Association between ultrasound features of adenomyosis and severity of menstrual pain

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1 Ultrasound Obstet Gynecol 2016; 47: Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: /uog Association between ultrasound features of adenomyosis and severity of menstrual pain J. NAFTALIN, W. HOO, N. NUNES, T. HOLLAND, D. MAVRELOS and D. JURKOVIC Gynaecology Diagnostic and Outpatient Treatment Unit, Elizabeth Garrett Anderson Wing, University College London Hospitals NHS Trust, London, UK KEYWORDS: adenomyosis; endometriosis; painful periods; transvaginal ultrasound ABSTRACT Objective To investigate the association between the ultrasound features of adenomyosis and the severity of menstrual pain. Methods This was a prospective observational study set in the general gynecology clinic of a university teaching hospital between January 2009 and January A total of 718 consecutive premenopausal women aged between 17 and 55 years attended the clinic and underwent structured clinical and transvaginal ultrasound examinations in accordance with the study protocol. Morphological features of adenomyosis on ultrasound scan were recorded systematically. A quantitative assessment of menstrual pain was made by completion of a numerical rating scale (NRS). Results One hundred and fifty-seven (21.9% (95% CI, %)) women were diagnosed with adenomyosis on ultrasound. Multiple linear regression analysis showed that an ultrasound diagnosis of adenomyosis and ultrasound and laparoscopic diagnoses of endometriosis were significantly associated with menstrual pain when measured by an NRS. In addition, there was a statistically significant positive correlation between the severity of menstrual pain and the number of ultrasound features of adenomyosis seen. Conclusions Women with ultrasound features of adenomyosis have more severe menstrual pain than do women without these features. The positive correlation between the number of ultrasound features of adenomyosis and the severity of menstrual pain could form the basis of a clinically relevant grading system for adenomyosis. A classification of severity of adenomyosis based on the number of ultrasound features present is a novel concept that should be evaluated prospectively in different populations. Copyright 2015 ISUOG. Published by John Wiley & Sons Ltd. INTRODUCTION Adenomyosis is a benign condition of the uterus defined by the presence of endometrial glands and stroma within the myometrium. Original descriptions of adenomyosis reported an association between the disease and a great deal of pain 1. Several later studies reported similar findings 2 4, but others have not shown significant differences in the prevalence of adenomyosis in women with and without a history of dysmenorrhea 5 7.Mostof these studies used retrospective histological examination of hysterectomy specimens to diagnose adenomyosis and compare it with clinical symptoms. The main problem with the use of histology for the diagnosis of adenomyosis in these studies is the heavy selection bias incurred 8.In addition, it is very difficult in retrospective studies to account for confounding variables such as endometriosis, which is a common cause of menstrual pain in women of reproductive age. Furthermore, the majority of studies made no attempt to use a standardized tool in their assessment of menstrual pain. Transvaginal ultrasound has recently been used for the non-invasive diagnosis of adenomyosis and to study both its prevalence and its association with menorrhagia The aim of this study was to investigate the association between ultrasound features of adenomyosis and the severity of menstrual pain. METHODS This was a prospective observational study of premenopausal women attending our general gynecology clinic. Women were considered to be premenopausal if they were beyond menarche but had not yet reached menopause. Women who did not undergo transvaginal ultrasound examination, those who had previously undergone a hysterectomy, were amenorrheic or who had not had a period for more than 60 days at the time of Correspondence to: Mr D. Jurkovic, GDOTU, Lower Ground floor, EGA Wing, UCH, London, NW1 2BU, UK ( davor.jurkovic@uclh.nhs.uk) Accepted: 22 October 2015 Copyright 2015 ISUOG. Published by John Wiley & Sons Ltd. ORIGINAL PAPER

2 780 Naftalin et al. assessment were excluded from the study, as were women with suspected malignancy. For all women a detailed clinical history was taken prior to the ultrasound examination. They were also asked about frequency and duration of menstrual periods and about any episodes of intermenstrual or postcoital bleeding. They were also asked to quantify their degree of menstrual pain using a numerical rating scale (NRS). The NRS is a scale in which the extremes are no pain (a score of 0) and pain as bad as it could be (a score of 10). Completion of the scale involved putting a mark on it to represent the intensity of the worst pain they experienced with their last period. NRSs have been shown to be sensitive and simple to use, with a low failure rate, and are preferred over traditional visual analog scales for the assessment of pain intensity They have been shown to have sufficient reliability and validity to be used in clinical research 15. The women in the study were also asked about any medication they were taking. Medication that can be used for the treatment of painful periods was considered as such, irrespective of whether that was the indication for its use. These included analgesics, combined hormonal contraceptives, progesterone-only contraceptives, cyclical progestogens, the levonorgestrel-releasing intrauterine system and gonadotropin-releasing hormone analogs. Transvaginal ultrasound examination was carried out using a 4 9-MHz probe with a three-dimensional (3D) facility (Voluson E8, GE Medical Systems, Zipf, Austria). All transvaginal ultrasound scans were performed in a standardized fashion by a single operator (J.N.) as follows: first the uterus was examined in the transverse plane to identify the cervical canal and the uterine cavity. The probe was then rotated 90 and the uterus and endometrium were visualized in the longitudinal plane. Fibroids were diagnosed based on direct visualization using previously described diagnostic criteria 16. The criteria for the ultrasound diagnosis of adenomyosis have been reported previously. Briefly, the diagnosis of adenomyosis was made if one or more of the following features were present: asymmetrical myometrial thickening, myometrial cysts, linear striations, parallel shadowing, adenomyomas, hyperechoic islands and an irregular endometrial myometrial junction on either B-mode or 3D imaging 10,17. The examination was then concluded by examining the adnexa and the pouch of Douglas, looking for features of endometriosis. Women were considered to have endometriosis if it had been diagnosed previously on laparoscopy or if the diagnosis was made at the time of the ultrasound scan. An ultrasound diagnosis of endometriosis was made if ovarian endometriomas or endometriotic nodules were visualized on ultrasound. Ovarian cysts were classified as endometriomas when they appeared as well-circumscribed thick-walled cysts that contained homogeneous low-level internal echoes ( ground glass ) 18. Endometriotic nodules were typically visualized as stellate hypoechoic or isoechogenic solid masses with irregular outer margins that were tender on palpation and fixed to the surrounding pelvic structures 19. Statistical analysis Statistical analysis was performed using multiple linear regression, as the NRS score was considered to be a continuous measurement. Variables included in the statistical analysis were a diagnosis of adenomyosis, endometriosis or fibroids and whether or not women were receiving treatment that would reduce menstrual pain. Three analyses were performed using predetermined combinations of predictor variables. The models were: Model 1: Adenomyosis, fibroids, endometriosis and medication affecting menstrual pain; Model 2: Number of ultrasound features of adenomyosis, fibroids, endometriosis and medication affecting menstrual pain; Model 3: Each ultrasound feature of adenomyosis (as independent variable), fibroids, endometriosis and medication affecting menstrual pain. A kappa analysis was performed to determine the level of agreement between ultrasound and histological diagnoses of adenomyosis in those women who subsequently underwent a hysterectomy. Statistical analysis was performed using SPSS software (SPSS Inc., Chicago, IL, USA), and P < 0.05 was regarded as statistically significant. Ethical approval was sought from the local research ethics committee, who approved the study and deemed that full ethical approval was not required. RESULTS A total of 891 consecutive premenopausal women attended the clinic between January 2009 and January 2010, of whom 173 women were excluded; 88 women had not had a period for more than 60 days, 47 did not undergo a transvaginal scan, 35 had previously undergone a hysterectomy and three were suspected of having a gynecological malignancy after their assessment. Thus, 718 women were entered into the study. The median age of the participating women was 38 (interquartile range, 30 43) years. Three hundred and seven (42.8% (95% CI, %)) women were nulligravid and 427 (59.5% (95% CI, %)) women were nulliparous. The primary indications for ultrasound examination, as determined by the referring physician, are listed in Table 1. The most common indications for ultrasound scans were pelvic pain (n = 130), menorrhagia (n = 118) and subfertility (n = 115). Painful periods alone was the primary indication for 18 women and menorrhagia alongside painful periods was the primary indication in a further 31. Following the ultrasound assessment, 157 (21.9%) women were diagnosed with adenomyosis, 244 (34.0%) with fibroids, 20 (2.8%) with endometriosis and 351 (48.9%) with none of these diagnoses. A further 37 (5.2%) women were considered to have endometriosis for the purposes of data analysis, having had it confirmed laparoscopically in the past. Sixty-nine of the 157 women with an ultrasound diagnosis of adenomyosis had a concomitant diagnosis

3 Adenomyosis and menstrual pain 781 Table 1 Primary indications for transvaginal ultrasound examination, as determined by referring physician, in 718 premenopausal women Principal indication n (%) Pelvic pain 130 (18.1) Menorrhagia 118 (16.4) Subfertility 115 (16.0) Intermenstrual or postcoital bleeding 68 (9.5) Oligomenorrhea 68 (9.5) Menorrhagia and painful periods 31 (4.3) Painful periods 18 (2.5) Dyspareunia 12 (1.7) Recurrent miscarriage 9 (1.3) Other 149 (20.8) of fibroids, endometriosis or both. In the subgroup of 157 women diagnosed with adenomyosis, asymmetrical myometrial thickening was present in 86 (54.8%), parallel shadowing in 23 (14.6%), linear striations in 54 (34.4%), myometrial cysts in 72 (45.9%), hyperechoic islands in 117 (74.5%), adenomyomas in 41 (26.1%) and an irregular endometrial myometrial junction in 101 (64.3%) cases. The results of the multiple linear regression analysis in which adenomyosis was assessed as a binary variable (Model 1) showed a strong independent positive association between NRS score and the presence of endometriosis and between NRS score and the presence of adenomyosis (Table 2). Neither the presence of fibroids nor receiving treatment that would ameliorate menstrual pain was significantly associated with NRS score. The regression analysis that included the number of ultrasound features of adenomyosis as a variable (Model 2) showed a significant positive association between the number of ultrasound features of adenomyosis present and NRS score (Table 3). This relationship is illustrated graphically in Figure 1. A breakdown of the number of each individual ultrasound feature of adenomyosis seen in the study population is given in Table 4. The final regression analysis included the individual features of adenomyosis (Model 3) in a single analysis alongside fibroids, endometriosis and treatment, and showed that, of the individual ultrasound features, only asymmetrical myometrial thickening and an irregular endometrial myometrial junction were significantly associated with increasing NRS score (Table 5). Of the 20 women who underwent hysterectomy within 2 years of assessment, nine did so for menorrhagia, four for prolapse, three for pain, two for urinary symptoms, one for pressure symptoms and one for endometrial hyperplasia. Four women had a large number of fibroids and were not used for comparison between ultrasound and histology diagnoses, as their pathologies became the primary focus of histological examination. The overall uterine size in women with high numbers of fibroids made it difficult to obtain systematic representative sections from every part of the pathological specimens. The sensitivity and specificity of ultrasound in diagnosing adenomyosis in the remaining women were 71.4% (95% CI, %) and 88.9% (95% CI, Table 2 Results of multiple linear regression analysis to determine scale (NRS), and studied variables, of which adenomyosis was studied as a binary variable (Model 1), in 718 premenopausal women Fibroids 0.2 ( 0.3 to 0.6) 0.40 Endometriosis 1.5 (0.7 to 2.2) < Treatment 0.1 ( 0.6 to 0.4) 0.61 Adenomyosis 0.9 (0.4 to 1.4) < between patients with and those without each factor. Treatment Table 3 Results of multiple linear regression analysis to determine scale (NRS), and studied variables, of which the number of ultrasound features of adenomyosis was included as a variable (Model 2), in 718 premenopausal women Fibroids 0.2 ( 0.2to0.6) 0.38 Endometriosis 1.4 (0.7 to 2.2) < Treatment 0.1 ( 0.6to0.4) 0.66 Number of ultrasound < features of adenomyosis Linear term 0.1 ( 0.5to0.4) Squared term 0.1 (0.0 to 0.2) between patients with and those without each factor, except for number of features, for which they represent the change in NRS score for an increase of 1 in the number of features. Treatment NRS score Number of ultrasound features 6 7 Figure 1 Relationship between number of ultrasound features of adenomyosis and painful periods, as evaluated by a numerical rating scale (NRS)., Predicted line; gray area shows 95% CI %), respectively. The positive predictive value was 83.3% (95% CI, %) and the negative predictive value was 80.0% (95% CI, %). A kappa analysis showed a good level of agreement between histology and transvaginal ultrasound in the diagnosis of adenomyosis (κ = (95% CI, ); standard error of κ, 0.199). A 2 2 table was constructed to compare ultrasound and final histological diagnoses in the 16 women who had a hysterectomy (Table 6).

4 782 Naftalin et al. Table 4 Number of ultrasound features of adenomyosis seen in 157 premenopausal women diagnosed with adenomyosis on transvaginal ultrasound examination Ultrasound features seen (n) Women (n (%)) 1 17 (10.8) 2 39 (24.8) 3 42 (26.8) 4 31 (19.7) 5 17 (10.8) 6 9 (5.7) 7 2 (1.3) Table 5 Results of multiple linear regression analysis to determine scale (NRS), and studied variables, of which individual ultrasound features of adenomyosis were included as variables (Model 3), in 718 premenopausal women Fibroids 0.2 ( 0.2 to 0.7) 0.32 Endometriosis 1.4 (0.6 to 2.1) Treatment 0.1 ( 0.6to0.4) 0.65 Asymmetrical myometrial 1.0 (0.1 to 2.0) 0.02 thickening Parallel shadowing 0.4 ( 1.0 to 1.7) 0.60 Linear striations 0.1 ( 1.1to0.9) 0.86 Myometrial cysts 0.1 ( 1.0to0.8) 0.85 Hyperechoic islands 0.3 ( 1.1to0.6) 0.53 Adenomyomas 0.3 ( 1.3to0.7) 0.57 Irregular endometrial myometrial junction 1.1 (0.2 to 2.1) 0.02 between patients with and those without each factor. Treatment Table 6 Kappa analysis assessing agreement between ultrasound diagnosis of adenomyosis and final histological diagnosis in 16 premenopausal women who underwent hysterectomy within 2 years of ultrasound assessment Ultrasound Histology Adenomyosis (n) No adenomyosis (n) Total (n) Adenomyosis No adenomyosis Total κ = (95% CI, ) (good agreement). Standard error of κ = DISCUSSION Our study shows an independent statistically significant association between the ultrasound features of adenomyosis and the severity of menstrual pain. There was also a significant positive correlation between the number of ultrasound features of adenomyosis and NRS score, as well as a positive correlation between the presence of two specific ultrasound features of adenomyosis and NRS score i.e. an irregular endometrial myometrial junction and asymmetrical myometrial thickening. The main strength of our study is that ultrasound was used to diagnose adenomyosis, minimizing the heavy selection bias seen when histology was used to assess symptomatology in the past. This also allowed for the inclusion of a relatively large number of women. All ultrasound scans were performed using top-of-the-range equipment by a single operator, thereby minimizing interobserver variability. Another major strength of the study was its prospective nature. The fact that all the demographic, ultrasound and pain data were collected prospectively means that it is likely to be more accurate than data used in retrospective studies. Moreover, the use of multiple linear regression analysis allowed the study to account for the presence of concomitant endometriosis, fibroids and the use of medication that might alleviate menstrual pain. As far as we are aware, this is the first prospective study to use ultrasound and a statistical analysis that accounts for numerous, potentially confounding, variables. A further strength of our study is that the assessment of pain was not just limited to the presence or absence of menstrual pain. The use of a validated, reproducible pain scoring system allowed a quantitative assessment of menstrual pain to be made. Without this quantitative assessment, we would not have been able to discover the positive, statistically significant correlation between the number of ultrasound features of adenomyosis and the severity of menstrual pain. A potential weakness of the study is the lack of histological confirmation of the diagnosis in the majority of women studied; however, in those women in the study population who underwent hysterectomy, there was good agreement between ultrasound and histological diagnoses. Similarly we were unable to use the gold standard test of laparoscopy to confirm or exclude the presence of endometriosis in our study population. It is, however, not possible to perform a laparoscopy on every woman attending a gynecology clinic with painful periods or pelvic pain. It has also been shown that many women with evidence of severe endometriosis on ultrasound are asymptomatic, therefore even if endometriosis is present at laparoscopy that is not proof that the condition is definitely the cause of the pain. We feel that our methodological approach reflects modern clinical practice and that our findings will be helpful to clinicians looking after gynecology patients. Some of the histological studies that found an association between the presence of adenomyosis and painful periods also found a correlation between the severity of adenomyosis and the prevalence of painful periods. Bird et al. 3 reported that painful periods were present in 4.3% of women whose uterus had histologically defined Grade I penetration, 42.4% with Grade II penetration and 83.3% with Grade III penetration. Levgur et al. 20 reported that increased histological severity of adenomyosis correlated with clinical symptoms. These findings are consistent with the results of our study, which also showed a positive correlation between the number of ultrasound features of adenomyosis and the severity of menstrual pain as defined by NRS score. In addition to finding a correlation between the number of ultrasound features of adenomyosis and the degree

5 Adenomyosis and menstrual pain 783 of menstrual pain, we also found that two particular ultrasound features of adenomyosis were associated with the degree of menstrual pain: asymmetrical myometrial thickening and an irregular endometrial myometrial junction. These individual features were also found to be significantly associated with menorrhagia 11. It is perhaps unsurprising that asymmetrical myometrial thickening has a greater correlation with symptoms than do other ultrasound features of adenomyosis, given that in order for this feature to be seen, the disease must have affected a significant proportion of the total myometrium. It is unclear why the presence of an irregular endometrial myometrial junction should be associated with painful periods, but these findings suggest that the morphological features of adenomyosis are of varying significance, and further work is needed to investigate this relationship. There remains no commonly accepted mechanism to explain how adenomyosis might cause menstrual pain. Bergeron et al. 21 suggested that it might be caused by myometrial irritability and inflammation secondary to bleeding into foci of adenomyosis, but this has yet to be proven. It may be secondary to the increased menstrual loss reported by women with adenomyosis 11. Zhang et al. 22 studied the presence of particular types of nerve fibers in women with adenomyosis and painful fibroids and concluded that PGP9.5-immunoactive nerve fibers may play a role in pain generation. Other authors have found a positive correlation between the severity of pain and the concentration of nerve fibers in adenomyotic hysterectomy specimens 23. However these studies were retrospective and had small numbers of participants, and it is clear that further work is needed to investigate this relationship. Our study did not find an association between the use of medication that would reduce menstrual pain and NRS score. While one might expect lower NRS scores in women undergoing treatment, owing to the anticipated ameliorating effect of the medication on pain, it is likely that the magnitude of any potential association may have been reduced by the fact that women with more severe menstrual pain would be more likely to take medication to reduce it. A better understanding of the relationship between adenomyosis and pain can help improve counseling of women regarding the significance of this common condition and make treatment options more focused. The positive relationship between the number of ultrasound features and the degree of menstrual pain adds to previous work showing a similar relationship with regard to menorrhagia 11. 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