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Endocrinology 2006;147:1997–2007. 3 What Is the Appropriate Imaging of the Polycystic Ovary Sophie Jonard, MD, Yann Robert, MD, Yves Ardaens, MD, and Didier Dewailly, MD CONTENTS 1 Introduction 2 2-D Ultrasonography 3 Other Techniques for Imaging PCO 4 Conclusions and Future Avenues of Investigation Summary The need for a calibrated imaging of polycystic ovaries (PCO) is now stronger than ever since the recent consensus conference held in Rotterdam, May 1–3, 2003. However, imaging PCO is not an easy procedure, and it requires a thorough technical and medical background. The two-dimensional (2-D) ultrasonography (U/S) remains the standard for imaging PCO and the current consensus definition of PCO determined at the joint ASRM/ESHRE consensus meeting on PCOS rests on this technique: either 12 or more follicles measuring 2–9 mm in diameter and/or increased ovarian volume (>10 cm 3 ). The other techniques such as Doppler, 3-D U/S, and magnetic resonance imaging (MRI) can help for the diagnosis but are so far only second-line techniques. Key Words: Polycystic ovary; two-dimensional ultrasonography; Doppler; three-dimensional ultrasono- graphy; magnetic resonance imaging; ovarian volume; ovarian area; follicle number. 1. INTRODUCTION The need for a calibrated imaging of polycystic ovaries (PCO) is now stronger than ever since the recent consensus conference held in Rotterdam in 2003. Indeed, the subjective criteria that were proposed 20 years ago and still used until recently by the vast majority of authors are now replaced by a stringent definition using objective criteria (1,2). Imaging PCO is not an easy procedure. It requires a thorough technical and medical background. The goal of this chapter is to provide the reader with the main issues From: Contemporary Endocrinology: Polycystic Ovary Syndrome Edited by: A. Dunaif, R. J. Chang, S. Franks, and R. S. Legro © Humana Press, Totowa, NJ 25 26 Jonard et al. ensuring a well-controlled imaging for the diagnosis of PCO. The two-dimensional (2-D) ultrasonography (U/S) will be first and extensively addressed as it remains the standard for imaging PCO. Other techniques such as Doppler, 3-D U/S, and magnetic resonance imaging (MRI) will be then more briefly described. 2. 2-D ULTRASONOGRAPHY 2.1. Technical Aspects and Recommendations The transabdominal route should always be the first step of pelvic sonographic exami- nation, followed by the transvaginal route, excepted in virgin or refusing patients. Of course, a full bladder is required for visualization of the ovaries. However, one should be cautious that an overfilled bladder can compress the ovaries, yielding a falsely increased length. The main advantage of this route is that it offers a panoramic view of the pelvic cavity. Therefore, it allows excluding associated uterine or ovarian abnor- malities with an abdominal development. Indeed, lesions with cranial growth could be missed by the transvaginal approach exclusively. With the transvaginal route, high-frequency probes (>6 MHz) with a better spatial resolution but a less examination depth can be used, because the ovaries are close to the vagina and/or the uterus and because the presence of fatty tissue is usually less disturbing (except when very abundant). With this technique, not only the size and the shape of ovaries are visualized but also their internal structure, namely follicles and stroma. It is now possible to get pictures that have a definition close to anatomical cuts. However, the evaluation of the ovarian size through the transvaginal approach is difficult. To be the most accurate, it requires choosing meticulously the picture where the ovary appears the longest and the widest. This picture must then be frozen. Two means can be proposed for calculating the ovarian area: either fitting an ellipse to the ovary in which the area is given by the machine or outlining by hand the ovary with automatic calculation of the outlined area. This last technique must be preferred in cases of a non-ellipsoid ovaries, as sometimes observed. The volume is the most complete approach. Traditionally, it can be estimated after the measurement of the length, width, and the thickness and use of the classical formula for a prolate ellipsoid: L×W×T×0.523 (3,4,5). However, the ovaries have to be studied in three orthogonal planes, a condition that is not always respected. The 3-D U/S is an attractive alternative for the accurate assessment of ovarian volume but this technique is not commonly available (see paragraph 3.1). To count the total number of “cysts” (in fact, follicles) and to evaluate their size and position, each ovary should be scanned in longitudinal and/or transversal cross-section from the inner to outer margins. 2.2. The Consensus Definition of PCO According to the literature review dealing with all available imaging systems and to the discussion at the joint ASRM/ESHRE consensus meeting on PCOS held in Rotterdam, May 1–3, 2003, the current consensus definition of PCO is the following: either 12 or more follicles measuring 2–9 mm in diameter in the whole ovary and/or increased ovarian volume (>10 cm 3 ). What Is the Appropriate Imaging of the Polycystic Ovary 27 The priority was given to the ovarian volume and to the follicle number because both have the advantage of being physical entities that can be measured in real time conditions and because both are still considered as the key and consistent features of PCO. 2.2.1. The Increased Ovarian Volume Many studies have reported an increased mean ovarian volume in series of patients with PCOS (4–9). However, the upper normal limit of the ovarian volume suffers from some variability in the literature (from 8 to 15.6 cm 3 ). Such variability may be explained by the following: • the small number of controls in some studies and/or • differences in inclusion or exclusion criteria for control women and/or • operator-dependent technical reasons: it is difficult indeed to obtain strictly longitudinal ovarian cuts, which is an absolute condition for accurate measures of the ovarian axis (length, width, and thickness). The consensus volume threshold to discriminate a normal ovary from a PCO is 10 cm 3 (1). It has been empirically retained by the expert panel for the Rotterdam consensus, as being the best compromise between the most complete studies (6,7). Indeed, no study published so far has used an appropriate statistical appraisal of sensitivity and specificity of the volume threshold. This prompted us to recently revisit this issue through a prospective study including 154 women with PCOS compared to 57 women with normal ovaries. The receiver operating characteristic (ROC) curves indicated that a threshold at 10 cm 3 yielded a good specificity (98.2%) but a bad sensitivity (39%). Setting the threshold at 7 cm 3 offered the best compromise between specificity (94.7%) and sensitivity (68.8%) (10). Thus, in our opinion, the threshold at 10 cm 3 should be lowered to increase the sensitivity of the ultrasound PCO definition. In agreement with this proposal, Carmina et al. (11) have recently compared 326 women with PCOS to 50 age-matched and weight-matched ovulatory women and confirmed our results by considering that ovarian volumes larger than 7.5 cm 3 were excessive. 2.2.2. The Increased Follicle Number The polyfollicular pattern (i.e., excessive number of small echoless regions less than 10 mm in diameter) is strongly suggestive of PCO. It is now broadly accepted that most of these cysts are in fact healthy oocyte-containing follicles and are not atretic. The consensus definition for a PCO is one that contains 12 or more follicles of 2–9 mm diameter. Again, the expert panel for the Rotterdam consensus considered this threshold as being the best compromise between the most complete studies, including the one in which we compared 214 patients with PCOS to 112 women with normal ovaries (12). By ROC analysis, a follicle number per ovary (FNPO) of ≥12 follicles of 2–9 mm diameter yielded the best compromise between sensitivity (75%) and specificity (99%) for the diagnosis of PCO. Since then, however, a recent study using 3-D U/S has disputed this threshold (13). These authors used appropriate statistical approach by ROC curves but their population samples were very small (29 normoandrogenic women and 10 PCOS patients). In 28 Jonard et al. addition, their patients had a severe PCOS with anovulation and obesity and did not represent therefore a “standard” PCOS population. Not surprisingly, they found a higher threshold for the FNPO (20) and for the ovarian volume (13 mL). Indeed, a FNPO set at 20 yielded 70% sensitivity and 100% specificity. However, if one looks closely at their data, setting the threshold lower would have improved the sensitivity without a substantial loss of specificity. Also, it is not known whether counting the follicles by 3-D U/S yields different values from those obtained by scanning the ovaries with conventional U/S. It is also debated whether the FNPO should be counted in the whole ovary or in a single median sonographic plane. No study using appropriate statistical approach has compared the two techniques. Therefore, it is so far not possible to validate any threshold for the latter. Finally, the Rotterdam consensus did not address the difficult issue about the presence of multi-follicular ovaries (MFO) in situations other than PCOS. Again, the terminology might be better annotated as multi-follicular rather than multi-cystic. There is no consensus definition for MFO although they have been described as ovaries in which there are multiple (≥6) follicles, usually 4–10 mm in diameter, with normal stromal echogenicity (4). No histological data about MFO are available. MFO are characteristically seen during puberty and in women recovering from hypothalamic amenorrhea—both situations being associated with follicular growth without consistent recruitment of a dominant follicle (14,15). Although the clinical pictures are theoret- ically different, there may be some overlap however, hence the confusion between PCO and MFO by inexperienced ultrasonographers. This issue stresses the need for considering carefully the other clinical and/or biological components of the consensus definition for PCOS. We recently revisited the ovarian follicular pattern in a group of women with hypothalamic amenorrhea. About one-third had a FNPO higher than 12 (unpublished personal data). As they were oligo-ovulatory, they could be considered as having PCOS if one applied the Rotterdam definition! This might be true in some of them if one supposes that the clinical and biological expression of their PCOS had been modified by the chronically suppressed LH levels due to their secondary hypothalamic dysfunction (16). In the others, however, such an overlap in the FNPO emphasizes the need for a wise and careful utilization of the Rotterdam criteria as well as for considering other ultrasound criteria for PCO in difficult situations. 2.3. Other Criteria and Other Definitions 2.3.1. External Morphological Signs of PCO At its beginning in the 1970’s, the weak resolution of U/S abdominal probes allowed only the external morphological ovarian features to be assessed. Thus, these features were used as the first criteria defining PCO: 1. the length, with an upper limit is 4 cm, is the simplest criterion, but this uni-dimensional approach may lead false positive results when a full bladder compresses the ovary (with the transabdominal route) or false negative results when the ovaries are spheric, with a relatively short length; 2. because of the increased ovarian size and the normal uterine width, the uterine width/ovarian length (U/O) ratio is decreased (<1) in PCO; What Is the Appropriate Imaging of the Polycystic Ovary 29 3. PCO often display a spherical shape in contrast to normal ovaries that are ellipsoid. This morphological change can be evaluated by the sphericity index (ovarian width/ovarian length), which is higher than 0.7 in PCO. These parameters are less used nowadays because of their poor sensitivity (17). 2.3.2. The Ovarian Area Ovarian area is less frequently used as a diagnostic criterion than the ovarian volume, and it was not retained in the consensus definition. However, in our recent study revisiting the ovarian volume (10), the ovarian area (assessed by the ROC curves) had a slightly better diagnostic value than the ovarian volume (sensitivity, 77.6% and specificity, 94.7% for a threshold at 5 cm²/ ovary). We also observed that the measured ovarian area (by outlining by hand the ovary or by fitting an ellipse to the ovary) was more informative than the calculated ovarian area (by using the formula for an ellipse: length × width × /4). Indeed, ovaries are not strictly ellipsoid, and this can explain why the diagnostic value of the former was better than the latter. We previously reported that the mean ovarian area was less than 5.5 cm 2 in a large group of normal women (18,19). However, from our recent data, a threshold at 5 cm² seems to offer the best compromise between sensitivity and specificity. Beyond this threshold, the diagnosis of PCO can be suggested. 2.3.3. The Increased Stroma Stromal hypertrophy is characterized by an increased component of the ovarian central part, which seems to be rather hyperechoic (Fig. 1). In our (17,18) and in others’ opinion (8), the stromal hypertrophy and hyperechogenicity are specific for PCO and help Fig. 1. Polycystic ovary (B mode). The ovarian outlined area (9.7 cm 2 at right and 8.9 cm² at left) is increased. The follicle number, with a diameter between 2 and 9 mm, is more than 12. The small follicles display a typical peripheral pattern, around the hyperechoic stroma. 30 Jonard et al. distinguishing between PCO and MFO. However, the estimation of hyperechogenicity is considered as highly subjective, mainly because it depends on the settings of the ultrasound machine. Likewise, in the absence of a precise quantification, the stromal hypertrophy is also a subjective sign. For standardizing the assessment of stromal hypertrophy, we designed a comput- erized quantification of ovarian stroma, allowing selective calculation of the stromal area by subtraction of the cyst area from the total ovarian area on a longitudinal ovarian cut (18,19). By this means, we were able to set the upper normal limit of the stromal area (i.e., 95th percentile of a large control group of 48 normal women) at 380 mm 2 per ovary. However, providing a precise outlining of the ovarian shape on a strictly longitudinal cut of the ovaries, the diagnostic value of the total ovary equaled the one of stromal area since both were highly correlated. Fulghesu et al. (9) proposed the ovarian stroma/total area ratio as a good criterion for the diagnosis of PCOS. The ovarian stromal area was evaluated by outlining with the caliper the peripheral profile of the stroma, identified by a central area slightly hyperechoic with respect to the other ovarian area. However, this evaluation might not be easy to reproduce in routine practice. Others have used a semi-quantitative measure of stromal echogenicity, scored 1 if normal, 2 if moderately increased, or 3 if frankly increased (20). In this study, this parameter correlated significantly to the total follicle number (both ovaries). Echogenicity has also been quantified by Al-Took et al. (21) as the sum of the product of each intensity level (ranging from 0–63 on the scanner) and the number of pixels for that intensity level divided by the total number of pixels in the measured area. By using the same formula, Buckett et al. (22) found no difference in the stromal echogenicity between women with PCOS and women with normal ovaries. They concluded that the subjective impression of increased stromal echogenicity was due to increased stromal volume but also to posterior echo reinforcement behind the follicles with reduced echogenicity. In summary, ovarian volume or area correlates well with ovarian function and is both more easily and reliably measured in routine practice than ovarian stroma. Thus, in order to routinely define the polycystic ovary, neither qualitative or quantitative assessment of the ovarian stroma is required. 2.3.4. Follicle Distribution In PCO, the follicle distribution is predominantly peripheral, with typically an echoless peripheral array, as initially described by Adams et al. (4) (Fig. 1). For some authors (23), younger patients display more often this peripheral distribution while a more generalized pattern, with small cysts in the central part of the ovary, is noticed in older women. At the Rotterdam meeting, this subjective criterion was judged to be too inconstant and subjective to be retained for the consensus definition of PCO (1). 3. OTHER TECHNIQUES FOR IMAGING PCO 3.1. 3-D Ultrasonography To avoid the difficulties and pitfalls in outlining or measuring the ovarian shape, the 3-D U/S has been proposed using a dedicated volumic probe or a manual survey of the ovary (24–26). From the stored data, the scanned ovarian volume is displayed on What Is the Appropriate Imaging of the Polycystic Ovary 31 the screen in three adjustable orthogonal planes, allowing the three dimensions and subsequently the volume to be more accurately evaluated. In a study of Kyei-Mensah et al. (27), three groups of patients were defined: (a) those with normal ovaries, (b) those with asymptomatic PCO, and (c) those with polycystic ovary syndrome The ovarian and stromal volumes were similar in groups b and c and both greater than group a. Stromal volume was positively correlated with serum androstenedione concentrations in group c only. The mean total volume of the follicles was similar in all groups, indicating that increased stromal volume is the main cause of ovarian enlargement in PCO. Nardo et al. (28) found good correlations between 2-D and 3-D ultrasound measurements of ovarian volume and polycystic ovary morphology. However, in this prospective study, total ovarian volume, ovarian stromal volume, follicular volume and follicle number did not correlate with testosterone concentration. Thus, 3-D imaging improves spatial awareness and stores information for later use. However, 3-D ultrasound requires an expensive equipment and an intensive training. Storage and analysis of data are time consuming. Therefore, its superiority over 2-D ultrasound for imaging PCO in clinical practice is so far not evident. In addition, no precise threshold for ovarian volume and FNPO has been proposed up to now with this technique, except in the aforementioned study of Allemand et al. (13) that needs to be validated in larger populations. 3.2. Doppler Ultrasonography The assessment of uterine arteries will not be addressed in this chapter exclusively devoted to PCO imaging. Color (or power) Doppler allows detection of the vascular- ization network within the ovarian stroma. Power Doppler is more sensitive to the slow flows and shows more vascular signals within the ovaries, but it does not discriminate between arteries and veins. Moreover, the sensitivity of the machines differs from one to another. The pulsed Doppler focuses on the hilum or internal ovarian arteries and offers a more objective approach. Because of the slow flows, the pulse repetition frequency (PRF) is at minimum (400 Hz) with the lowest frequency filter (50 Hz). The study of the ovarian vascularization by these techniques is still highly subjective. The blood flow is more frequently visualized in PCOS (88%) than in normal patients (50%) in early follicular phase and seems to be increased (29). No significant difference was found between obese and lean women with PCO, but the stroma was less vascu- larized in patients displaying a general cystic pattern than in those with peripherical cysts. In the latter, the pulsatility index (PI) values were significantly lower and inversely correlated to the follicle-stimulating hormone/luteinizing hormone (FSH/LH) ratio (30). In an other study (31), the resistive index (RI) and PI were significantly lower in PCOS (RI = 0.55 + 0.01 and PI = 0.89 + 0.04) than in normal patients (RI = 0.78 + 0.06 and PI = 1.87 + 0.38), and the peak systolic velocity was greater in PCOS (11.9 + 3.2) than in normal women (9.6 + 2.1). No correlation was found with the number of follicles and the ovarian volume but there was a positive correlation between LH levels and increased peak systolic velocity. In Zaidi et al. (32) study, no significant difference in PI values was found between the normal and PCOS groups, whereas the ovarian flow, as reflected by the peak sytolic velocity, was increased in the former. Some data indicate that Doppler blood flow may have some value in predicting [...]... with polycystic ovary syndrome Human Reprod 1998; 13: 1 437 –1441 28 Nardo LG, Buckett WM and Khullar V Determination of the best-fitting ultrasound formulaic method for ovarian volume measurement in women with polycystic ovary syndrome Fertil Steril 20 03; 79: 632 – 633 29 Battaglia C, Artini PG, Genazzani AD, Sgherzi MR, Salvatori M, Giulini S, Volpe A Color Doppler analysis in lean and obese women with polycystic. .. echogenicity in women with normal and polycystic ovaries Human Reprod 1999;14: 618–621 23 Battaglia C, Artini PG, Salvatori M, Giulini S, Petraglia F, Maxia N, Volpe A Ultrasonographic pattern of polycystic ovaries: color Doppler and hormonal correlations Ultrasound Gynaecol Obstet 1998;11: 33 2 33 6 24 Wu M-H, Tang H-H, Hsu C-C, Wang S-T, Huang K-E The role of three-dimensional ultrasonographic imaging... MR 1998;19:90–1 03 38 Yoo RY, Sirlin CB, Gottschalk M, Chang RJ Ovarian imaging by magnetic resonance in obese adolescent girls with polycystic ovary syndrome: a pilot study Fertil Steril 2005;84:985–995 4 Polycystic Ovary Versus Polycystic Ovary Syndrome A Necessary Distinction Adam Balen, MD, FRCOG CONTENTS 1 Introduction 2 Polycystic Ovaries in the Absence of Hyperandrogenism 3 Polycystic Ovaries... for the diagnosis of polycystic ovary syndrome: the ovarian stroma/ total area ratio Fertil Steril 2001;76: 32 6 33 1 10 Jonard S, Robert Y, Dewailly D Revisiting the ovarian volume as a diagnostic criterion for polycystic ovaries Hum Reprod 2005;20:28 93 2898 11 Carmina E, Orio F, Palomba S, Longo RA, Lombardi G, Lobo RA Ovarian size and blood flow in women with polycystic ovary syndrome and their correlations... Obstet 1996;7: 34 2 34 6 30 Battaglia C, Genazzani AD, Salvatori M, et al Doppler, ultrasonographic and endocrinological environment with regard to the number of small subcapsular follicles in polycystic ovary syndrome Gynecol Endocrinol 1999; 13: 1 23 129 31 Aleem FA, Predanic MP Transvaginal color Doppler determination of the ovarian and uterine blood flow characteristics in polycystic ovary disease Fertil... D Ultrasound assessment of the polycystic ovary: international consensus definitions Human Reprod Update 20 03; 9: 505–514 2 The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group Revised 20 03 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS) Human Reprod 2004;19: 41–47 3 Sample WF, Lippe BM, Gyepes MT Grey-scale ultrasonography of the normal... polycystic ovary (PCO) is the morphological ovarian phenotype in women with the polycystic ovary syndrome (PCOS) There are several extra-ovarian aspects to the pathophysiology of PCOS, yet ovarian dysfunction is central The definition From: Contemporary Endocrinology: Polycystic Ovary Syndrome Edited by: A Dunaif, R J Chang, S Franks, and R S Legro © Humana Press, Totowa, NJ 37 38 Balen of the syndrome. .. Fertil Steril 1995;64: 30 7 31 2 20 Pache TD, Hop WC, Wladimiroff JW, Schipper J and Fauser BCJM Transvaginal sonography and abnormal ovarian appearance in menstrual cycle disturbances Ultrasound Med Biol 1991;17: 589–5 93 21 Al-Took S, Watkin K, Tulandi T, Tan SL Ovarian stromal echogenicity in women with clomiphene citrate-sensitive and clomiphene citrate-resistant polycystic ovary syndrome Fertil Steril... expression of PCOS This chapter will discuss the particular relevance of having polycystic ovaries either alone or in the context of the syndrome Conclusions Polycystic ovaries are detected in 1 9 -3 3% of the “normal population”, of whom approximately 80% have symptoms of PCOS, albeit usually mild ∴ 20% of women with polycystic ovaries are symptom free The presence of polycystic ovaries may be a marker for increased... 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