Polycystic ovarian syndrome: Are radiology departments contributing to the misdiagnosis?

Polycystic ovarian syndrome: Are radiology departments contributing to the misdiagnosis? Poster No.: C-1238 Congress: ECR 2010 Type: Scientific Exhibit Topic: Genitourinary Authors: G. Tony, N. V. Gurjar, F. W. F. Hanna, I. Britton; Stoke-on-Trent/ UK Keywords: polycystic ovary, transvaginal ultrasound, Rotterdam DOI: 10.1594/ecr2010/C-1238 Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply ECR's endorsement, sponsorship or recommendation of the third party, information, product or service. ECR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold ECR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies, ppt slideshows and any other multimedia files are not available in the pdf version of presentations. www.myesr.org Page 1 of 20

Purpose PURPOSE: Polycystic Ovarian Syndrome (PCOS) is a relatively common condition which generates a considerable number of requests for pelvic trans-vaginal (TV) ultrasound (US) scans querying the diagnosis. It is a widely accepted fact that the presence of polycystic ovarian morphology on US by itself is not enough to make a diagnosis of PCOS. This requires correlation with a clinical and/or biochemical profile consistent with hyperandrogenism and clinical and/or biochemical evidence of ovarian dysfunction. Hormonal tests are also essential to rule out other causes for hyperandrogenism or infertility. The purpose of this study was to assess the local accuracy of the diagnosis of PCOS, based on TV US findings and hormonal status and to assess adherence to the current accepted standards as set by the ESHRE (European Society for Human Reproduction and endocrinology)/ ASRM (American Society of reproductive Medicine) Rotterdam criteria (2003). Methods and Materials BACKGROUND: PCOS is considered to be one of the most common endocrine abnormalities amongst women of a reproductive age. Due to its uncertain aetiology, varied presentation and the significant short & long-term implications a diagnosis carries, a consensus regarding definition and diagnostic criteria has been hard to reach. The Rotterdam criteria produced by the ESHRE/ ASRM sponsored (2003) consensus workshop defines PCOS as the presence of two of the following three criteria: 1. ovulatory dysfunction (oligo-/ an-ovulation) 2. hyperandrogenism (clinical and/or biochemical) and 3. polycystic ovarian morphology Page 2 of 20

with the exclusion of other potential causes. The more recent AE (Androgen Excess)-PCOS Society criteria requires BOTH of the following criteria to make a diagnosis of PCOS: hyperandrogenism (clinical or biochemical, or both) ovarian dysfunction (oligo-ovulation/ an-ovulation or polycystic ovaries, or both) Oligo- /an-ovulation 25-30% of all women with oligomenorrhoea or menstrual dysfunction have PCOS. On the other hand, although the majority of women with PCOS will present with overt oligomenorrhoea, 20-30% of women with PCOS may present with a history of eumenorrhoea (but would actually be oligo-ovulatory which can be checked by measuring progesterone in the latter part of the cycle). So women with clinical/ biochemical evidence of hyperandrogenism and apparently normal menstrual cycles should ideally have their end of cycle progesterone levels checked to assess their ovulatory function further to confirm ovulatory function. Hormonal tests may also be required to rule out other causes of ovulatory dysfunction like hypothalamic amenorrhoea or primary ovarian failure. Hyperandrogenism The use of hirsutism as sole criteria for clinical hyperandrogenism is limited due to the following reasons: assessment is still largely subjective scoring scales are not used widely and consistently by clinicians no normative data for large populations is available racial and age-related variations The other potential markers for clinical hyperandrogenism like alopecia and acne are even less studied and reliable. The measurement of circulating androgens is also not perfect given the inaccuracy and inconsistencies with the laboratory methods used. (Ideally, Free Testosterone (Free T) should be calculated from measurements of Total T and serum hormone binding globulin (SHBG) levels). However, given it's superior sensitivity, at the present time biochemically proven hyperandrogenism is probably the best indicator for hyperandrogenism in general. Page 3 of 20

(Note: An elevated LH level or raised LH/FSH ratio is useful in making a diagnosis if positive. However, clinicians should be wary about false negative results in obese women and variability based on the phase of the menstrual cycle during which the test has been pereformed.) Polycystic ovaries With regards to the presence of polycystic morphology on ultrasound assessment, the Rotterdam consensus definition states that at least one of the ovaries should meet at least one of the following criteria: 12 or more follicles of 2-9 mm in size, and/or An ovarian volume of > 10 cc [calculated using the simplified formula for the volume of a prolate ellipsoid (0.5 x length x width x thickness)] [Figure 1] on page 7 It further goes on to state the following recommendations: TV scanning should be used when possible as it has a significantly higher sensitivity and specificity than trans-abdominal scanning. If a dominant follicle (>10 mm) or corpus luteum is seen, the scan should be considered unreliable and repeated during the early follicular phase (day 3-5) of the next menstrual cycle. [Figure 2] on page 7[Figure 3] on page 8 [Figure 4] on page 9 [Figure 5] on page 10 Subjective criteria traditionally used to describe polycystic morphology like stromal echogenicity and follicular distribution are not reliable and should not be used in assessment. Ovarian volume has been proven to be a good surrogate for stromal volume and is more easily and consistently measured. [Figure 6] on page 11 [Figure 7] on page 12 These criteria cannot be applied to women on the OCP as they would have reduced ovarian volume in spite of polycystic morphology "A woman having PCO in the absence of an ovulation disorder or hyperandrogenism ("asymptomatic PCO") should not be considered as having PCOS, until more is known about this situation." [Figure 8] on page 13 [Figure 9] on page 14 Exclusions: Other potential causes for hyperandrogenism and ovulatory dysfunction like dysthyroidism, hyperprolactinaemia, non-classical Congenital Adrenal Hyperplasia, androgen secreting tumours and Cushing's syndrome need to be ruled out using further Page 4 of 20

appropriate hormonal tets among cases where clinical suspicion is high or in high-risk populations. As is obvious from above, not only are biochemical tests currently the most reliable gauge of hyperandrogenism, they are also essential in helping to exclude other causes for hyperandrogenism and infertility. Implications of making a Diagnosis of PCOS: Short Term: Increased risk of infertility and dysfunctional bleeding Long Term: Increased risk of developing obesity, type 2 diabetes mellitus, dyslipidaemia, hypertension, cardiovascular disease (metabolic syndrome) and endometrial carcinoma with the associated anxiety of screening and regular monitoring that this entails. A diagnosis may signify life-long medication, and a considerable psychological burden. Therefore, the diagnosis of PCOS should only be made if absolutely sure based on robust criteria. This study aimed to address the following questions that were raised as a result of our initial analysis of a sample data set: Are all the TV scans performed within the department querying a diagnosis of PCOS appropriately correlated with a biochemical profile for hyperandrogenism - if yes, are the right hormonal tests being used? And if not, are these scans potentially inappropriate, as they are unnecessarily subjecting a large number of women to an invasive examination? Are women who are incompletely assessed being wrongly labelled as having PCOS? How beneficial would it be to departmental efficiency if this issue were rectified? Could this issue be rectified by making hormonal tests compulsory prior to making a request to assess ovaries for polycystic morphology? How many radiology departments within the region were using the Rotterdam ultrasound criteria for reporting on polycystic morphology and how many were aware whether the scans performed were being correlated with a hormonal profile or not? Page 5 of 20

METHODS AND ANALYSIS: The request cards and verified reports of all TV scans performed between 01/01/2008 to 10/04/2008 were acquired. These were then filtered based on the presence of the following keywords within their respective request cards or reports - Polycystic ovaries (PCO)/ Polycystic ovarian syndrome (PCOS)/ Polycystic ovarian disease (PCOD). A total of 143 TV scans were performed which met this criteria. 7 of these were excluded (4 - polycystic ovaries were an incidental finding; 1 - only transabdominal imaging was performed; 1 - patient refused the scan; 1 - patient had the wrong investigation performed). The remaining 136 then formed the patient data base that was analysed in detail along with a review of their respective images, where possible. For the sake of clarity, the data was analysed in two separate ways: Radiological Criteria Adherence Study The first part of the study involved comparing existing practice in the radiology department regarding the TV ultrasound diagnosis of polycystic ovaries with the Rotterdam criteria. Departmental compliance rates were assessed for each of the major criteria stated in the Rotterdam criteria. This was done by checking whether the reports mentioned follicle number, follicle size, ovarian volume, the presence of a dominant follicle, the LMP and the need for hormonal/ biochemical correlation. The reports were also assessed to see how often stromal echogenicity/ volume and follicular distribution were being used as criteria. (21 out of the 136 women were excluded from this part of the study as they did not have any radiological findings to suggest PCO and would therefore introduce unfair bias to the compliance of operator reporting) Hormonal Correlation Study The second part of the study involved checking whether appropriate hormonal correlation/ biochemical tests had been performed in association with the scan in question in order to confirm or refute the diagnosis of PCOS. To this end we considered any hormonal tests performed 12 months prior to or 3 months after the date of the scan in question as being relevant/ associated. As per the recommendations of the Rotterdam and AEPCOS Society, a free T/ FAI was considered an appropriate primary test to seek hormonal correlation. LH/FSH ratio, prolactin, estradiol and progesterone levels were considered Page 6 of 20

as accessory investigations. Results were checked using the hospital ICM and pathology MasterLab systems. (19 out of the 136 women were excluded from this part of the study as they were known cases of PCOS as per their request cards and therefore given the benefit of the doubt that they may have had appropriate hormonal tests in the past, i.e., before 12 months) An informal telephone audit was conducted of the prevalent standards/ guidelines used by 8 other radiology departments within the region, selected at random. Images for this section: Fig. 1: Image 1: Positive polycystic ovarian morphology on TV US images of a 26 year old woman showing an enlarged ovary with a volume of 11cc and more than 12 follicles each of which measures between 2-9mm in size. Page 7 of 20

Fig. 2: Image 2: TS image of an ovary with a dominant follicle measuring 12mm in size in a 27 year old woman who underwent TV US scanning as part of her assessment for PCOS. Note how the ovary does not fit the criteria for PCO morphology on this scan. Page 8 of 20

Fig. 3: Image 3: LS image of an ovary with a dominant follicle measuring 12mm in size in a 27 year old woman who underwent TV US scanning as part of the assessment for PCOS. Note how the ovary does not fit the criteria for PCO morphology on this scan. Page 9 of 20

Fig. 4: Image 4: The same woman whose scan showed a dominant follicle and unconvincing evidence of PCO morphology [Images ] was re-scanned on day 5 of her cycle. On this occasion, the TV-US scan (TS) of the same ovary demonstrates more than 12 follicles of 2-9mm size, thus fulfilling the Rotterdam criteria for PCO. This emphasises the unreliability of a scan done in the presence of a dominant follicle or corpus luteum. Page 10 of 20

Fig. 5: Image 5: The same woman whose scan showed a dominant follicle and unconvincing evidence of PCO morphology [Images ] was re-scanned on day 5 of her cycle. On this occasion, the TV-US scan (LS) of the same ovary demonstrates more than 12 follicles of 2-9mm size, thus fulfilling the Rotterdam criteria for PCO. This emphasises the unreliability of a scan done in the presence of a dominant follicle or corpus luteum. Page 11 of 20

Fig. 6: Image 6: This 38 year old woman had a scan request for pelvic pain which stated "known PCOS". Her past TV-US reports mentioned PCO morphology based on the findings of "enlarged ovaries" and "multiple peripheral follicles". However, a review of these images (TS) showed that the ovaries did not fit the Rotterdam criteria by either ovarian volume or follicle number criteria. Moreover, she has not had any relevant biochemical tests to confirm hyperandrogenism or rule out other causes to date. Page 12 of 20

Fig. 7: Image 7: This 38 year old woman had a scan request for pelvic pain which stated "known PCOS". Her past TV-US reports mentioned PCO morphology based on the findings of "enlarged ovaries" and "multiple peripheral follicles". However, a review of these images showed that the ovaries did not fit the Rotterdam criteria by either ovarian volume or follicle number criteria. Moreover, she has not had any relevant biochemical tests to confirm hyperandrogenism or rule out other causes to date. Page 13 of 20

Fig. 8: Image 8: The TV-US scan of this 23 year old woman demonstrates an LS image of an ovary that fulfills the Rotterdam criteria for PCO with regards to follicle number and size. On subsequent scan requests her relevant history included "known PCOS". However, she had undergone appropriate biochemical tests which were all negative and therefore she had PCO (polycystic ovarian morpholgy) not PCOS (polycystic ovarian syndrome). Page 14 of 20

Fig. 9: Image 9: The TV-US scan of this 23 year old woman demonstrates an TS image of an ovary that fulfills the Rotterdam criteria for PCO with regards to follicle number and size. On subsequent scan requests her relevant history included "known PCOS". However, she had undergone appropriate biochemical tests which were all negative and therefore she had PCO (polycystic ovarian morpholgy) not PCOS (polycystic ovarian syndrome). Page 15 of 20

Results RESULTS: Radiological Criteria Adherence Study: [Table 1] on page 17 Within the radiological criteria segment of the audit, we found that apart from the mention of the LMP (74%) adherence to the Rotterdam criteria was quite poor. Less than 5% of the reports stated follicle number (however, in the absence of prior agreed departmental consensus on the minimum number of follicles required to meet the description of being polycystic, the use of the descriptor "multiple" could be justified and this took the adherence rate to 100%). Less than 40% stated follicular size and ovarian volume in their reports. Only 25% of the reports specified that hormonal correlation was required to make a diagnosis of PCOS, even if polycystic ovaries were seen on scanning. Not surprisingly, or consequently, a large number of reports used stromal echogenicity/ volume (50%) and follicular distribution (70%) to describe polycystic morphology. Hormonal Correlation Study: [Table 2] on page 18 59 women (50.4% of those who underwent scanning as part of the assessment for PCOS) did not have any relevant biochemical tests to establish hyperandrogenism or rule out other causes. It can be argued that given these scans would not help towards making a complete diagnosis that they are potentially wasted or inappropriate. Amongst the 58 women that did have hormonal assays, 45 had negative assays and 13 had positive assays. In keeping with current literature approximately 30% of the women with negative assays have PCO morphology (but no PCOS). Among those with positive hormonal assays, 50% had PCO morphology on scanning. The remaining 50% would still fall under the category of PCOS as per the Rotterdam and AE-PCOS Society criteria as long as they fit the definition and oligo-/an- ovulation. Page 16 of 20

18.8% of all the women who underwent scanning and had negative biochemical tests had no evidence of PCO. 3.4% ended up having the negative biochemical tests after their scans were done. Therefore, this 22.2% could be considered as possibly having had scans which were unnecessary as their biochemical tests were negative. Informal Telephone Audit of Regional practice: Out of the 8 radiology departments contacted within the region, only one had guidelines for diagnosing PCO along the lines of the Rotterdam criteria. The remainder either had only informal training based guidelines or criteria based on stromal echogenicity/ volume and follicular distribution. 3 of the trusts were currently in the process of trying to update their guidelines. Images for this section: Fig. 1: Table 1: Results of the study that looked into the adherence or compliance to the Rotterdam Radiological Criteria for diagnosis of PCOS. Informal departmental criteria, Page 17 of 20

although not recognised by the Rotterdam definition, were also assessed for frequency of usage. Fig. 2: Table 2: Results of the study that looked into hormonal/ biochemical correlation of TV-US scans in making a diagnosis of PCOS. Page 18 of 20

Conclusion CONCLUSION: It is widely accepted that there are serious limitations to using clinical signs such as hirsutism and oligo-/ an-ovulation as sole indicators of hyperandrogenism or ovarian dysfunction. Therefore, valid measurements of free testosterone, estradiol and other related hormones would be necessary to - 1) make a safe diagnosis of PCOS in conjunction with TV US findings of polycystic ovarian morphology and 2) exclude other potential causes for hyperandrogenism and infertility. Also, it is a well documented fact that almost 20% of women with polycystic ovarian morphology (who constitute almost 20% of the total population of women in the reproductive age group) do not have the positive biochemical profile to support a diagnosis of PCOS. Therefore, excessive reliance on the presence of polycystic ovarian morphology without proper hormonal/ biochemical correlation runs the risk of labelling a large population of women with a condition that has immense short and long-term implications. Our study showed that requests with "? PCOS" as an indication constituted a significant proportion of all TV US scan requests (% of all requests) received by the department. A significant number of these scans that were performed do not appear to have been correlated with biochemical results and therefore, for all practical purposes, represent potentially wasted scanning time and machine usage. Obviously, this in turn has serious financial implications to the Trust. All of this gives more weight to our argument that hormonal tests should precede subjecting such a large number of the female population to TV US scanning, a relatively invasive procedure. This would also reduce the risk of women undergoing TV US scanning as their first line investigation and then not having appropriate subsequent hormonal testing to either confirm or refute a complete diagnosis of PCOS. References REFERENCES: Page 19 of 20

1. 2. 3. 4. 5. The Rotterdam ESHRE/ ASRM - sponsored PCOS consensus workshop group (2004) Revised 2003 consensus on diagnostic criteria and long-term health risks related to PCOS. Hum Reprod, 19, pp 41-7 Balen, A.H., Laven, J.S.E., Tan, S., Dewailly, D. (2003) Ultrasound assessment of the polycystic ovary: international consensus definitions. Hum Reprod Update, 9, pp 505-14 Franks, S. (2005) Diagnosis of Polycystic Ovarian Syndrome: In Defence of the Rotterdam Criteria. J Clin Endocrinol Metab, 91, 786-9 Azziz, R., Carmina, E., Dewailly, D., DIamanti-Kandarakis, E., EscobarMorreale, H.F., Futterweit, W., et al (2009) The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril, 91, 456-88 Balen, A., Homburg, R., Franks, S., (2009) Defining polycystic ovary syndrome: New criteria say that hyperandrogenism and ovarian dysfunction are needed. BMJ, 338: a2968 Personal Information Dr. G Tony Specialist Registrar City General Hospital University Hospital North Staffordshire NHS Trust Stoke-on-Trent, UK. Correspondence: 48, Spitfire Way Stoke-on-Trent ST6 5XQ Staffordshire, UK Mob: 07960146176 Page 20 of 20