Transvaginal sonographic ovarian findings in a random sample of women years old

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1 Ultrasound Obstet Gynecol 1999;13: Transvaginal sonographic ovarian findings in a random sample of women years old C. Borgfeldt and E. Andolf Department of Obstetrics and Gynecology, University Hospital, Lund, Sweden Key words: TRANSVAGINAL SONOGRAPHY, OVARIAN CYSTS, OVARIAN NEOPLASM, OVARIAN CANCER, ADNEXAL LESION, PREMENOPAUSE, POLYCYSTIC OVARY SYNDROME, OVARIAN VOLUME ABSTRACT Objective To investigate the occurrence rate of adnexal lesions in premenopausal women. Methods A random sample of women years old was invited to undergo a transvaginal ultrasound examination, and 335 women were examined. The criteria used to define an adnexal lesion were either a cystic lesion with its largest diameter of at least 25 mm within the pelvic region, or the appearance of solid parts in any lesion regardless of size. Results Adnexal lesions were found in 26/335 cases, (7.%) (95% confidence interval (CI), ± 2.9%). The occurrence rate of ovarian cysts was 22/335 (6.6%) (95% CI, ± 2.7%). There were no differences between the women with or without ovarian cysts related to age, smoking habits, parity or body mass index. At follow-up 3 months later, 1 of the 22 (2%) cysts had disappeared (95% CI, ± 16%). Women using progesterone contraception (either oral contraception or an intrauterine device with levonorgestrel) had a significantly higher relative risk of 2.7 (95% CI, ) of functional cysts as compared to women with natural cycles. Polycystic ovaries were found in 10.2% (95% CI, ± 4.2%) of the women not using any hormonal contraception. The mean volumes of the polycystic ovaries were significantly larger compared to those in natural cycles. Conclusion Adnexal lesions are common in asymptomatic women in the age group years, but four out of five ovarian cysts disappeared spontaneously after 3 months. The ultrasound appearance of the cyst, the woman s family history and her own feelings must be considered if a persisting cyst is to be surgically removed or followed by repeated transvaginal ultrasound. INTRODUCTION Before the advent of ultrasonography, management of ovarian enlargement was easy. Prompt surgical removal was recommended in postmenopausal patients. In menstruating women, surgery was recommended for persisting lesions. With the introduction of ultrasound it became possible to visualize the internal morphology of the lesion and differentiation of cysts became feasible. Small non-palpable tumors were now detectable but their significance in relation to ovarian cancer was unclear. As a result, even lesions as small as 3 mm in postmenopausal women were regarded with suspicion and many of these lesions were surgically removed, especially after the introduction of laparoscopic surgery, which was considered to be less traumatic. Whether this development is of benefit for the patient is unclear, especially as it has been shown that a higher rate of surgery for ovarian cysts is not associated with an earlier diagnosis of ovarian cancer 1. The rate of occurrence of ovarian lesions in elderly postmenopausal women has been more thoroughly investigated than in menstruating women. More studies have been conducted in these older age groups as the risk for ovarian cancer is higher. In asymptomatic postmenopausal women, lesions have been detected in 3 17% depending on the ultrasound equipment and the smallest size for inclusion in the study 2,3. In the latter study with the 17% prevalence, more than half of the lesions were below 1 cm in size. The rate of occurrence of ovarian lesions in menstruating women is unclear. Published studies have been either designed to measure the size of the ovaries 4 or performed in a selected group of women 5, in women over 40 years of age 6,7 or to detect polycystic ovaries. The aim of this study Correspondence: Dr E. Andolf, Department of Obstetrics and Gynecology, University Hospital, S Lund, Sweden ORIGINAL PAPER 345 Received Revised Accepted

2 was to investigate the rate of occurrence of adnexal lesions and ovarian findings in a random sample of women years old. METHODS A random sample of women years old living in the county of Lund was selected from the population register in March This register is connected to the South Swedish Cancer Register (SSCR) where all cancers in this area are noted. Patients treated for ovarian and endometrial cancer were excluded. Only Swedish citizens were included. The data concerning parity from the nonparticipating group were obtained from the Swedish Birth Register. According to statistical calculation, 360 women needed to be examined on the assumption that 10 ± 3% of the women would have an adnexal lesion and a 95% confidence interval (CI) was used. In the period March 1996 to September 1997, a letter was sent to 554 women inviting them to have a transvaginal ultrasound examination. If no contact was established, another letter was sent and thereafter the woman was contacted by telephone if possible. All women were examined by one of the two authors with an Acuson 12XP/10 ultrasound machine with a 7.0-MHz transvaginal transducer or a Hitachi EBU 565 equipped with a 6.5-MHz transducer. The ovaries were measured in three planes: the length in an oblique sagittal section, and the width and height in the frontal section after a 90 rotation of the transducer. The criterion used to define an adnexal lesion was a cystic lesion within the pelvis with its largest diameter of at least 25 mm, or solid parts in any lesion regardless of size. The ovarian volume was calculated using the formula for an ellipsoid, (π width depth length)/6. The women with adnexal lesions were excluded from the calculation of mean ovarian volumes. Polycystic ovaries were defined as ten or more cysts 2 mm in diameter associated with an increase in ovarian stroma 9. A pelvic bimanual examination was performed on each woman. All were asked to fill in a questionnaire regarding previous illness, menstrual periods, method of contraception, pregnancies and deliveries. Height, weight, smoking habits, occupation and civil status were noted. All women with an ovarian lesion were scheduled for a repeat scan 3 months later, regardless of the phase of the menstrual cycle. If the ovarian lesion was unchanged or had increased in size, surgery was recommended. The study was approved by the Ethical Committee of the Medical Faculty, Lund University, Sweden. Stastistical methods For statistical analysis, the χ 2 test without Yates correction and the paired t test were used. Two-tailed p values were given with 5% as the level of significance, if not otherwise noted. Confidence intervals were calculated from the exact binomial distribution or the normal distribution, where appropriate. One-way ANOVA and subsequent post hoc analysis were used to test differences in the ovarian volumes between the groups. Simple linear regression analysis was used when correlating body mass index, age and parity to ovarian volumes. Non-parametric regression analysis was used to model the development of the ovary over the menstrual cycle. All statistical analyses were carried out with the aid of MS Excel and SPSS programs on an IBM compatible personal computer. RESULTS In total, 554 women were invited to participate. In 6 cases, the exclusion criteria were fulfilled by the women being mentally retarded (n = 1), being pregnant (n = 20), having moved out of the catchment area during the study period (n = 56), having undergone salpingoophorectomy or being under gynecological or surgical treatment at the time of the study (n = 9). Of the remaining women, 133 declined the invitation, the reasons for refusal not being systematically reviewed. Many claimed they were short of time and others did not want to participate in research. The number of malignant tumors (cases with cancer of the uterus and ovaries had already been excluded) reported to the SSCR were few and similar in the non-participating group and the examined group. The non-participating group was younger than the examined group with a mean of 31.5 years (SD 4.6) vs years (SD 4.6) (p < 0.05). They more frequently lived alone, 77/133 (5%) vs. 3/335 (25%) (p < 0.001). The non-participating group also had fewer children in the age groups of years, 1.2 children vs. 1.7 (p < 0.05), while there was no difference in parity in the age groups of years. The percentages of women born outside Sweden were equal in both groups. In total, 335 of the 46 women without exclusion criteria were examined (72%). Adnexal lesions were found in 26 cases (7.%) (95% CI, ± 2.9%), consisting of 22 ovarian cysts, one para-ovarian cyst, two cases of hydrosalpinx, and one solid tumor. The solid tumor fulfilled the criteria for a dermoid 10 and was unchanged at follow-up. The occurrence rate of ovarian cysts with a size of 25 mm or more (largest diameter) was 6.6% (22/335) (95% CI, ± 2.7%). The 22 cysts were unilocular except for one with several septae, and all were without solid parts. Six cysts were mm, ten cysts were mm, five cysts were mm, including the multilocular cyst, and one cyst was 111 mm. In 12 women, cystic areas of mm were found in at least one ovary. At follow-up 3 months later, 1 of the 22 (2%) cysts had disappeared (95% CI, ± 16%). Three of the women with persistent cysts underwent laparascopic cystectomy, including the woman with multilocular cysts, and one woman is currently being followed with repeat transvaginal ultrasound examinations. All removed cysts were benign, non-functional cysts. There were no differences between the women with or without ovarian cysts related to age (Table 1), smoking habits (9/22 vs. 70/309), parity with 1.5 children (SD 1.4) 346 Ultrasound in Obstetrics and Gynecology

3 vs. 1.3 (SD 1.2), and body mass index 22.0 (SD 2.) vs (SD 3.6). There was an association between different types of hormonal contraception and ovarian cysts (Table 2). Only two of the 1 women on combined second- or thirdgeneration oral contraceptives had cystic lesions larger than 25 mm and ten had follicles of mm. Five out of 41 women using an intrauterine device releasing 20 µg/24 h levonorgestrel had an ovarian cyst, which makes a relative risk of 5.5 (95% CI, ) compared with women with an ovarian cyst using a combined oral contraceptive. All these five cysts disappeared within 3 months. Combining the groups using low-dose progestogen-only contraceptives (intrauterine device releasing 20 µg/24 h levonorgestrel or oral administration of levonorgestrel 30 µg/24 h), eight out of 53 women had an ovarian cyst, with a relative risk of 7.0 (95% CI, ) compared with women using combined oral contraceptives. We were not able to identify ten of the expected 662 ovaries (1.5%). Eight ovaries had been removed in the 335 women. In some cases, we could visualize the ovaries but were not able to measure all three dimensions. There were no significant differences between the mean ovarian volumes of the right and the left ovaries in any of the groups with different contraception methods (Table 3). Table 1 Examined Ovarian cysts Age (years) n n % 95% CI Presence of ovarian cysts related to age Total CI, confidence interval Oral contraceptive users had significantly smaller ovarian volumes than women with natural cycles, intrauterine device users, and the users of intrauterine devices releasing levonorgestrel (p < 0.01). No differences were found between the three latter groups. In the progestogen-only oral contraceptive group, there were too few women for the differences to reach statistical significance. In the group of women with natural cycles without ovarian cysts > 25 mm, there was no correlation between ovarian volumes, related to age (Table 4), parity, body mass index or smoking habits. If the largest ovary in each of the examined women was selected and the ovarian volume was related to cycle day, we found a maximum volume around day 15 (Figure 1). The mean volume of the largest ovaries was 7.5 ml (SD 3.4) compared to 4.2 ml (SD 2.1) for the smallest ovaries (p < 0.001). The size of the largest follicle was also related to cycle day with increasing size until day 15. Polycystic ovaries were found in 20 of the 197 (10.2%) women not using any hormonal contraception (95% CI, ± 4.2%). The mean volumes of the polycystic ovaries were significantly larger at 7.4 ml (SD 2.3) compared with the ovaries in natural cycles at 5. ml (mean of both right and left ovaries, SD 3.3), but with a considerable overlap in the volumes (range ml). There was no statistical difference in body mass index between women with polycystic ovaries or not, at 24. (SD 5.2) vs (SD 3.6), respectively. Five out of the 20 women had oligo- or amenorrhea, one had hirsutism and five had had infertility problems leading to some kind of medical intervention. DISCUSSION This is the first study to investigate the occurrence rate of adnexal lesions and ovarian findings in a random sample of menstruating women below 40 years of age. Adnexal Table 2 Relative risk of ovarian cyst according to contraceptive method No hormonal contraception Combined oral contraceptive IUD with levonorgestrel (20 µg/24 h) IUD with levonorgestrel or oral levonorgestrel 30 µg/24 h IUD, intrauterine device; CI, confidence interval Relative risk 95% CI Examined Ovarian cysts 25 mm Table 3 Ovarian volume, including polycystic ovaries, of women aged years Natural cycles Oral contraceptives IUD IUD with levonorgestrel Progestogen-only oral contraceptives n Mean age (years) Right (ml) SD n 3.3* Mean age (years) Left (ml) Total *p < 0.05; difference in ovarian volume between the oral contraceptive group and the other groups (except for the progestogen-only oral contraceptive group which was excluded due to an insufficient number of women); IUD, intrauterine device; SD, standard deviation * SD Ultrasound in Obstetrics and Gynecology 347

4 Table 4 Ovarian volume in women with natural cycles, including polycystic ovaries Right Left Age (years) n (ml) SD n (ml) Total range Figure 1 Ovarian volume of the largest ovary in women not using hormonal contraception related to cycle day lesions were found in 7.% and ovarian cysts in 6.6%. Ultrasound cannot differentiate between ovarian cysts and normal or luteinized follicles. Normal follicles may sometimes be up to 25 mm in size, but there is little consensus in the literature as to which is the upper limit for an ovarian follicle. We chose the criterion to define an adnexal lesion as the largest diameter being at least 25 mm, or solid parts in any lesion regardless of size. The limit of 25 mm may be too small but one of six cysts of mm turned out to be a non-functional simple cyst. The occurrence rate of lesions in this study is less than half of the maximal rate found in asymptomatic postmenopausal women, but in that study lesions as small as 3 mm were regarded as cysts 3. In asymptomatic premenopausal women over 40 years old, using the criteria of ovarian volume exceeding 1 cm 3 or solid morphological pattern to define abnormality, 2% were shown to have an abnormal ovary 11. This number of adnexal lesions seems to be an underestimation, probably due to measuring of the volume of the ovary instead of the lesion, which should be more accurate, and a too high cut-off value of 1 cm 3. The analysis of the non-participating group revealed small differences in age, marital status and number of children compared to the control group. The only factor known to influence the prevalence of ovarians cysts is the method of contraception. In the examined group of women, this prevalence was in agreement with a recent study investigating sexual behavior and contraceptive methods in a random sample of women in Sweden 12. SD Functional ovarian cysts are influenced by the sex hormones. Our data showing only two cysts in the group of women using combined oral contraceptives agrees with previous studies where combined oral contraceptives had a protective effect against functional ovarian cysts 13. However, we found a significantly higher rate of cysts in women on low-dose progestogen-only contraceptives (intrauterine devices releasing levonorgestrel or oral administration of levonorgestrel) compared with women with natural cycles. These results are supported by other reports of the physiological disturbance in follicular growth and rupture in women on low-dose progestogen-only contraceptives Our measurement of the ovarian volume showed no difference between the right and left ovaries, agreeing with other studies 17,1. In accordance with Christensen and colleagues 1, we found smaller ovarian volumes in women using combined oral contraceptives but, in contrast to Christensen and colleagues 1, intrauterine device users did not have larger ovarian volumes than women with natural cycles. In our study, the largest ovary in women with natural cycles reached its maximum volume around day 15 in the cycle, agreeing with the time of ovulation. This finding differs somewhat from that of Christensen and colleagues 1, who found the maximum diameter at day 19, and Granberg and Wikland 19 who found the largest ovarian volumes in the preovulatory phase, days Physiologically, the normal ovary should reach its maximum volume on the day on which the leading follicle bursts. The prevalence of polycystic ovaries was 10% in women without any hormonal contraception. Other reports have shown figures as high as 17 27%, but the participating sections of the invited women in the random samples have been as low as 11% 20 and 1% 21, as compared to our percentage of 72%, or the examination has been performed in a selected population using transabdominal ultrasonography,22. The clinical significance of the discovery of polycystic ovaries is unclear. Only 25% in our group of women with polycystic ovaries had menstrual disturbances and only one of 20 had hirsutism, which is in agreement with the study by Clayton and colleagues 21 where 30% of women with polycystic ovaries had an irreglar menstrual pattern and 14% had hirsutism, but the majority had normal serum androgen levels. Polycystic ovaries as a single finding may be a biological variation in morphology, but, in combination with irregular menstruations, acne or subfertility, the ultrasound finding implies that a hormonal investigation is necessary. The fact, that 2% of the asymptomatic ovarian lesions had disappeared in 3 months, stresses the importance of waiting for functional cysts to disappear spontaneously. In the study by Osmers and colleagues 23, 53% of all cysts and 90% of the functional cysts disappeared in 6 weeks. If a wait of 6 weeks or, as in our study, 3 months is advocated, the check-up must be related to the patient s age, symptoms, family history and the sonomorphological appearance of the cyst 23,24. The management of ovarian cysts is important from two points of view: the risk of torsion and the risk of 34 Ultrasound in Obstetrics and Gynecology

5 malignancy. The risk of torsion is unclear but acute abdominal pain has been reported in less than 1% of cases 23. The risk of malignancy is also unclear as the natural history of ovarian cancer is unknown. Ovarian cancer is thought to arise in the mesothelial surface epithelium of the ovary 25, but dysplasia and transition from benign to malignant epithelium have been found in ovarian cystadenocarcinomas 26 2, indicating that ovarian cysts may be precursors of ovarian cancer. Epidemiological data also suggest malignant potential in certain benign ovarian tumors 29. On the other hand, abnormal morphological changes have been found in macroscopically normal ovaries in asymptomatic women undergoing surgery because of a strong family history 30. The incidence of ovarian cancer is 3/ per year for women below the age of 40 years in Sweden 31.We found ovarian cysts in 6.6% of the asymptomatic women. Of these, almost 20% persisted after 3 months; in other words 1200 asymptomatic cysts per women. If this calculation is true, we have to remove 400 cysts in order to find one cancer. In reality, we would probably find more than one cancer in 400 cysts, as the incidence of cancer represents those that present with symptoms. Initially, cancer is often asymptomatic, as two-thirds of the patients are already in advanced stages of the disease (FIGO stages III and IV) at the time of diagnosis, and so face a poor prognosis 32. We would have to surgically remove many cysts in young women to find one cancer. Are we able to select cysts that are more likely to be or to become malignant? The ultrasound appearance of the cyst can be useful, as the risk of malignancy in simple ovarian cysts is low (0 0.%) compared to the risk of 17 46% in ovarian cysts with solid parts 23,33,34. However, scoring systems discriminating benign from malignant ovarian cysts have a relatively high rate of false-positive results Color flow Doppler and color Doppler energy studies have shown promising results. However, using pulsed Doppler sonography to quantify and compare the measurements, there is often some degree of overlap between pulsatility and resistance indices, peak systolic velocity and time-averaged maximum velocity measurements of benign and malignant masses In premenopausal women, measurements are also unreliable due to neoangiogenisis in functional cysts 45. Cyst puncture and analyses of cystic fluid with cytology, CA 125 or steroid hormones do not discriminate between benign and malignant tumors 46. Non-functional cysts often recur after puncture 47. Levels of the most useful serum tumor marker, CA 125, are elevated in 0 5% of cases of epithelial ovarian cancer, in less than 66% in cases of mucinous ovarian cancer, and in 20% in cases of non-epithelial ovarian cancer 4. Different types of combined scoring systems such as risk of malignancy index (RMI), created by Jacobs and colleagues in 1990 based on serum CA 125, ultrasound findings and age may facilitate the discrimination, but this index also overlooks stage I tumors 49. Tailor and colleagues 50 used multivariate logistic regression analysis and included age, time-averaged maximum velocity and the papillary projection score in predicting the probability of malignancy in adnexal masses. Using a cut-off value of 25% probability of malignancy, the sensitivity was 93.3% and the specificity was 90.4%. In future, it may be possible to include other, better techniques or models to identify early-stage ovarian cancer. 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