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doi:10.1111/jog.12491
J. Obstet. Gynaecol. Res. Vol. 41, No. 1: 92–98, January 2015
Correlation between ovarian chocolate cyst and serum carbohydrate antigen 125 level and the effect of ultrasound-guided interventional sclerotherapy on serum carbohydrate antigen 125 level Si-Ming Wang, Huai-Qiu Cai, Xiao-Qiu Dong, Qiu-Lan Fan, Lu-Lu Wang, Xiao-Hui Shao and Li-Wei Zhang Department of Ultrasonography, the Fourth Hospital of Harbin Medical University, Harbin, China
Abstract Aim: This study was to investigate the correlation between ovarian chocolate cysts and serum carbohydrate antigen (CA)-125 levels and to demonstrate the effect of ultrasound-guided interventional sclerotherapy (UGIS) on serum CA-125 levels. Methods: Based on the serum CA-125 level, as determined by chemiluminescence detection prior to UGIS, 105 patients with ovarian chocolate cysts were divided into the normal group (CA-125 ≤ 35 U/mL, 45 patients) and the abnormal group (35 U/mL < CA-125 ≤ 200 U/mL, 60 patients). There were six clinical indicators including age, disease duration, dysmenorrhea history, child-bearing history, abortion history and surgical history. The ultrasonography characteristics were cyst diameter, cyst wall thickness and the side on which the cyst occurred. The correlations between serum CA-125 levels pretreatment and the clinical indicators and ultrasonography characteristics was analyzed. The serum CA-125 levels pretreatment, 3 months post-treatment and 6 months post-treatment were compared. Results: The pretreatment serum CA-125 levels of the 105 patients positively correlated with disease duration (r = 0.3932, P = 0.0040), dysmenorrhea history (r = 0.2351, P = 0.0111), cyst diameter (r = 0.3415, P < 0.0001) and cyst wall thickness (r = 0.4263, P < 0.0001). Compared with the pretreatment level, the mean serum CA-125 level in the abnormal group at 3 months post-treatment was significantly lower (P < 0.01), and at 6 months post-treatment, the mean serum CA-125 level had decreased to a normal level (P < 0.01). Conclusion: UGIS significantly decreased abnormal serum CA-125 levels in patients with ovarian chocolate cysts. Key words: ovarian chocolate cyst, serum carbohydrate antigen 125, ultrasound-guided interventional sclerotherapy.
Introduction Ovarian chocolate cysts are thought to be a common type of endometriosis. While endometriosis is a benign disease, it has implantation and metastatic characteris-
tics that are similar to malignant tumors.1,2 It is a frequently refractory gynecological disease with a high recurrence rate and costs through medication or surgery.3 It has been reported that ovarian chocolate cysts secrete carbohydrate antigen (CA)-125 and that
Received: November 8 2013. Accepted: April 28 2014. Reprint request to: Dr Xiao-Qiu Dong, Department of Ultrasonography, the Fourth Hospital of Harbin Medical University, 37 Yiyuan Street, Harbin, Heilongjiang Province 150001, China. Email: [email protected]
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© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Effect of UGIS on CA125 in ovarian chocolate cyst
CA-125 levels can be used to screen for endometriosis and evaluate therapeutic efficacy.4–6 Currently, patients with ovarian chocolate cysts are principally treated with laparoscopic surgery. With the progression of minimally invasive technologies, ultrasound-guided interventional sclerotherapy (UGIS) has been reported in many studies.7,8 Regardless of the method used to treat ovarian chocolate cysts, efficacy is often demonstrated by decreased CA-125 levels after removing the lesions. Several articles have reported a correlation between the mechanism of ovarian chocolate cysts and increased CA-125 levels.9–11 Other papers have investigated the effects of laparoscopic surgery on CA-125 levels before and post-treatment and have reported that serum CA-125 levels generally decrease in varying degrees.12,13 In contrast, research on UGIS is rare. The objective of this study was to investigate the effect of UGIS on serum CA-125 levels. We measured serum CA-125 levels before and post-treatment and found that they decreased significantly following treatment in patients who had elevated pretreatment CA-125 levels.
Methods Patients The treatment was conducted from June 2010 to June 2012 in the Fourth Hospital of Harbin Medical University. There were 105 patients treated by UGIS, all of whom were cured at one time. The mean age of the 105 patients was 38 ± 12 years (range, 18–48), and the mean diameter of ovarian chocolate cyst was 6.8 ± 1.7 cm (range, 3.5–15.0). Seventy-seven patients were under initial treatment of ultrasound-guided interventional therapy. Twenty-eight patients had the experience of surgical or laparoscopic therapy. The duration of disease, side of the cyst occurrence, child-bearing history, abortion history and dysmenorrhea history is showed in Table 1. For serum CA-125 levels prior treatment, 45 persons were normal (27.0 ± 5.4 U/mL) and 60 persons were abnormal (62.5 ± 25.4 U/mL). Ultrasonography excluded adenomyosis, ovarian malignant tumor and severe pelvic inflammation in all patients examined. The tuberculin examination was used to
Table 1 Correlation between serum carbohydrate antigen (CA)-125 level of pretreatment and the clinical indicators and ultrasonography characteristics of chocolate cysts (n = 105) Clinical indicators Age (years) ≤35 >35 Disease duration ≤12 months >12 months Dysmenorrhea history Yes No Child-bearing history Yes No Abortion history Yes No Surgical history Yes No Side of cyst occurrence Left Right Cyst diameter ≤6.0 cm >6.0 cm Cyst wall thickness ≤0.2 cm >0.2 cm
Cases (n)
Serum CA-125 levels before treatment Normal group (%) Abnormal group (%)
50 55
23 (46.0) 22 (40.0)
27 (54.0) 33 (60.0)
47 58
29 (61.7) 16 (27.6)
18 (38.3) 42 (72.4)
65 40
20 (30.8) 25 (62.5)
45 (69.2) 15 (37.5)
56 49
23 (41.1) 22 (44.9)
33 (58.9) 27 (55.1)
46 59
19 (41.3) 26 (44.1)
27 (58.7) 33 (55.9)
28 77
13 (46.4) 32 (41.6)
15 (53.6) 45 (58.4)
65 40
28 (43.1) 17 (42.5)
37 (56.9) 23 (57.5)
48 57
30 (62.5) 15 (26.3)
18 (37.5) 42 (73.7)
45 60
28 (62.2) 17 (28.3)
17 (37.8) 43 (71.7)
R
P
0.1456
0.1382
0.3932
0.0004
0.2351
0.0111
0.1905
0.0515
0.1042
0.2902
0.0089
0.9283
0.0657
0.8625
0.3415
P < 0.0001
0.4263
P < 0.0001
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exclude pelvic tuberculosis. All the patients had no history of alcohol allergy. Laboratory tests including blood and urine routine, electrocardiogram, chest X rays, bleeding time (BT) and clotting time (CT) were performed on all patients prior to the procedure. The results of all tests were within the normal range. Each patient was told the details of the interventional sclerotherapy procedure, safety, adverse effects and prognosis. All the patients signed the informed consent forms prior to interventional sclerotherapy. This study was approved by the institutional review board of the Fourth Hospital of Harbin Medical University, China.
Diagnostic criteria Clinical criteria All the patients were in the woman of childbearing age with or without the dysmenorrhea history. It was observed a cyst by gynecologic examination. The cyst of the patient was located in one-side of ovary and was solitary. Ultrasonography criteria One cyst was observed in the ovarian. The wall of the cyst was thick, and sac liquid was not clear, with intensive pitting echo. Ethanol sclerotherapy criteria The chocolate-brown fluid blood could be aspirated during the procedure. Laboratory criteria Malignant cells were excluded.
Group dividing criteria Groups were divided based on the serum CA-125 levels standard. According to preoperative levels, the 105 patients enrolled in this study were divided into the normal group (45 patients, CA-125 ≤ 35 U/mL) and abnormal group (60 patients, 35 U/mL < CA125 < 200 U/mL). Instruments and methods A Technos MPX DU-8 (Esaote, Genoa, Italy) color Doppler ultrasonic diagnostic apparatus with EC123 (7.0–12 MHz) probes and equipped with an adaptor for in-plane needle guidance was used. Disposable PTC needles (16- or 18-G PTC needle, 20 cm in length; Hakko, Chikuma-shi, Japan) were employed. All patients received a local anesthetic of 2% lidocaine (Fuxing Zhaohui, Shanghai, China). The 0.9% saline
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solution used in the experiments was produced by Tonghua Dongbao Medicine (Tonghua, China). The 95% ethanol used was produced by the Qiqihar Disinfectant Factory (Qiqihar, China). One group of antiinflammatory triple drug includes etimicin sulfate injection (4 mL: 200 mg; Jiangxi Jiminkexin Group Co., Wuxi, China), dexamethasone sodium phosphate injection (1 mL: 5 mg; Chongqing LUMMY Pharmaceutical Co., Ltd., Chongqing, China) and chymotrypsin for injection (4000 U, Shanghai, China). CA-125 levels were tested with an Elecsys-601 (Roche, Mannheim, Germany) with a CA-125 quantitative determination kit (Boson Biotech Co., Ltd., Xiamen, China). Transvaginal ultrasound was performed on all patients. The ultrasonography reports concerning the patient uterus and ovaries (location, size, shape of cysts) were kept in computerized medical records. Clinical and laboratory tests were combined to exclude adenomyosis, ovarian malignant tumor and severe pelvic inflammation. Patients emptied their bladders before treatment. The imaging plane for needle guidance was selected to avoid accidental injury of the intestine, the blood vessels and the bladder. The puncture site was initially disinfected. Under the guidance of ultrasound, we punctured needles into the cysts. After complete evacuation of the cyst, the empty cavity of the cyst was washed thoroughly with warm saline (0.9%) until the color of the aspirated fluid changed from chocolatebrown to clear. Next, we injected 5 mL of 2% lidocaine (2–5 mL) and 95% ethanol (half of the cyst fluid volume, maximum dose of 100 mL) was left in situ. After the needle evacuated the cavity, two groups of antiinflammatory triple drug were injected into the pelvis and adverse effects were observed. After the treatment, none of patients took any oral medicine and no other medical treatment was performed. All patients were followed-up at 3 and 6 months post-treatment. Serum CA-125 levels of the patients treated by sclerotherapy were detected pretreatment, and at 3 and 6 months post-treatment on the menstrual cycle (follicular phase). A 2-mL venous blood sample was collected from the patient’s elbow i.v. between 07.00 and 10.00 hours.
Statistical analyses All statistical analyses were performed with the Statistical Package for Social Sciences version 18.0 (SPSS, Chicago IL, USA). The data were presented as mean ± standard deviation. Comparisons of CA-125 were performed with repeated measures anova. Group comparisons of categorical variables were
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Effect of UGIS on CA125 in ovarian chocolate cyst
Figure 1 Ultrasound images of one typical case of ultrasoundguided interventional sclerotherapy. (a) The needle in the chocolate cyst during ultrasound-guided interventional sclerotherapy. (b) Saline washings. The chocolate cyst is in the right ovary. (c) Ethanol (95%) was retained in the cystic cavity. (d) The chocolate cyst disappeared completely 6 months after interventional sclerotherapy. F, normal follicles; N, needle; RC, right chocolate cyst; ROV, right ovary.
(a)
(b)
(c)
(d)
Table 2 Change in the mean serum carbohydrate antigen 125 level pre- and post-treatment (U/mL) Groups
n
Pretreatment
3 months post-treatment
6 months post-treatment
Normal group Abnormal group
45 60
26.90 ± 4.22 58.45 ± 23.93
24.57 ± 4.75 31.07 ± 10.88*
22.62 ± 4.73 24.55 ± 5.24**
*P < 0.01 versus pretreatment group; **P < 0.01 versus pretreatment group.
evaluated by the χ2-test, and the correlation analyses were performed using Spearman’s rank correlation coefficient. P < 0.05 was considered statistically significant.
Results All ultrasound-guided interventional procedures in the 105 patients were successfully performed on the first attempt, and the chocolate cysts disappeared completely 6 months after interventional therapy (Fig. 1).
Correlations between serum CA-125 level, clinical indicators of ovarian chocolate cysts and ultrasonography characteristics The pretreatment serum CA-125 levels were measured in 105 patients. These levels positively correlated with disease duration (r = 0.3932, P = 0.004), dysmenorrhea history (r = 0.2351, P = 0.0111), cyst diameter (r = 0.3415, P < 0.0001) and cyst wall thickness (r = 0.4263, P < 0.0001). The serum CA-125 levels did not correlate
with age, child-bearing history, abortion history, surgical history or the side on which the cyst occurred (P > 0.05, Table 1).
Change in the mean serum CA-125 level preand post-treatment Compared with the pretreatment level, the mean serum CA-125 level was significantly lower (P < 0.01) in the abnormal group at 3 and at 6 months posttreatment. Also, the mean serum CA-125 level of pretreatment in the abnormal group had decreased to a normal level (P < 0.01). However, in the normal group, the serum CA-125 levels at 3 and 6 months posttreatment remained in the normal range, and there was no significant difference between pretreatment and post-treatment (P ≥ 0.05, Table 2). Analysis of patients in the abnormal group with CA-125 levels that did not decrease to normal levels by 3 months post-treatment Six patients in the abnormal group demonstrated serum CA-125 levels that did not decrease to normal
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Table 3 Analysis of six patients in the abnormal group with CA-125 levels that did not decrease to normal levels by 3 months post-treatment Patient no.
Disease duration (months)
Dysmenorrhea history (yes/no)
Cyst diameter (cm)
Cyst wall thickness (cm)
Pretreatment
1 2 3 4 5 6
42 36 42 18 24 48
Yes Yes Yes Yes Yes Yes
9.7 6.8 9.7 7.4 8.6 12.8
0.41 0.39 0.42 0.24 0.35 0.46
98.73 112.72 100.52 82.34 101.28 151.82
levels by 3 months post-treatment. Prior to treatment, the serum CA-125 levels of these six patients had been significantly higher than the CA-125 levels in the other patients, with a mean of 107.90 ± 9.64 U/mL. At 3 months post-treatment, their mean CA-125 level was 53.73 ± 4.10 U/mL, and at 6 months post-treatment, it was 28.48 ± 2.24 U/mL. The common features of these six patients were long disease duration, history of dysmenorrhea, large-diameter cysts and thick-walled cysts (Table 3).
Discussion Previous reports have shown that the endometrial cells of patients with ovarian chocolate cysts secrete CA-125 at levels 2–4-times greater than normal endometrium.14,15 Increased CA-125 levels positively correlate with pelvic tissue adhesions and reduced immune function.16 As the illness progresses, serum CA-125 levels can continue to increase.17,18 Thus, increased serum CA-125 levels can indicate that a patient’s disease progression is serious. Surgical operation and laparoscopic procedures to remove ovarian chocolate cyst lesions reportedly reduce serum CA-125 levels.13,19 However, these procedures have a higher recurrence rate and higher costs. In recent years, with the development of interventional techniques, UGIS has been increasingly recognized by clinicians as a reliable surgical alternative for treating endometrial cysts with many advantages, including minimal trauma, fewer risks and complication, lower costs and decreased recurrence rates.20,21 Previous studies have shown that estrogen can stimulate and maintain the growth and proliferation of ectopic endometrial tissue. Estrogen secretion decreases after 35 years of age.22,23 Liu et al. reported that patients’ conditions gradually worsened with disease duration of more than 12 months for cyst
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Serum CA-125 levels 3 months 6 months post-treatment post-treatment 51.42 70.83 52.73 39.84 56.35 51.46
20.92 32.83 32.44 24.76 25.65 34.53
growing.24 Thus, our study’s statistical boundaries were a 1-year duration and an age of 35 years. We used six clinical indicators for patients with chocolate cysts, including age, child-bearing history, abortion history, dysmenorrhea history, surgical history and disease duration. The pretreatment serum CA-125 levels in the 105 patients positively correlated with the disease duration and dysmenorrhea history. The serum CA-125 levels did not correlate with age, child-bearing history, abortion history and surgical history (P > 0.05). Previous results have shown that CA-125 levels in patients with ovarian chocolate cysts increase as their illness progresses and that CA-125 levels positively correlate with the degree of dysmenorrhea, pelvic tissue adhesions and with the disease duration. The most likely reason for these relationships is that disease progression is associated with severe inflammation; thus, the degree of pelvic tissue adhesion worsens.17,25 As the duration of the disease extends, the growing ectopic lesions reproduce and generate more endometrial cells, which produce more CA-125 that is released into the blood. Similarly, Berkley et al. demonstrated that the degree of dysmenorrhea was related to pelvic adhesions and disease duration.26 Thus, among the six indicators, disease duration and dysmenorrhea history were the factors most strongly associated with patient outcomes. In this study, three ultrasonography characteristics of chocolate cysts were analyzed, including cyst diameter, cyst wall thickness and the side on which the cyst occurred. Previous reports have suggested that the incidence of endometrial cysts is greater in the left ovary than the right.27 However, in our study, we found that there was no relationship between the pretreatment CA-125 levels and the side on which the cyst occurred (P > 0.05). Takehara et al. demonstrated that the patients whose cysts were larger than 6 cm have severe pelvic tissue adhesion.28 Kafali et al. reported
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Effect of UGIS on CA125 in ovarian chocolate cyst
that cure rates decreased when the cyst wall thickness was more than 0.2 cm.29 Therefore, in this study, the statistical boundaries were a cyst diameter of 6 cm and a cyst wall thickness of 0.2 cm. Our results showed that the pretreatment serum CA-125 levels positively correlated with cyst diameter and cyst wall thickness (P < 0.01). The likely explanation for these relationships is that the inner wall of the cysts is comprised of glandular epithelial cells. At the early stage, the inner wall of the cysts is thin and the cells are little. As the illness progresses, the cysts grow and the inflammatory response surrounding the lesions increases. The cyst walls produce new blood vessels and become significantly thicker, and the number of epithelial cells in the cyst walls increases. The result of this chain of events leads to more epithelial cells secreting more CA-125, thereby increasing the serum CA-125 levels.23 Changes in the serum CA-125 levels before and after UGIS are described below. In the normal group, the post-treatment serum CA-125 levels at 3 and 6 months remained in the normal range, and there was no significant difference compared with the pretreatment levels (P > 0.05). In the abnormal group, at 3 months post-treatment, the mean serum CA-125 levels was significantly lower (P < 0.01), and at 6 months posttreatment, the mean serum CA-125 level had decreased to a normal level (P < 0.01). There were two reasons for the increased CA-125 levels in patients with ovarian chocolate cysts: (i) the epithelial cells in cyst walls secrete CA-125; and (ii) the function of the variety of growth factors in the cystic fluid.30 If these two factors could be eliminated, the objective of reducing serum CA-125 levels in patients with ovarian chocolate cysts can be achieved. Our research group has published a paper discussing ovarian chocolate cysts, ethanol sclerotherapy, sclerosing agent dosage and the curative effects of this treatment.20 In ethanol sclerotherapy, saline washings and high concentrations of ethanol retention were two key procedures. Initially, washing several times with warm saline guaranteed that the cystic fluid was removed to clearly and completely expose endometrial cells. This procedure eliminated the cystic fluid that it could stimulate ectopic cell proliferation. Second, ethanol (95%) was retained in the cystic cavity as a sclerosing agent and was not aspirated. This procedure ensured that the concentration of the sclerosing agent and sclerosing time for the glandular epithelial cells were sufficient. This process inactivated the cyst wall cells and completely closed the cyst wall vessels. This procedure successfully eliminated the factor causing increased serum CA-125
levels. Combined, saline washings and ethanol sclerotherapy allow the serum CA-125 levels to decrease. Previous research has shown that the amount of peritoneal fluid and the serum CA-125 levels in patients with chronic pelvic inflammatory disease are increased to varying degrees.31 The ovarian chocolate cyst lesions can aggravate the degree of chronic pelvic inflammation. Thus, most patients with ovarian chocolate cysts suffer from chronic pelvic inflammatory disease. The final step of the sclerotherapy procedure was to inject an anti-inflammatory triple drug into the pelvic cavity to relieve the chronic pelvic inflammation. The results showed that the drugs associated with ethanol sclerotherapy decreased the CA-125 levels. This study analyzed six patients whose serum CA-125 levels had not decreased to the normal range by 3 months post-treatment. The mean pretreatment serum CA-125 levels of these six patients were significantly greater than those of the other patients (82.34– 151.82 U/mL). Because of our careful screening process, which included ultrasonography, clinical symptoms, vital signs, laboratory data and disease history follow-up, the following diseases were not found in our research patients: adenomyosis, malignant ovarian tumor, pelvic tuberculosis and severe pelvic inflammation. The increased serum CA-125 levels were likely related to other factors, such as longer disease duration, more severe dysmenorrhea history, increased degree of pelvic tissue adhesion and lesion size. A few patients had atypical endometriosis and small endometrial lesions that could not be examined with ultrasonography and other clinical means. In conclusion, the pretreatment serum CA-125 levels were positively correlated with dysmenorrhea history and disease duration. With respect to the ultrasonography characteristics of the ovarian chocolate cysts, the pretreatment serum CA-125 levels were positively correlated with cyst diameter and cyst wall thickness. The serum CA-125 levels were not correlated with age, child-bearing history, abortion history, surgical history or the side on which the cyst occurred. UGIS significantly decreased abnormal serum CA-125 levels in patients with ovarian chocolate cysts.
Acknowledgments The sponsors of this study were the National Natural Science Foundation of China (grant no. 81271646 to X. Q. Dong), Heilongjiang Key Technologies R&D
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Program funds of China and Harbin Science and Technology Bureau Innovation Research Program Fund of China.
Disclosure None declared.
References 1. Mirkin D, Murphy-Barron C, Iwasaki K. Actuarial analysis of private payer administrative claims data for women with endometriosis. J Manag Care Pharm 2007; 13: 262–272. 2. Le J. Obstetrics and Gynaecology Science, 6th edn. Bei Jing: People’s Medical Publishing House, 2004; 354. 3. Simoens S, Hummelshoj L, D’Hooghe T. Endometriosis: Cost estimates and methodological perspective. Hum Reprod Update 2007; 13: 395–404. 4. Kataoka T, Watanabe Y, Hoshiai H. Retrospective evaluation of tumor markers in ovarian mature cystic teratoma and ovarian endometrioma. J Obstet Gynaecol Res 2012; 38: 1071– 1076. 5. McBean JH, Brumsted JR. In vitro CA-125 secretion by endometrium from women with advanced endometriosis. Fertil Steril 1993; 59: 89–92. 6. Pittaway DE, Rondinone D, Miller KA et al. Clinical evaluation of CA-125 concentrations as a prognostic factor for pregnancy in infertile women with surgically treated endometriosis. Fertil Steril 1995; 64: 321–324. 7. Gatta G, Parlato V, Di Grezia G et al. Ultrasound-guided aspiration and thanol sclerotherapy for treating endometrial cysts. Radiol Med 2010; 115: 1330–1339. 8. Hsieh CL, Shiau CS, Lo LM et al. Effectiveness of ultrasoundguided aspiration and sclerotherapy with 95%ethanol for treatment of recurrent ovarian endometriomas. Fertil Steril 2009; 91: 2709–2713. 9. Barbieri RL, Niloff JM, Bast RC Jr et al. Elevated serum concentrations of CA-125 in patients with advanced endometriosis. Fertil Steril 1986; 45: 630–634. 10. Harada T, Kubota T, Aso T. Usefulness of CA-199 versus CA125 for the diagnosis of endometriosis. Fertil Steril 2002; 78: 733–739. 11. Hornstein MD, Harlow BL, Thomas PP et al. Use of a new CA125 assay in the diagnosis of endometriosis. Hum Reprod 1995; 10: 932–934. 12. Kras´nicki D. Serum and peritoneal fluid CA-125 concentration in women with endometriosis. Ginekol Pol 2001; 72: 1365– 1369. 13. Mohamed ML, El Behery MM, Mansour SA. Comparative study between VEGF-A and CA-125 in diagnosis and follow-up of advanced endometriosis after conservative laparoscopic surgery. Arch Gynecol Obstet 2013; 287: 77–82.
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14. Hornstein MD, Thomas PP, Gleason RE et al. Menstrual cyclicity of CA-125 in patients with endometriosis. Fertil Steril 1992; 58: 279–283. 15. Kitawaki J, Ishihara H, Koshiba H et al. Usefulness and limits of CA-125 in diagnosis of endometriosis without associated ovarian endometriomas. Hum Reprod 2005; 20: 1999–2003. 16. Patankar MS, Jing Y, Morrison JC et al. Potent suppression of natural killer cell response mediated by the ovarian tumor marker CA125. Gynecol Oncol 2005; 99: 704–713. 17. Muyldermans M, Cornillie FJ, Koninckx PR. CA125 and endometriosis. Hum Reprod Update 1995; 1: 173–187. 18. Bianchi M, Macaya R, Durruty G et al. Correlation between CA-125 marker with the presence and severity of pelvic endometriosis. Rev Med Chil 2003; 131: 367–372. 19. Chen FP, Soong YK, Lee N. The use of serum CA-125 as a marker for endometriosis in patients with dysmenorrhea for monitoring therapy and for recurrence of endometriosis. Acta Obstet Gynecol Scand 1998; 77: 665–670. 20. Wang LL, Dong XQ, Shao XH et al. Ultrasound-Guided Interventional therapy for recurrent ovarian chocolate cysts. Ultrasound Med Biol 2011; 37: 1596–1602. 21. Nikolaou M, Adonakis G, Zyli P et al. Transvaginal ultrasound-guided aspiration of benign ovarian cysts. J Obstet Gynaecol 2014; 31: 1–4. 22. Deng B, Zhang XM, Ren P et al. Five kinds of predictive indicators of ovarian reserve in the clinical research. Chin J Birth Health Hered 2006; 14: 102–104, 106. 23. Badawy SZ, Cuenca V, Kumar S et al. Effects of chocolate cyst fluid on endometrioma cell growth in culture. Fertil Steril 1998; 70: 827–830. 24. Qiu JJ, Liu YL, Liu MH et al. Ovarian interstitial blood flow changes assessed by transvaginal colour Doppler sonography: Predicting ovarian endometrioid cyst-induced injury to ovarian interstitial vessels. Arch Gynecol Obstet 2012; 285: 423–433. 25. Yan L, Wang AM, Zhang YC. Clinical evaluation of serum CA125 concentrations in patients with endometriosis. Med J Chin PAPF 2011; 22: 320–322. 26. Berkley KJ, Rapkin AJ, Papka RE. the pains of endometriosis. Science 2005; 308: 1587–1589. 27. Ghezzi F, Beretta P, Franchi M et al. Recurrence of ovarian endometriosis and anatomical location of the primary lesion. Fertil Steril 2001; 75: 136–140. 28. Takehara M, Ueda M, Yamashita Y et al. Vascular endothelial growth factor A and C gene expression in endometriosis. Hum Pathol 2004; 35: 1369–1375. 29. Kafali H, Eser A, Duvan CI et al. Recurrence of ovarian cyst after sclerotherapy. Minerva Ginecol 2011; 63: 19–24. 30. Funamizu A, Fukui A, Kamoi M et al. Expression of natural cytotoxicity receptors on peritoneal fluid natural killer cell and cytokine production by peritoneal fluid natural killer cell in women with endometriosis. Am J Reprod Immunol 2014; 71: 359–367. 31. Johansson J, Santala M, Kauppila A. Explosive rise of serum CA 125 following the rupture of ovarian endometrioma. Hum Reprod 1998; 13: 3503–3504.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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doi:10.1111/jog.12491
J. Obstet. Gynaecol. Res. Vol. 41, No. 1: 92–98, January 2015
Correlation between ovarian chocolate cyst and serum carbohydrate antigen 125 level and the effect of ultrasound-guided interventional sclerotherapy on serum carbohydrate antigen 125 level Si-Ming Wang, Huai-Qiu Cai, Xiao-Qiu Dong, Qiu-Lan Fan, Lu-Lu Wang, Xiao-Hui Shao and Li-Wei Zhang Department of Ultrasonography, the Fourth Hospital of Harbin Medical University, Harbin, China
Abstract Aim: This study was to investigate the correlation between ovarian chocolate cysts and serum carbohydrate antigen (CA)-125 levels and to demonstrate the effect of ultrasound-guided interventional sclerotherapy (UGIS) on serum CA-125 levels. Methods: Based on the serum CA-125 level, as determined by chemiluminescence detection prior to UGIS, 105 patients with ovarian chocolate cysts were divided into the normal group (CA-125 ≤ 35 U/mL, 45 patients) and the abnormal group (35 U/mL < CA-125 ≤ 200 U/mL, 60 patients). There were six clinical indicators including age, disease duration, dysmenorrhea history, child-bearing history, abortion history and surgical history. The ultrasonography characteristics were cyst diameter, cyst wall thickness and the side on which the cyst occurred. The correlations between serum CA-125 levels pretreatment and the clinical indicators and ultrasonography characteristics was analyzed. The serum CA-125 levels pretreatment, 3 months post-treatment and 6 months post-treatment were compared. Results: The pretreatment serum CA-125 levels of the 105 patients positively correlated with disease duration (r = 0.3932, P = 0.0040), dysmenorrhea history (r = 0.2351, P = 0.0111), cyst diameter (r = 0.3415, P < 0.0001) and cyst wall thickness (r = 0.4263, P < 0.0001). Compared with the pretreatment level, the mean serum CA-125 level in the abnormal group at 3 months post-treatment was significantly lower (P < 0.01), and at 6 months post-treatment, the mean serum CA-125 level had decreased to a normal level (P < 0.01). Conclusion: UGIS significantly decreased abnormal serum CA-125 levels in patients with ovarian chocolate cysts. Key words: ovarian chocolate cyst, serum carbohydrate antigen 125, ultrasound-guided interventional sclerotherapy.
Introduction Ovarian chocolate cysts are thought to be a common type of endometriosis. While endometriosis is a benign disease, it has implantation and metastatic characteris-
tics that are similar to malignant tumors.1,2 It is a frequently refractory gynecological disease with a high recurrence rate and costs through medication or surgery.3 It has been reported that ovarian chocolate cysts secrete carbohydrate antigen (CA)-125 and that
Received: November 8 2013. Accepted: April 28 2014. Reprint request to: Dr Xiao-Qiu Dong, Department of Ultrasonography, the Fourth Hospital of Harbin Medical University, 37 Yiyuan Street, Harbin, Heilongjiang Province 150001, China. Email: [email protected]
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© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Effect of UGIS on CA125 in ovarian chocolate cyst
CA-125 levels can be used to screen for endometriosis and evaluate therapeutic efficacy.4–6 Currently, patients with ovarian chocolate cysts are principally treated with laparoscopic surgery. With the progression of minimally invasive technologies, ultrasound-guided interventional sclerotherapy (UGIS) has been reported in many studies.7,8 Regardless of the method used to treat ovarian chocolate cysts, efficacy is often demonstrated by decreased CA-125 levels after removing the lesions. Several articles have reported a correlation between the mechanism of ovarian chocolate cysts and increased CA-125 levels.9–11 Other papers have investigated the effects of laparoscopic surgery on CA-125 levels before and post-treatment and have reported that serum CA-125 levels generally decrease in varying degrees.12,13 In contrast, research on UGIS is rare. The objective of this study was to investigate the effect of UGIS on serum CA-125 levels. We measured serum CA-125 levels before and post-treatment and found that they decreased significantly following treatment in patients who had elevated pretreatment CA-125 levels.
Methods Patients The treatment was conducted from June 2010 to June 2012 in the Fourth Hospital of Harbin Medical University. There were 105 patients treated by UGIS, all of whom were cured at one time. The mean age of the 105 patients was 38 ± 12 years (range, 18–48), and the mean diameter of ovarian chocolate cyst was 6.8 ± 1.7 cm (range, 3.5–15.0). Seventy-seven patients were under initial treatment of ultrasound-guided interventional therapy. Twenty-eight patients had the experience of surgical or laparoscopic therapy. The duration of disease, side of the cyst occurrence, child-bearing history, abortion history and dysmenorrhea history is showed in Table 1. For serum CA-125 levels prior treatment, 45 persons were normal (27.0 ± 5.4 U/mL) and 60 persons were abnormal (62.5 ± 25.4 U/mL). Ultrasonography excluded adenomyosis, ovarian malignant tumor and severe pelvic inflammation in all patients examined. The tuberculin examination was used to
Table 1 Correlation between serum carbohydrate antigen (CA)-125 level of pretreatment and the clinical indicators and ultrasonography characteristics of chocolate cysts (n = 105) Clinical indicators Age (years) ≤35 >35 Disease duration ≤12 months >12 months Dysmenorrhea history Yes No Child-bearing history Yes No Abortion history Yes No Surgical history Yes No Side of cyst occurrence Left Right Cyst diameter ≤6.0 cm >6.0 cm Cyst wall thickness ≤0.2 cm >0.2 cm
Cases (n)
Serum CA-125 levels before treatment Normal group (%) Abnormal group (%)
50 55
23 (46.0) 22 (40.0)
27 (54.0) 33 (60.0)
47 58
29 (61.7) 16 (27.6)
18 (38.3) 42 (72.4)
65 40
20 (30.8) 25 (62.5)
45 (69.2) 15 (37.5)
56 49
23 (41.1) 22 (44.9)
33 (58.9) 27 (55.1)
46 59
19 (41.3) 26 (44.1)
27 (58.7) 33 (55.9)
28 77
13 (46.4) 32 (41.6)
15 (53.6) 45 (58.4)
65 40
28 (43.1) 17 (42.5)
37 (56.9) 23 (57.5)
48 57
30 (62.5) 15 (26.3)
18 (37.5) 42 (73.7)
45 60
28 (62.2) 17 (28.3)
17 (37.8) 43 (71.7)
R
P
0.1456
0.1382
0.3932
0.0004
0.2351
0.0111
0.1905
0.0515
0.1042
0.2902
0.0089
0.9283
0.0657
0.8625
0.3415
P < 0.0001
0.4263
P < 0.0001
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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exclude pelvic tuberculosis. All the patients had no history of alcohol allergy. Laboratory tests including blood and urine routine, electrocardiogram, chest X rays, bleeding time (BT) and clotting time (CT) were performed on all patients prior to the procedure. The results of all tests were within the normal range. Each patient was told the details of the interventional sclerotherapy procedure, safety, adverse effects and prognosis. All the patients signed the informed consent forms prior to interventional sclerotherapy. This study was approved by the institutional review board of the Fourth Hospital of Harbin Medical University, China.
Diagnostic criteria Clinical criteria All the patients were in the woman of childbearing age with or without the dysmenorrhea history. It was observed a cyst by gynecologic examination. The cyst of the patient was located in one-side of ovary and was solitary. Ultrasonography criteria One cyst was observed in the ovarian. The wall of the cyst was thick, and sac liquid was not clear, with intensive pitting echo. Ethanol sclerotherapy criteria The chocolate-brown fluid blood could be aspirated during the procedure. Laboratory criteria Malignant cells were excluded.
Group dividing criteria Groups were divided based on the serum CA-125 levels standard. According to preoperative levels, the 105 patients enrolled in this study were divided into the normal group (45 patients, CA-125 ≤ 35 U/mL) and abnormal group (60 patients, 35 U/mL < CA125 < 200 U/mL). Instruments and methods A Technos MPX DU-8 (Esaote, Genoa, Italy) color Doppler ultrasonic diagnostic apparatus with EC123 (7.0–12 MHz) probes and equipped with an adaptor for in-plane needle guidance was used. Disposable PTC needles (16- or 18-G PTC needle, 20 cm in length; Hakko, Chikuma-shi, Japan) were employed. All patients received a local anesthetic of 2% lidocaine (Fuxing Zhaohui, Shanghai, China). The 0.9% saline
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solution used in the experiments was produced by Tonghua Dongbao Medicine (Tonghua, China). The 95% ethanol used was produced by the Qiqihar Disinfectant Factory (Qiqihar, China). One group of antiinflammatory triple drug includes etimicin sulfate injection (4 mL: 200 mg; Jiangxi Jiminkexin Group Co., Wuxi, China), dexamethasone sodium phosphate injection (1 mL: 5 mg; Chongqing LUMMY Pharmaceutical Co., Ltd., Chongqing, China) and chymotrypsin for injection (4000 U, Shanghai, China). CA-125 levels were tested with an Elecsys-601 (Roche, Mannheim, Germany) with a CA-125 quantitative determination kit (Boson Biotech Co., Ltd., Xiamen, China). Transvaginal ultrasound was performed on all patients. The ultrasonography reports concerning the patient uterus and ovaries (location, size, shape of cysts) were kept in computerized medical records. Clinical and laboratory tests were combined to exclude adenomyosis, ovarian malignant tumor and severe pelvic inflammation. Patients emptied their bladders before treatment. The imaging plane for needle guidance was selected to avoid accidental injury of the intestine, the blood vessels and the bladder. The puncture site was initially disinfected. Under the guidance of ultrasound, we punctured needles into the cysts. After complete evacuation of the cyst, the empty cavity of the cyst was washed thoroughly with warm saline (0.9%) until the color of the aspirated fluid changed from chocolatebrown to clear. Next, we injected 5 mL of 2% lidocaine (2–5 mL) and 95% ethanol (half of the cyst fluid volume, maximum dose of 100 mL) was left in situ. After the needle evacuated the cavity, two groups of antiinflammatory triple drug were injected into the pelvis and adverse effects were observed. After the treatment, none of patients took any oral medicine and no other medical treatment was performed. All patients were followed-up at 3 and 6 months post-treatment. Serum CA-125 levels of the patients treated by sclerotherapy were detected pretreatment, and at 3 and 6 months post-treatment on the menstrual cycle (follicular phase). A 2-mL venous blood sample was collected from the patient’s elbow i.v. between 07.00 and 10.00 hours.
Statistical analyses All statistical analyses were performed with the Statistical Package for Social Sciences version 18.0 (SPSS, Chicago IL, USA). The data were presented as mean ± standard deviation. Comparisons of CA-125 were performed with repeated measures anova. Group comparisons of categorical variables were
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Effect of UGIS on CA125 in ovarian chocolate cyst
Figure 1 Ultrasound images of one typical case of ultrasoundguided interventional sclerotherapy. (a) The needle in the chocolate cyst during ultrasound-guided interventional sclerotherapy. (b) Saline washings. The chocolate cyst is in the right ovary. (c) Ethanol (95%) was retained in the cystic cavity. (d) The chocolate cyst disappeared completely 6 months after interventional sclerotherapy. F, normal follicles; N, needle; RC, right chocolate cyst; ROV, right ovary.
(a)
(b)
(c)
(d)
Table 2 Change in the mean serum carbohydrate antigen 125 level pre- and post-treatment (U/mL) Groups
n
Pretreatment
3 months post-treatment
6 months post-treatment
Normal group Abnormal group
45 60
26.90 ± 4.22 58.45 ± 23.93
24.57 ± 4.75 31.07 ± 10.88*
22.62 ± 4.73 24.55 ± 5.24**
*P < 0.01 versus pretreatment group; **P < 0.01 versus pretreatment group.
evaluated by the χ2-test, and the correlation analyses were performed using Spearman’s rank correlation coefficient. P < 0.05 was considered statistically significant.
Results All ultrasound-guided interventional procedures in the 105 patients were successfully performed on the first attempt, and the chocolate cysts disappeared completely 6 months after interventional therapy (Fig. 1).
Correlations between serum CA-125 level, clinical indicators of ovarian chocolate cysts and ultrasonography characteristics The pretreatment serum CA-125 levels were measured in 105 patients. These levels positively correlated with disease duration (r = 0.3932, P = 0.004), dysmenorrhea history (r = 0.2351, P = 0.0111), cyst diameter (r = 0.3415, P < 0.0001) and cyst wall thickness (r = 0.4263, P < 0.0001). The serum CA-125 levels did not correlate
with age, child-bearing history, abortion history, surgical history or the side on which the cyst occurred (P > 0.05, Table 1).
Change in the mean serum CA-125 level preand post-treatment Compared with the pretreatment level, the mean serum CA-125 level was significantly lower (P < 0.01) in the abnormal group at 3 and at 6 months posttreatment. Also, the mean serum CA-125 level of pretreatment in the abnormal group had decreased to a normal level (P < 0.01). However, in the normal group, the serum CA-125 levels at 3 and 6 months posttreatment remained in the normal range, and there was no significant difference between pretreatment and post-treatment (P ≥ 0.05, Table 2). Analysis of patients in the abnormal group with CA-125 levels that did not decrease to normal levels by 3 months post-treatment Six patients in the abnormal group demonstrated serum CA-125 levels that did not decrease to normal
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Table 3 Analysis of six patients in the abnormal group with CA-125 levels that did not decrease to normal levels by 3 months post-treatment Patient no.
Disease duration (months)
Dysmenorrhea history (yes/no)
Cyst diameter (cm)
Cyst wall thickness (cm)
Pretreatment
1 2 3 4 5 6
42 36 42 18 24 48
Yes Yes Yes Yes Yes Yes
9.7 6.8 9.7 7.4 8.6 12.8
0.41 0.39 0.42 0.24 0.35 0.46
98.73 112.72 100.52 82.34 101.28 151.82
levels by 3 months post-treatment. Prior to treatment, the serum CA-125 levels of these six patients had been significantly higher than the CA-125 levels in the other patients, with a mean of 107.90 ± 9.64 U/mL. At 3 months post-treatment, their mean CA-125 level was 53.73 ± 4.10 U/mL, and at 6 months post-treatment, it was 28.48 ± 2.24 U/mL. The common features of these six patients were long disease duration, history of dysmenorrhea, large-diameter cysts and thick-walled cysts (Table 3).
Discussion Previous reports have shown that the endometrial cells of patients with ovarian chocolate cysts secrete CA-125 at levels 2–4-times greater than normal endometrium.14,15 Increased CA-125 levels positively correlate with pelvic tissue adhesions and reduced immune function.16 As the illness progresses, serum CA-125 levels can continue to increase.17,18 Thus, increased serum CA-125 levels can indicate that a patient’s disease progression is serious. Surgical operation and laparoscopic procedures to remove ovarian chocolate cyst lesions reportedly reduce serum CA-125 levels.13,19 However, these procedures have a higher recurrence rate and higher costs. In recent years, with the development of interventional techniques, UGIS has been increasingly recognized by clinicians as a reliable surgical alternative for treating endometrial cysts with many advantages, including minimal trauma, fewer risks and complication, lower costs and decreased recurrence rates.20,21 Previous studies have shown that estrogen can stimulate and maintain the growth and proliferation of ectopic endometrial tissue. Estrogen secretion decreases after 35 years of age.22,23 Liu et al. reported that patients’ conditions gradually worsened with disease duration of more than 12 months for cyst
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Serum CA-125 levels 3 months 6 months post-treatment post-treatment 51.42 70.83 52.73 39.84 56.35 51.46
20.92 32.83 32.44 24.76 25.65 34.53
growing.24 Thus, our study’s statistical boundaries were a 1-year duration and an age of 35 years. We used six clinical indicators for patients with chocolate cysts, including age, child-bearing history, abortion history, dysmenorrhea history, surgical history and disease duration. The pretreatment serum CA-125 levels in the 105 patients positively correlated with the disease duration and dysmenorrhea history. The serum CA-125 levels did not correlate with age, child-bearing history, abortion history and surgical history (P > 0.05). Previous results have shown that CA-125 levels in patients with ovarian chocolate cysts increase as their illness progresses and that CA-125 levels positively correlate with the degree of dysmenorrhea, pelvic tissue adhesions and with the disease duration. The most likely reason for these relationships is that disease progression is associated with severe inflammation; thus, the degree of pelvic tissue adhesion worsens.17,25 As the duration of the disease extends, the growing ectopic lesions reproduce and generate more endometrial cells, which produce more CA-125 that is released into the blood. Similarly, Berkley et al. demonstrated that the degree of dysmenorrhea was related to pelvic adhesions and disease duration.26 Thus, among the six indicators, disease duration and dysmenorrhea history were the factors most strongly associated with patient outcomes. In this study, three ultrasonography characteristics of chocolate cysts were analyzed, including cyst diameter, cyst wall thickness and the side on which the cyst occurred. Previous reports have suggested that the incidence of endometrial cysts is greater in the left ovary than the right.27 However, in our study, we found that there was no relationship between the pretreatment CA-125 levels and the side on which the cyst occurred (P > 0.05). Takehara et al. demonstrated that the patients whose cysts were larger than 6 cm have severe pelvic tissue adhesion.28 Kafali et al. reported
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Effect of UGIS on CA125 in ovarian chocolate cyst
that cure rates decreased when the cyst wall thickness was more than 0.2 cm.29 Therefore, in this study, the statistical boundaries were a cyst diameter of 6 cm and a cyst wall thickness of 0.2 cm. Our results showed that the pretreatment serum CA-125 levels positively correlated with cyst diameter and cyst wall thickness (P < 0.01). The likely explanation for these relationships is that the inner wall of the cysts is comprised of glandular epithelial cells. At the early stage, the inner wall of the cysts is thin and the cells are little. As the illness progresses, the cysts grow and the inflammatory response surrounding the lesions increases. The cyst walls produce new blood vessels and become significantly thicker, and the number of epithelial cells in the cyst walls increases. The result of this chain of events leads to more epithelial cells secreting more CA-125, thereby increasing the serum CA-125 levels.23 Changes in the serum CA-125 levels before and after UGIS are described below. In the normal group, the post-treatment serum CA-125 levels at 3 and 6 months remained in the normal range, and there was no significant difference compared with the pretreatment levels (P > 0.05). In the abnormal group, at 3 months post-treatment, the mean serum CA-125 levels was significantly lower (P < 0.01), and at 6 months posttreatment, the mean serum CA-125 level had decreased to a normal level (P < 0.01). There were two reasons for the increased CA-125 levels in patients with ovarian chocolate cysts: (i) the epithelial cells in cyst walls secrete CA-125; and (ii) the function of the variety of growth factors in the cystic fluid.30 If these two factors could be eliminated, the objective of reducing serum CA-125 levels in patients with ovarian chocolate cysts can be achieved. Our research group has published a paper discussing ovarian chocolate cysts, ethanol sclerotherapy, sclerosing agent dosage and the curative effects of this treatment.20 In ethanol sclerotherapy, saline washings and high concentrations of ethanol retention were two key procedures. Initially, washing several times with warm saline guaranteed that the cystic fluid was removed to clearly and completely expose endometrial cells. This procedure eliminated the cystic fluid that it could stimulate ectopic cell proliferation. Second, ethanol (95%) was retained in the cystic cavity as a sclerosing agent and was not aspirated. This procedure ensured that the concentration of the sclerosing agent and sclerosing time for the glandular epithelial cells were sufficient. This process inactivated the cyst wall cells and completely closed the cyst wall vessels. This procedure successfully eliminated the factor causing increased serum CA-125
levels. Combined, saline washings and ethanol sclerotherapy allow the serum CA-125 levels to decrease. Previous research has shown that the amount of peritoneal fluid and the serum CA-125 levels in patients with chronic pelvic inflammatory disease are increased to varying degrees.31 The ovarian chocolate cyst lesions can aggravate the degree of chronic pelvic inflammation. Thus, most patients with ovarian chocolate cysts suffer from chronic pelvic inflammatory disease. The final step of the sclerotherapy procedure was to inject an anti-inflammatory triple drug into the pelvic cavity to relieve the chronic pelvic inflammation. The results showed that the drugs associated with ethanol sclerotherapy decreased the CA-125 levels. This study analyzed six patients whose serum CA-125 levels had not decreased to the normal range by 3 months post-treatment. The mean pretreatment serum CA-125 levels of these six patients were significantly greater than those of the other patients (82.34– 151.82 U/mL). Because of our careful screening process, which included ultrasonography, clinical symptoms, vital signs, laboratory data and disease history follow-up, the following diseases were not found in our research patients: adenomyosis, malignant ovarian tumor, pelvic tuberculosis and severe pelvic inflammation. The increased serum CA-125 levels were likely related to other factors, such as longer disease duration, more severe dysmenorrhea history, increased degree of pelvic tissue adhesion and lesion size. A few patients had atypical endometriosis and small endometrial lesions that could not be examined with ultrasonography and other clinical means. In conclusion, the pretreatment serum CA-125 levels were positively correlated with dysmenorrhea history and disease duration. With respect to the ultrasonography characteristics of the ovarian chocolate cysts, the pretreatment serum CA-125 levels were positively correlated with cyst diameter and cyst wall thickness. The serum CA-125 levels were not correlated with age, child-bearing history, abortion history, surgical history or the side on which the cyst occurred. UGIS significantly decreased abnormal serum CA-125 levels in patients with ovarian chocolate cysts.
Acknowledgments The sponsors of this study were the National Natural Science Foundation of China (grant no. 81271646 to X. Q. Dong), Heilongjiang Key Technologies R&D
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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Program funds of China and Harbin Science and Technology Bureau Innovation Research Program Fund of China.
Disclosure None declared.
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© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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