDougall et al (1993) compared 76 patients with an US diagnosis of PCO who were undergoing in vitro fertilization (IVF) with a matched control group of women with normal ovaries. The patients with PCO developed significantly more follicles in association with higher peak serum oestradiol levels (Figure 2A and 2B), produced more oocytes despite receiving smaller quantities of gonadotrophins and were at greater risk of ovarian hyperstimulation syndrome. MacDougall et al (1993) therefore suggested that it is prudent to assess ovarian morphology before treatment, i.e. by performing a base-line scan, so that stimulation regimens can be individualized to reduce the incidence of these complications (Jones et al, 1991). Occasionally, PCO may co-exist in the same patient with another condition causing oligoamenorrhoea, such as hypogonadotrophic hypogonadism (Shoham et al, 1992). In such cases, PCO is likely to be

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(A)

(B) Figure 2. (A) 3D US of ovm'y after controlled superovulation for IVF therapy. (B) 3D US image of hyperstimulated ovary in a woman with PCO undergoing superovulation.

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Figure 3. Suppressed PCOs. Numerous peripheral follicles are still apparent despite prolonged administration of a gonadotrophin-releasing hormone analogue.

suppressed and not directly responsible for the presenting complaint. Correction of the overriding disorder, for example by gaining weight after anorexia, may lead to unmasking of the underlying PCO and expression of the expected functional disorder. It is very important to diagnose suppressed PCO on scan (Figure 3) because it carries the same risks for ovulation induction and superovulation therapy. THE PATHOGENESIS OF PCOS: THE ROLE OF NEW T E C H N O L O G Y

The most consistent feature of PCOS is hyperandrogenaemia, which has been shown to originate from the ovary (Kirschner et al, 1976; McNatty et al, 1980; Chang et al, 1983). Excessive production of ovarian androgens may be caused by dysregulation of cytochrome P450c17 in thecal interstitial cells (see Chapter 1 in this volume): increasing research interest in the ovarian stroma has highlighted the need for a reliable and objective method of stromal analysis because stromal hyperechogenicity (Adams et al, 1985) is a notoriously subjective parameter. As ultrasonographic visualization improves, stromal characteristics may become more important than follicular pattern for the diagnosis of PCO (Pache et al, 1991; Dewailly et al, 1994). Sophisticated new computerized US systems can now be used to measure the area and volume of the ovary and may provide a valuable opportunity for truly objective comparative studies of normal and potycystic ovaries. Similarly, the development of transvaginal colour Doppler

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US may improve our knowledge of the haemodynamic changes within the ovary and give useful insight into possible pathogenic mechanisms in PCOS (Battaglia et al, 1995; Zaidi et al, 1995).

US ASSESSMENT OF OVARIAN STROMAL AREA Dewailly et al (1994) used a computerized two-dimensional (2D) US system to measure ovarian stromal and cyst area in 57 women with hyperandrogenism, t7 women with hypothalamic anovulation and 20 normal women. The measurement technique involved recording the US examination on a videotape and selecting a longitudinal cut in the middle part of the ovary. This section was outlined and subsequently pasted onto a calibrated 'virginal image'. The area of the cysts and the ovarian stroma was calculated automatically by selection of the range of grey scale values corresponding to these stnactures. The authors correlated this information with serum androgen, insulin and gonadotrophin concentrations and found that stromal area in hyperandrogenaemic women was significantly greater than in those with normal androgen levels and correlated positively with serum androstenedione and 17-hydroxyprogesterone concentrations, but not with basal insulin or testosterone concentrations. This linking of a quantitative stromal parameter with markers of androgenic dysfunction represents a convergence of the two diagnostic approaches to PCOS (KyeiMensah and Jacobs, 1994).

THREE-DIMENSIONAL ULTRASONOGRAPHY: MEASUREMENT OF OVARIAN V O L U M E Three-dimensional ultrasound (3D US) is an exciting technological innovation that may improve our current diagnostic capabilities in obstetrics and gynaecology. We have evaluated the Combison 530 system (Kretztechnik AG, Zipf, Austria), which can be used to capture and store scanned volume data for analysis. This stored volume can subsequently be 'resliced' in any plane, thereby providing information that is not available from 2D ulta'asonography. 3D systems can visualize the transverse plane of the pelvis, producing views of the coronal or C-plane, which is parallel to the transducer face, in addition to conventional 2D longitudinal and transverse views (Feichtingel, 1994). The scanned volume can be displayed on screen as computer-generated reformatted sections in three perpendicular planes (Figure 4). The perpendicular orientation of these planes is maintained throughout any manipulation so that serial translation results in an US tomogram from which volume can be measured. Fascinating research is in progress to investigate the use of 3D US in such diverse applications as assessment of fetal malformations (Merz et al, 1995), observation of embryonic brain cavity development (Blaas et al, 1995) and diagnosis of congenital uterine anomalies (Jurkovic et al, 1995), since the endometrial cavity between the uterine angles can now be visualized (Figure 5).

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Figure 4. 3D US image of a PCO in the early follicular phase. The tfiplanar view gives a better indication of follicular numbers.

Figure 5. 3D US image of the endometfium at midcycle. The shape of the endometrial cavity is demonstrated in the coronal or C-plane view (bottom left-hand corner).

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3D US is governed by the same physical principles as conventional 2D US, so its efficacy is also reduced when unfavourable conditions such as obesity prevail, resulting in poor definition of tissue planes. Expertise is also required to capture volume data of sufficient quality to permit meaningful analysis--several attempts may be necessary. If these requirements are satisfied, however, images that may have been poorly visualized using 2D US can be projected in any orientation, thus allowing more detailed morphological examination and possible clarification of diagnostic ambiguities. The relevance of this technique to PCOS lies in its abitity to provide objective ovarian volume measurements. Stromal volume can be calculated from the difference between total ovarian volume and follicular volume. Correlation with endocrine parameters such as androgen production should increase our knowledge of the complex interrelationships governing this condition. We have assessed the accuracy (Kyei-Mensah et al, 1995a) and reproducibility (Kyei-Mensah et al, 1995b) of ovarian volume measurements as an essential preliminary step before undertaking detailed stromal volume estimations in women with normal and polycystic ovaries. The method of obtaining a scanned ovarian volume is fairly simple. First, the ovaries are localized in the same way as with the conventional 2D mode. The system is then switched into 'volume mode', causing the simultaneous appearance of a mobile sector on the screen defining the 'region of interest'. The ovary is centralized within this sector and the patient is requested to remain still while the volume acquisition setting is activated. The 7.5 MHz endovaginal transducer is held stationary while the transducer crystal rotates mechanically through 360 ° across the sector for about 8 seconds, storing sections in the computer memory. After about 5 seconds, the scanned ovarian volume is displayed on the screen in three adjustable orthogonal planes and can subsequently be stored on a cartridge hard disk. Scan consultation time is only about 10 minutes, and patients do not need to be present for analysis. 3D US ovarian volume measurement is also straightforward. The plane that allows the clearest view of the ovarian outline across its entire width is highlighted, and then the ovarian contours are serially outlined using a rollerball cursor. The area and volume of each 'slice' appears at the bottom of the screen until the whole ovary has been sectioned and the final values are displayed. When we compared 2D and 3D ovarian follicular volume measurements with the corresponding follicular aspirates obtained at oocyte collection in 25 women undergoing IVF therapy, we found that 2D and 3D measurements were accurate over the relevant follicular volume range for IVF cycles but that 3D measurements had a higher degree of precision (KyeiMensah et al, 1995a). Independent analysis of 20 scanned volumes obtained on day 2 of the menstrual cycle by three experienced observers (Kyei-Mensah et al, 1995b) also showed a high degree of reproducibility of ovarian volume measurements both within and between observers. The reliability of a single measurement by one or more observers as a reflection of the true ovarian volume was found to be 95%. The intra-observer and inter-observer coefficients of variation were 8% and 9% respectively. Now

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that the technique has been validated, we are currently examining the relationship between stromal volume and various endocrine indices (particularly androgens) in patients with normal and polycystic ovaries. COLOUR AND PULSED DOPPLER ULTRASOUND: APPLICATIONS IN PCOS

Transvaginal colour and pulsed Doppler US in combination with B-mode imaging may be used as a non-invasive method to assess blood flow changes in the pelvic organs. It is possible to study the haemodynamic changes in the uterine and/or ovarian arteries during the menstrual cycle in women with normal ovaries (Scholtes et al, 1989; Steer et al, 1990; Collins et al, 1991; Campbell et al, 1993; Sladkevecius et al, 1993), to assess uterine and endometrial receptivity in women undergoing IVF (Sterzik et al, 1989; Favre et al, 1993; Steer et al, 1993; Zaidi et al, 1995a) and to improve accuracy in diagnosing malignant pelvic masses (Bourne et al, 1989; Kurjak et al, 1989). Similarly, assessment of vascular changes in the ovarian and uterine arteries in women with PCO may improve our understanding of the pathogenesis of this condition and provide additional parameters for its US diagnosis. We have used transvaginal colour and pulsed Doppler US to study the vascular changes that occur during the early follicular phase in the ovarian stroma of women embarking on IVF therapy (Zaidi et al, 1995b). The women were divided into three groups: group 1 consisted of women with regular, ovulatory menstrual cycles and normal ovaries on US scan; group 2 consisted of women similar to group 1 but with PCO on US scan; and group 3 consisted of women with biochemical evidence of previous anovulatory cycles and/or oligomenorrhoea and/or elevated serum LH concentrations (greater than 10 IU/1) in the early follicular phase, together with PCO on ultrasound scan. After placing the colour Doppler box over the ovarian stroma, it was apparent that the intensity and quantity of coloured areas in the ovarian stroma appeared to be less in group 1 compared with both groups 2 and 3. We measured ovarian stromal peak systolic blood flow velocity (Vm~x) and ovarian stromal time averaged maximum velocity (TAMX) by activating the pulsed Doppler function and sampling the Doppler shifted frequencies within the sample volume, and found that V ..... and TAMX were significantly greater in groups 2 and 3 than group 1. The pulsatility index (PI), which estimates blood flow impedance distal to the point of sampling, was not significantly different between the three groups. This suggests that intraovarian vascular perfusion is greater in women with PCO and PCOS compared with women with normal ovaries. It may in part explain the hypersensitivity to ovarian stimulation observed in this group of women (Zaidi et al, 1995a). Battaglia et al (1995) assessed intraovarian and uterine artery indices of impedance to blood flow in women with PCOS and compared the results with normal female volunteers. They noted that there was a significantly greater uterine artery PI and lower ovarian stromal resistance index in

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women with PCOS compared with the controls. They also showed a positive correlation between PI, androgens and the LH/FSH ratio. These studies suggest that there are significant differences in vascularization between women with PCOS and women with normal ovaries. The observation of similarities in intraovarian vascularization between women with PCO and PCOS (Zaidi et al, 1995b) supports the theory that PCO is a primary disorder of the ovary. Furthermore, although the gene coding for PCO has not yet been located, there is evidence that PCO may be a familial trait (Hague et al, 1988) with a dominant mode of inheritance (Carey et al, 1993).

SUMMARY The US diagnostic criteria of the PCO have been refined with each successive advance in US technology. Diagnostic accuracy has evolved from a mere appreciation of overall ovarian size to the recognition of characteristic follicular patterns of distribution and subtle textural changes in the ovarian stroma. The most consistent features are the presence of multiple small follicles arranged around, or scattered through, a dense echogenic ovarian stroma, although recognition of the latter is highly subjective. Sophisticated innovations such as 3D US, together with colour and pulsed Doppler US, should improve the objectivity of observations and allow quantitative analysis of the ovarian stroma, which is known to be the source of the characteristic hyperandrogenaemia in PCOS. Valid comparative studies of women with normal and polycystic ovaries should now be feasible and will hopefully bring us closer to understanding the pathogenesis of this fascinating condition.

Acknowledgements We would like to thank Leonard Golding of Kretztechnik for his technical advice and assistance with the Combison 530 system.

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