- Email: [email protected]
The Prevalence of Ovarian Varices in Patients with Endometriosis
Accepted Manuscript The Prevalence of Ovarian Varices in Patients with Endometriosis Kennedy Gonçalves Pacheco, Maria Raquel Fortes de Oliveira PII:
S0890-5096(16)30232-1
DOI:
10.1016/j.avsg.2015.12.027
Reference:
AVSG 2772
To appear in:
Annals of Vascular Surgery
Received Date: 4 September 2015 Revised Date:
8 December 2015
Accepted Date: 10 December 2015
Please cite this article as: Pacheco KG, de Oliveira MRF, The Prevalence of Ovarian Varices in Patients with Endometriosis, Annals of Vascular Surgery (2016), doi: 10.1016/j.avsg.2015.12.027. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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The Prevalence of Ovarian Varices in Patients with
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Endometriosis
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Nome: Kennedy Gonçalves Pacheco Email: [email protected] Sociedade Brasileira de Angiologia e de Cirurgia Vascular Rua Álvaro Alvim 37 Salas 805 33 - Centro, RJ, 20071-000 - (21) 2215-1919 Nome: Maria Raquel Fortes de Oliveira Email: [email protected] Colégio Brasileiro Radiologia Av. Paulista, 37, São Paulo - SP, 01311-000 - (11) 3284-8171
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State University of Rio de Janeiro
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Research performed in the Medical Gynaecological Offices of the University Hospital of the
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Brasil, Tel.: 5521 998118965; Mailing address: Rua Alcindo Guanabara, 25 – 1304, Centro
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da Cidade, Rio de Janeiro – RJ, Brasil – ZIP code: 20031130; E-mail: kennedy-
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[email protected]; Fax number: +552124525739 , +5521998118965
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Corresponding author: Kennedy Gonçalves Pacheco, Vascular Surgeon and Phlebologist,
Short title: Ovarian Varices and Endometriosis
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Abstract
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Objective: To study the possible association between endometriosis and ovarian varices. These diseases manifest with similar symptomologies and the hormone estradiol is implicated in both. Design: Observational case control.
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Setting: Hospital Universitário Pedro Ernesto (UERJ) – Rio de Janeiro - Brazil
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Patients: The sample consisted of 48 female patients between the ages of 18 and 50 years old. There were 25 patients who had been diagnosed with endometriosis. 15 had been confirmed by surgery and histopathology and 10 by nuclear magnetic resonance. There were also 23 patients without endometriosis who were considered to be the control group.
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Interventions: Ultrasound system with endovaginal transducer of 4 to 8 MHz. The researchers attempted to identify the anechoic, circular, linear, and non-pulsatile structures in the broad ligament of the uterus. This study was conducted from May 2013 to September 2014.
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Mains outcomes measures: Varices with dilation of equal to or greater than 5 mm in the longitudinal cut, with tortuous veins with reflux in the adnexal region.
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Results: The prevalence of ovarian varices in patients with endometriosis was 80%, whereas, the control group was only 26,1%. The elevated percentage of ovarian varices in patients with endometriosis is highly significant, with a difference of 53.9% and 95% confidence interval of 30% to 78%. The criteria for the determination of significance that we adopted was the level of 5%.The statistical analysis was processed using the statistical software SAS system, version 6.11 (SAS Institute, inc., Cary, North Carolina).
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Conclusion: Our results suggest that ovarian varices may play a very important role in the
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physiopathology of endometriosis. Ovarian varices may evolve with oxidative stress in the function of the
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ovary, provoking an imbalance in its genetic, hormonal, and immunological aspects, provoking the
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chronic inflammatory process particular to endometriosis.
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Key words: endometriosis; pelvic ovarian veins; varices; oxidative stress; varicocele
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Introduction Endometriosis was described by Daniel Shroen, in 1690, as multiple ulcers in the
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abdomen between the instestines and pelvic organs that provoked adherences and fibrosis
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scars [1]. The chronic venous insufficiency can evolve, also, with ulcers and fibrosis scars
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[2].
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Endometriosis is a multi-focal, oestrogen-dependent disease that is characterized by the presence of endometrial tissue outside of the uterus and chronic inflammation, primarily
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in the pelvis [3]. The principal clinical complaints are chronic pelvic pain, dysmenorrhea, and
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dyspareunia, and up to 71% of patients with this condition have chronic pelvic pain and
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infertility [4, 5]. The differential diagnosis is done with gynaecologocial causes, (i.e pelvic
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inflammatory disease and ovarian torsion, amongst others) and with non gynaecological
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causes (i.e renal stone and diverticulitis, amongst others) [6, 7].The formation of ectopic
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endometrial implants requires the development of angiogenic capacity [8].
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Similar to metastatic tumours, ectopic endometrial implants require
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neovascularization to guarantee the suppression of oxygen and essential nutrients [9].
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Uncontrolled angiogenesis occurs in various pathologies, such as endometriosis, rheumatoid
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arthritis, psoriasis, proliferative diabetic retinopathy, and cancer [10]. The pelvic congestion
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syndrome, described by Richet in 1857 as chronic pelvic pain and feeling of heaviness in the
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pelvis, has been associated to ovarian varicose veins by Cotte in 1928 and Taylor in 1949 [11,
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12, 13].
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Ovarian varices are veins that are dilated, tortuous, and congested. They are caused by
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retrograde reflux originating from incompetent valves in the ovarian veins [6]. The main
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complaint of patients with ovarian varices is chronic pelvic pain [14]. Transvaginal
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ultrasound with colour Doppler is the exam of choice to identify ovarian varices [15].
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Selective phlebography of the ovarian veins may be performed to confirm or rule out the
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presence of ovarian varices with certainty [16]. Although laparoscopy is a useful resource for
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detecting endometriosis, it has been proven ineffective for identifying pelvic varicosities in
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the overwhelming majority of cases (80-90% of patients) [17, 18]. Ovarian varices are found
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in approximately 50% of women with chronic pelvic pain [14, 19, 20]. Ovarian hormone
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levels in the groin veins of patients with pelvic varices have been reported to be two times
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higher than those in blood collected from the arm [21]. Women with ovarian varices tend to
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have a larger uterus and more ovarian cysts as a result of oestrogenic stimulation [22]. One of
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the ways in which oestrogen functions to regulate cellular metabolism in different tissues is
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via protein-specific intra-nuclear receptors [23].
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These receptors are also located in the endothelial cells of the vein [23, 24].
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Endometriosis patients have aberrant expression of oestrogen, progesterone receptors and
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factors that interfere with angiogenesis [22, 25]. Endometriotic lesions are densely
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vascularized as a result of angiogenesis [3, 26]. Vascular endothelial growth factor (VEGF) is
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a principal angiogenic factor [27], and endometrial VEGF expression is enhanced by
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oestradiol [28]. Researchers have shown that the expression and concentration of VEGF are
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elevated in tissues from endometriotic patients [29, 30]. Oxidative stress present in
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endometriosis as well as in the varicose dilations plays an important role in these pathologies,
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interfering with genetics, angiogenesis and in the chronic inflammatory process [2, 31-33].
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Furthermore, pelvic pain is an important and common symptom of these pathologies. No
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studies have been published further demonstrating the relationship between endometriosis
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and ovarian varices. Thus, in this study, we have confirmed that ovarian varices are highly
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prevalent in endometriosis patients.
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Methods
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The sample consisted of 48 female patients between the ages of 18 and 50 years. This study was conducted in the city of Rio de Janeiro in the southwest region of Brasil from May 2013 to September 2014. The patients were recruited from the Gynaecology Clinic of the State University of Rio de Janeiro (UERJ). This study was authorized by the Ethics Committee, and the patients signed waivers of consent.
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Having as a main objective to evaluate if there is a significant difference in the proportion of pelvic venous disease between the groups of patients with endometriosis and the control group (without endometriosis), suppositions considered for the calculation of the sample size included the level of significance of 5% (bilateral) and the power of the statistical test of 80%.The expected difference between the groups was relatively “large” (above 50%), also known as the size of effect.
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According to JACOB, the minimum number of cases is of 25 in each group, adding up to 50 patients in the study according to the calculation (when in fact the number of patients in the study was of 48).
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The patients were examined by a radiologist who specialized in ultrasound, and they
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were monitored by the primary author of the study. We used an ultrasound system with
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endovaginal transducer of 4 to 8 MHz. The patients emptied their bladders before being
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examined. They then laid flat on their backs (in the supine position) with their knees bent at
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an angle of 30-45 degrees.
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An endovaginal transducer was coated with a lubricated condom and introduced into the vaginal canal of each patient, which allowed for identification of the ovaries and vascular
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structures in each adnexal region. The researchers attempted to identify the anechoic,
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circular, linear, and non-pulsatile structures in the broad ligament of the uterus.
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Anechoic structures that were found with a diameter of equal to or larger than 5 mm
were examined by colour scale and pulsed-wave Doppler. Paraovarian varices were defined by dilation of equal to or greater than 5 mm in the
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longitudinal cut, with tortuous veins with reflux in the adnexal region [15, 16, 34, 35].
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Significant reflux was defined as retrograde flux lasting for longer than 0.5 s [36], as
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monitored by Doppler pulse wave. We were careful to adjust the gain, filter, and repetition of
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the pulses.
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The descriptive analysis presented the observed data in the form of tables, expressed
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by average, median standard deviation, interquartile range (Q1 and Q30, minimum and
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maximum for numerical data and through frequency (n) and percentage (%) the categorical
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(qualitative) data. The inferential analysis was composed by the comparison of clinical variables, the
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measures of reproductive device and gestation between the groups (with and without
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endometriosis), it was evaluated by the Mann-Whitney test for numerical data and by the chi-
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square test (x squared) or Fisher exact for categorical data, the comparison Non-parametric
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methods were applied, as the variables did not present normal distribution (Gaussian), due to
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asymmetry and rejection of the hypothesis of normality of the Shapiro-Wilks test.
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The criterion for determination of significance adopted was the level of 5%. The
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statistical analysis was processed by the statistical software SAS ® System, version 6.11
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(SAS Institute, Inc., Cary, North Carolina).
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Results
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A total of 25 patients had been diagnosed with endometriosis, with 15 confirmed by
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surgery and histopathology and 10 confirmed by nuclear magnetic resonance. An additional
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23 patients without endometriosis were placed in a control group. This group was matched
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alongside the former group in terms of sex, race, body mass index, and age, as shown in table
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1.
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Table 1 – Analysis of the clinical numerical variable and, measurements of the reproductive device and of
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gestation according to the group.
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The members of the control group were selected based the following criteria: no
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history of gynaecological diseases and absence of the main symptoms of endometriosis, such
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as chronic pelvic pain, dysmenorrhea and dyspareunia. 6
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The endometriosis patients had a much higher frequency of ovarian varices compared with the controls (80% vs. 26.1%, respectively). This elevation in the percentage of ovarian
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varices in the patients was highly significant, with a difference of 53.9% and a 95%
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confidence interval of 30% to 78%. We used a threshold of 5 mm, and the mean diameter of
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the right ovarian veins with reflux found in our sample was 6.2 mm (p=0.016), while that of
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the left ovarian veins was 5.8 mm (p=0.0001) , as shown in Fig 1a e 1b. In addition, the
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endometriosis patients had a significantly larger left ovarian vein diameter of ≥ 5 mm
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(p<0.0001), larger right ovarian vein diameter of ≥5 mm (p<0.0001), increased left vein
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reflux (p=0.023), pelvic pain (p=0.0003), dysmenorrhea (p=0.036), dyspareunia (p=0.001)
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and intestinal constipation (p=0.018) compared with the control patients without
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endometriosis. Other categorical variables did not present any significant differences at the
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level of 5% between the groups. The endometriosis patients also exhibited an increased
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tendency of mild/strong pain in the lumbar region compared with the controls (p=0.097), as
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shown in table 2.
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Table 2 – Analysis of the categorical variables according to group.
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The results of our study confirm the high prevalence of ovarian varices in
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Discussion
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endometriosis patients, as they were found at a frequency of 80% in the patients compared
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with 26.1% of the controls.
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Similar prevalences as those determined in the present study have been previously
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reported in the medical literature, including reports of 12.2% pelvic varicose veins in the
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general population [6, 15], 50% in patients with chronic pelvic pain (a group suspected to
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have endometriosis and/or ovarian varices) [14, 20, 37] and 100% in patients with
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endometrioma in the left ovary [38]. Matalliotakis et al. have suggested a new mechanical
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theory of implication, the female varicocele theory, suggesting that these veins may play a
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fundamental role in the development of ovarian endometriosis [38]. We identified varicose
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veins beside the endometrioma in our research, as shown below in Figure 2. Carolina Wassong et al. [39] have described a 13-year-old child with endometriosis
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associated with ovarian varices. Ghosh et al. [40] performed video-laparoscopy to treat an
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endometriosis patient and found ovarian varices, which were then treated. Three months after
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this treatment, the patient became pregnant [40]. In our study, we found endometriotic
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patients with ovarian varices of 5 to 8 mm. There is no agreement in the literature concerning
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the ideal threshold for the correlation between the adnexal vein diameter measured by
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transvaginal Doppler ultrasound and the presence of reflux. Moreover, many threshold values
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have been reported in a variety of studies, ranging from 5 to 8 mm [15, 16, 34, 35]. Two
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recent studies have shown that oxidative stress (OS) is greater in varicose veins with
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insufficient valves [41, 42]. OS is the result of an imbalance between pro-oxidants and
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antioxidants [43]. This ratio can be altered by the following factors: increased levels of
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reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) or decreased activity
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of antioxidant defence mechanisms [44, 45]. Varicose veins are considered common
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manifestations of venous insufficiency and venous hypertension, and they may provoke
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chronic venous insufficiency in the lower limbs [46]. Venous hypertension in the lower limbs
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may cause increases in the plasmatic level of VEGF [32], endothelial activation by leucocyte
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adhesion, and OS and altered skin microcirculation [2, 41-43].
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Studies have found that patients with “a high level of OS” and varicose veins may be
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treated by surgery, namely long saphenous vein stripping or therapy with compression socks,
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which have been demonstrated to reduce the levels of local reactive oxygen metabolites in
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patients with venous disease of the lower limbs [32, 33].
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Ovarian varices may provoke alterations in the ovaries that are similar to those of
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varicoceles beside the testicles, resulting in OS, DNA damage, infertility, and changes in
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hormonal production with alterations in the hypothalamic-pituitary-testis (HPT) axis. The
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treatment of varicoceles by surgery, sclerotherapy, or embolization normally results in
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improvements in the integrity of sperm DNA and OS and increases fertility and the chance of
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pregnancy by intrauterine insemination [47]. Moreover, in adolescents, if surgery is
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performed before damage becomes severe and irreversible, the testicles resume growth [48].
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Studies have shown that not all patients with a varicocele develop infertility, suggesting that
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other factors are involved in this process [49]. The increased DNA damage in spermatozoa,
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oocytes and embryos seems to be responsible for the numerous fertilization and implantation
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failures experienced by endometriotic patients [50].
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A medical team treating “hypofunctional ovaries due to varicosities of the ovarian veins “with embolization of the pelvic veins has reported that after treatment, of 19 patients
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considered to be infertile, 14 later became pregnant [51].
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embolization of pelvic varices in the medical literature [16, 40, 51-55]. An association among endometriosis, hyperprolactinaemia and luteal insufficiency
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We found 23 cases of pregnancy in women with a confirmed history of infertility after
has been described as a possible cause of infertility due to ovulatory dysfunction [56].
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Up to 50% of women with ovarian varicose veins have polycystic ovaries, which
could play a role in the development of ovulatory dysfunction [17]. Data have shown that functional disturbances in the ovaries and testicles in relation to
the hypothalamic-pituitary axis are associated with various diseases [57, 58]. Premature ovarian insufficiency manifests through disturbances in the functioning of
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the hypothalamic-pituitary-ovarian axis, ovulatory dysfunction, and infertility [57], and it has
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been associated with several endocrine (thyroid, adrenal, and hypoparathyroid disorders,
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diabetes and hypophysitis) and non-endocrine diseases (systemic lupus erythematous,
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rheumatoid arthritis, autoimmune haemolytic anaemia and others) [57-59].
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Research has shown high rates of autoimmune and endocrine disorders, including hypothyroidism, chronic fatigue syndrome, systemic lupus erythematous, rheumatoid arthritis
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and multiple sclerosis, in women with endometriosis [60].
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In addition, the majority of male subjects with multiple sclerosis have abnormal functioning of the HPT-axis and impaired fertility [60].
Pacheco et al. [52] have reported a patient with deep endometriosis and infertility who
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became pregnant at 4 months after the treatment of ovarian varices by embolization and
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sclerotherapy. Three days after the procedure, the patient reported that her chronic pelvic
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pain, which she had been experiencing for ten years, had disappeared. In addition, she stated
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that she was no longer experiencing intestinal constipation, which had lasted for 8 days, and
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that she was having regular bowel movements and intestinal functioning [52]. In our study,
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we found that 44% of the endometriosis patients complained of intestinal constipation,
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whereas only 13% of the controls reported this symptom (p=0.018). Studies have shown an
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association of varicoceles and ovarian varices with chronic intestinal constipation [61, 62].
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Increasing evidence suggests that a combination of hormonal, genetic, environmental,
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anatomical, and immunological factors play crucial roles in the pathogenesis of endometriosis
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[63, 64]. OS has been reported to play an important role in the promotion of angiogenesis, in
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endometriotic implantation and in increased VEGF production. OS can cause genetic and
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molecular alterations and contribute to the pathogenesis of “endometriosis with associated
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infertility “[65].
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ROS can directly disrupt endothelial cell functioning and cellular interactions, thereby
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promoting microvascular thrombosis and organ dysfunction [66]. Furthermore, ovarian
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dysfunction is associated with endometriosis and infertility [67]. Venous hypertension causes
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distension and OS in endothelial cells and as a result, the expression of numerous genes may
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become altered [31]. Therefore, we postulate that OS present in varices located beside the
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ovary triggers dysfunctional microcirculation in the ovary itself. Previous reports in the
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literature have indicated that the treatment of varices may relieve OS. Various authors have
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shown that the treatment of pelvic varices with embolization confers positive results and a
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low risk of complications [16, 34, 68]. Medical suppression of ovarian function and
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hysterectomy with or without bilateral salpingo-oophorectomy have also been mentioned as
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possible alternatives [14, 69, 70] however, these procedures are not commonly practiced.
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Open surgical division of the ovarian veins is not widely performed due to the associated
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complications, but laparoscopic division has been performed with positive results [71]. Case
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reports have shown that the lack of treatment of ovarian varices may lead to complications
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that evolve into venous thrombosis and pulmonary embolism [72, 73]. There are two
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principal objectives in the treatment of endometriosis: the alleviation of pelvic pain and
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successful achievement of pregnancy in infertile patients [74].
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Just as positive results have been demonstrated for the treatment of varicose veins in
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the lower limbs, ovarian varices, and varicoceles [16, 33, 34, 47, 48, 69] success can also be
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obtained in the treatment of ovarian varicose veins in some patients with endometriosis and
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endometriosis-associated infertility.
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Conclusions
Varices in the lower limbs are associated with OS, leucocyte adhesion, and
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endothelial dysfunction, and they can cause alterations in skin microcirculation, resulting in
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chronic venous insufficiency with hyperpigmentation, eczema, lipodermatosclerosis and
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ulcerations [2]. Tissue damage may also be provoked by varices in the scrotal sack.
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Varicoceles in men are associated with OS, endothelial dysfunction, DNA fragmentation in
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sperm, altered hormone production, altered functioning of the HPT axis and even testicular
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atrophy [47, 48].
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It is possible that ovarian varices also provoke OS, endothelial dysfunction, and alterations in the formation of follicles and oocytes, causing an imbalance in the genetic,
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hormonal, and immunological composition of the ovaries. Our finding of the high prevalence
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of ovarian varices in the endometriosis patients warrants further studies of the roles of pelvic
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varicose veins in infertility and endometriosis.
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Disclosures
This paper resulted from research performed at the Pedro Ernesto University Hospital
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(UERJ-Brasil) with the purpose of obtaining a master’s degree at the Universidade Federal do
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Rio Grande do Sul in Brasil. The abstract of this study will be presented during the poster
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session at the SEOUL UIP 2015.
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The authors declare that there are no conflicts of interest with respect to the authorship and/or publication of this paper.
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Conflicts of interest
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Acknowledgements
The authors wish to thank Dr. Rodolfo Acatauassú Nunes for his valuable
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contributions and permission to collect and examine patients of the gynaecological service of
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the University Hospital Pedro Ernesto – UERJ - Brasil in this study.
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Authors Contribution:
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KGP – Performed the research
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MRFO – She examined the patients with ultrasound
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GBBP – Advisor Search
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AHP – Co-advisor Search
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38. Matalliotakis IM, Cakmak H, Koumantakis EE, Margariti A, Neonaki M, Goumenou AG: arguments for a left lateral predisposition of endometrioma. Fertil Steril 2009;91:975– 978.
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39. Wassong C, Shah B, Kanayama M, Bjarnason H, Milla SS: Radiologic findings of pelvic venous congestion in an adolescent girl with angiographic confirmation and interventional treatment. Pediatr Radiol 2012;42:636–640.
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40. Ghosh A, Shafie-Pour H, Ayers KJ: Laparoscopic sclerotherapy in a case of pelvic congestion syndrome. BJOG 2006;113:610-611.
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41. Krzyściak W, Kózka M: Generation of reactive oxygen species by a sufficient, insufficient and varicose vein wall. Acta Biochim Pol 2011;58:89-94.
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42. Karatepe O, Unal O, Ugurlucan M, Kemik A, Karahan S, Aksoy M, Kurtoglu M: The impact of valvular oxidative stress on the development of venous stasis ulcer valvular oxidative stress and venous ulcers. Angiology 2010;61:283-288.
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43. Al-Gubory KH, Fowler PA, Garrel C: The roles of cellular reactive oxygen species, oxidative stress and antioxidants in pregnancy outcomes. Int J Biochem Cell Biol 2010;42:1634-1650.
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44. Ruder EH, Hartman TJ, Goldman MB: Impact of oxidative stress on female fertility. Curr Opin Obstet Gynecol 2009;21:219–222.
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45. Burton GJ, Jauniaux E: Oxidative stress. Best Pract Res Clin Obstet Gynaecol 2011;25:287–299.
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46. Evans CJ, Fowkes FG, Ruckley CV, Lee AJ: Prevalence of varicose veins and chronic venous insufficiency in men and women in the general population: Edinburgh vein study. J Epidemiol Comm Health 1999;53:149-153.
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47. Chen SS, Huang WJ, Chang LS, Wei YH: Attenuation of oxidative stress after varicocelectomy in subfertile patients with varicocele. J Urol 2008;179:639–642.
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48. Lemack GE, Uzzo RG, Schlegel PN, Goldstein M: Microsurgical repair of the adolescent varicocele. J Urol 1998;160:179-181.
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49. Peng BC, Tomashefsky P, Nagler HM: The cofactor effect: varicocele and infertility. Fertil Steril 1990;54:143–148.
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50. Mansour G, Abdelrazik H, Sharma RK, Radwan E, Falcone T, Agarwal A: L-carnitine supplementation reduces oocyte cytoskeleton damage and embryo apoptosis induced by incubation in peritoneal fluid from patients with endometriosis. Fertil Steril 2009;91:20792086.
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51. Galkin EV, Grakova LS, Naumova EB: [Roentgeno-endovascular surgery of hypofunctional ovaries in varicosities of the ovarian veins]. Vestn Rentgenol Radiol 1991;5:51-59.
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52. Pacheco KG, Fortes R: Pregnancy after sclerotherapy and embolization of ovarian varicose veins in a patient with infertility and deep endometriosis. Gynecol Obstet 2014;4:2161-0932.
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53. Tarazov P, Prozorovskij K, Rumiantseva S: Pregnancy after embolization of an ovarian varicocele associated with infertility: report of two cases. Diagn Interv Radiol 2011;17:174–176.
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54. Venbrux AC, Chang AH, Kim HS, Montague BJ, Hebert JB, Arepally A, Rowe PC, Barron DF, Lambert D, Robinson JC: Pelvic congestion syndrome (pelvic venous incompetence): impact of ovarian and internal iliac vein embolotherapy on menstrual cycle and chronic pelvic pain. J Vasc Interv Radiol 2002;13:171–178.
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55. Bachar GN, Belenky A, Greif F, Atar E, Gat Y, Itkin M, Verstanding A: Initial experience with ovarian vein embolization for the treatment of chronic pelvic pain syndrome. Isr Med Assoc J 2003;5:843–846.
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56. Cunha-Filho JS, Gross JL, Lemos NA, Brandelli A, Castillos M, Passos EP: Hyperprolactinemia and luteal insufficiency in infertile patients with mild and minimal endometriosis. Horm Metab Res 2001;33:216–220.
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57. Safarinejad MR: Evaluation of endocrine profile and hypothalamic-pituitary-testis axis in selective serotonin reuptake inhibitor-induced male sexual dysfunction. J Clin Psychopharmacol 2008;28:418–423.
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58. Hoek A, Schoemaker J, Drexhage HA: Premature ovarian failure and ovarian autoimmunity. Endocr Rev 1997;18:107–134.
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59. Doldi N, Belvisi L, Bassan M, Fusi FM, Ferrari A: Premature ovarian failure: steroid synthesis and autoimmunity. Gynecol Endocrinol 1998;12:23–28.
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60. Sinaii N1, Cleary SD, Ballweg ML, Nieman LK, Stratton P. High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: a survey analysis. Hum Reprod. 2002 Oct;17(10):2715-24.
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61. Turgut AT, Ozden E, Koşar P, Koşar U, Cakal B, Karabulut A: Chronic constipation as a causative factor for development of varicocele in men: a prospective ultrasonographic study. J Ultrasound Med 2007;26:5–10.
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62. Bachar GN, Belenky A, Greif F, Atar E, Gat Y, Itkin M, Verstanding A: Initial experience with ovarian vein embolization for the treatment of chronic pelvic pain syndrome. Isr Med Assoc J 2003;5:843–846.
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63. Nisolle M, Donnez J: Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril 1997;68:585–596.
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64. Heilier JF, Donnez J, Lison D: Organochlorines and endometriosis: a mini-review. Chemosphere 2008;71:203–210.
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65. Wu Y, Kajdacsy-Balla A, Strawn E, Basir Z, Halverson G, Jailwala P,Wang Y, Wang X, Ghosh S, Guo S.-W: Transcriptional characterizations of differences between Eutopic and ectopic endometrium. Endocrinology 2006;147:232–246.
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66. Martins PS, Kallas EG, Neto MC, Dalboni MA, Blecher S, Salomão R: Upregulation of reactive oxygen species generation and phagocytosis, and increased apoptosis in human neutrophils during severe sepsis and septic shock. Shock 2003;20:208–212.
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67. Cahill DJ, Wardle PG, Maile LA, Harlow CR, Hull MG: Ovarian dysfunction in endometriosis-associated and unexplained infertility. J Assist Reprod Genet 1997;14:554– 557.
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68. Creton D, Hennequin L, Kohler F, Allaert FA: Embolisation of symptomatic pelvic veins in women presenting with non-saphenous varicose veins of pelvic origin - three-year follow-up. Eur J Vasc Endovasc Surg 2007;34:112–117.
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69. Soysal ME, Soysal S, Vicdan K, Ozer S: A randomized controlled trial of goserelin and medroxyprogesterone acetate in the treatment of pelvic congestion. Hum Reprod 2001;16:931-939.
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70. Beard RW, Kennedy RG, Gangar KF, Stones RW, Rogers V, Reginald PW, Anderson M: Bilateral oophorectomy and hysterectomy in the treatment of intractable pelvic pain associated with pelvic congestion. Br J Obstet Gynaecol 1991;98:988–992.
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71. Gettman MT, Lotan Y, Cadeddu J: Laparoscopic treatment of ovarian vein syndrome. JSLS 2003;7:257-260.
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72. Everarts P, Poelaert D, Bormans P, Guisgand M, Debehogne G, Marot J: Pelvic varicose veins thrombosis in a patient with pulmonary. JBR-BTR 2008;91:200-202.
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73. Benfayed WH, Torreggiani WC, Hamilton S: Detection of pulmonary emboli resulting from ovarian vein thrombosis. AJR Am J Roentgenol 2003;181:1430–1431.
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S0890-5096(16)30232-1
DOI:
10.1016/j.avsg.2015.12.027
Reference:
AVSG 2772
To appear in:
Annals of Vascular Surgery
Received Date: 4 September 2015 Revised Date:
8 December 2015
Accepted Date: 10 December 2015
Please cite this article as: Pacheco KG, de Oliveira MRF, The Prevalence of Ovarian Varices in Patients with Endometriosis, Annals of Vascular Surgery (2016), doi: 10.1016/j.avsg.2015.12.027. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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The Prevalence of Ovarian Varices in Patients with
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Endometriosis
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Nome: Kennedy Gonçalves Pacheco Email: [email protected] Sociedade Brasileira de Angiologia e de Cirurgia Vascular Rua Álvaro Alvim 37 Salas 805 33 - Centro, RJ, 20071-000 - (21) 2215-1919 Nome: Maria Raquel Fortes de Oliveira Email: [email protected] Colégio Brasileiro Radiologia Av. Paulista, 37, São Paulo - SP, 01311-000 - (11) 3284-8171
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State University of Rio de Janeiro
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Research performed in the Medical Gynaecological Offices of the University Hospital of the
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Brasil, Tel.: 5521 998118965; Mailing address: Rua Alcindo Guanabara, 25 – 1304, Centro
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da Cidade, Rio de Janeiro – RJ, Brasil – ZIP code: 20031130; E-mail: kennedy-
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[email protected]; Fax number: +552124525739 , +5521998118965
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Corresponding author: Kennedy Gonçalves Pacheco, Vascular Surgeon and Phlebologist,
Short title: Ovarian Varices and Endometriosis
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Abstract
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Objective: To study the possible association between endometriosis and ovarian varices. These diseases manifest with similar symptomologies and the hormone estradiol is implicated in both. Design: Observational case control.
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Setting: Hospital Universitário Pedro Ernesto (UERJ) – Rio de Janeiro - Brazil
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Patients: The sample consisted of 48 female patients between the ages of 18 and 50 years old. There were 25 patients who had been diagnosed with endometriosis. 15 had been confirmed by surgery and histopathology and 10 by nuclear magnetic resonance. There were also 23 patients without endometriosis who were considered to be the control group.
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Interventions: Ultrasound system with endovaginal transducer of 4 to 8 MHz. The researchers attempted to identify the anechoic, circular, linear, and non-pulsatile structures in the broad ligament of the uterus. This study was conducted from May 2013 to September 2014.
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Mains outcomes measures: Varices with dilation of equal to or greater than 5 mm in the longitudinal cut, with tortuous veins with reflux in the adnexal region.
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Results: The prevalence of ovarian varices in patients with endometriosis was 80%, whereas, the control group was only 26,1%. The elevated percentage of ovarian varices in patients with endometriosis is highly significant, with a difference of 53.9% and 95% confidence interval of 30% to 78%. The criteria for the determination of significance that we adopted was the level of 5%.The statistical analysis was processed using the statistical software SAS system, version 6.11 (SAS Institute, inc., Cary, North Carolina).
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Conclusion: Our results suggest that ovarian varices may play a very important role in the
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physiopathology of endometriosis. Ovarian varices may evolve with oxidative stress in the function of the
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ovary, provoking an imbalance in its genetic, hormonal, and immunological aspects, provoking the
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chronic inflammatory process particular to endometriosis.
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Key words: endometriosis; pelvic ovarian veins; varices; oxidative stress; varicocele
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Introduction Endometriosis was described by Daniel Shroen, in 1690, as multiple ulcers in the
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abdomen between the instestines and pelvic organs that provoked adherences and fibrosis
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scars [1]. The chronic venous insufficiency can evolve, also, with ulcers and fibrosis scars
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[2].
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Endometriosis is a multi-focal, oestrogen-dependent disease that is characterized by the presence of endometrial tissue outside of the uterus and chronic inflammation, primarily
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in the pelvis [3]. The principal clinical complaints are chronic pelvic pain, dysmenorrhea, and
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dyspareunia, and up to 71% of patients with this condition have chronic pelvic pain and
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infertility [4, 5]. The differential diagnosis is done with gynaecologocial causes, (i.e pelvic
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inflammatory disease and ovarian torsion, amongst others) and with non gynaecological
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causes (i.e renal stone and diverticulitis, amongst others) [6, 7].The formation of ectopic
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endometrial implants requires the development of angiogenic capacity [8].
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Similar to metastatic tumours, ectopic endometrial implants require
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neovascularization to guarantee the suppression of oxygen and essential nutrients [9].
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Uncontrolled angiogenesis occurs in various pathologies, such as endometriosis, rheumatoid
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arthritis, psoriasis, proliferative diabetic retinopathy, and cancer [10]. The pelvic congestion
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syndrome, described by Richet in 1857 as chronic pelvic pain and feeling of heaviness in the
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pelvis, has been associated to ovarian varicose veins by Cotte in 1928 and Taylor in 1949 [11,
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12, 13].
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Ovarian varices are veins that are dilated, tortuous, and congested. They are caused by
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retrograde reflux originating from incompetent valves in the ovarian veins [6]. The main
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complaint of patients with ovarian varices is chronic pelvic pain [14]. Transvaginal
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ultrasound with colour Doppler is the exam of choice to identify ovarian varices [15].
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Selective phlebography of the ovarian veins may be performed to confirm or rule out the
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presence of ovarian varices with certainty [16]. Although laparoscopy is a useful resource for
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detecting endometriosis, it has been proven ineffective for identifying pelvic varicosities in
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the overwhelming majority of cases (80-90% of patients) [17, 18]. Ovarian varices are found
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in approximately 50% of women with chronic pelvic pain [14, 19, 20]. Ovarian hormone
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levels in the groin veins of patients with pelvic varices have been reported to be two times
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higher than those in blood collected from the arm [21]. Women with ovarian varices tend to
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have a larger uterus and more ovarian cysts as a result of oestrogenic stimulation [22]. One of
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the ways in which oestrogen functions to regulate cellular metabolism in different tissues is
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via protein-specific intra-nuclear receptors [23].
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These receptors are also located in the endothelial cells of the vein [23, 24].
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Endometriosis patients have aberrant expression of oestrogen, progesterone receptors and
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factors that interfere with angiogenesis [22, 25]. Endometriotic lesions are densely
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vascularized as a result of angiogenesis [3, 26]. Vascular endothelial growth factor (VEGF) is
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a principal angiogenic factor [27], and endometrial VEGF expression is enhanced by
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oestradiol [28]. Researchers have shown that the expression and concentration of VEGF are
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elevated in tissues from endometriotic patients [29, 30]. Oxidative stress present in
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endometriosis as well as in the varicose dilations plays an important role in these pathologies,
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interfering with genetics, angiogenesis and in the chronic inflammatory process [2, 31-33].
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Furthermore, pelvic pain is an important and common symptom of these pathologies. No
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studies have been published further demonstrating the relationship between endometriosis
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and ovarian varices. Thus, in this study, we have confirmed that ovarian varices are highly
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prevalent in endometriosis patients.
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Methods
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The sample consisted of 48 female patients between the ages of 18 and 50 years. This study was conducted in the city of Rio de Janeiro in the southwest region of Brasil from May 2013 to September 2014. The patients were recruited from the Gynaecology Clinic of the State University of Rio de Janeiro (UERJ). This study was authorized by the Ethics Committee, and the patients signed waivers of consent.
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Having as a main objective to evaluate if there is a significant difference in the proportion of pelvic venous disease between the groups of patients with endometriosis and the control group (without endometriosis), suppositions considered for the calculation of the sample size included the level of significance of 5% (bilateral) and the power of the statistical test of 80%.The expected difference between the groups was relatively “large” (above 50%), also known as the size of effect.
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According to JACOB, the minimum number of cases is of 25 in each group, adding up to 50 patients in the study according to the calculation (when in fact the number of patients in the study was of 48).
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The patients were examined by a radiologist who specialized in ultrasound, and they
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were monitored by the primary author of the study. We used an ultrasound system with
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endovaginal transducer of 4 to 8 MHz. The patients emptied their bladders before being
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examined. They then laid flat on their backs (in the supine position) with their knees bent at
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an angle of 30-45 degrees.
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An endovaginal transducer was coated with a lubricated condom and introduced into the vaginal canal of each patient, which allowed for identification of the ovaries and vascular
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structures in each adnexal region. The researchers attempted to identify the anechoic,
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circular, linear, and non-pulsatile structures in the broad ligament of the uterus.
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Anechoic structures that were found with a diameter of equal to or larger than 5 mm
were examined by colour scale and pulsed-wave Doppler. Paraovarian varices were defined by dilation of equal to or greater than 5 mm in the
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longitudinal cut, with tortuous veins with reflux in the adnexal region [15, 16, 34, 35].
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Significant reflux was defined as retrograde flux lasting for longer than 0.5 s [36], as
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monitored by Doppler pulse wave. We were careful to adjust the gain, filter, and repetition of
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the pulses.
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The descriptive analysis presented the observed data in the form of tables, expressed
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by average, median standard deviation, interquartile range (Q1 and Q30, minimum and
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maximum for numerical data and through frequency (n) and percentage (%) the categorical
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(qualitative) data. The inferential analysis was composed by the comparison of clinical variables, the
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measures of reproductive device and gestation between the groups (with and without
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endometriosis), it was evaluated by the Mann-Whitney test for numerical data and by the chi-
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square test (x squared) or Fisher exact for categorical data, the comparison Non-parametric
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methods were applied, as the variables did not present normal distribution (Gaussian), due to
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asymmetry and rejection of the hypothesis of normality of the Shapiro-Wilks test.
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The criterion for determination of significance adopted was the level of 5%. The
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statistical analysis was processed by the statistical software SAS ® System, version 6.11
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(SAS Institute, Inc., Cary, North Carolina).
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Results
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A total of 25 patients had been diagnosed with endometriosis, with 15 confirmed by
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surgery and histopathology and 10 confirmed by nuclear magnetic resonance. An additional
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23 patients without endometriosis were placed in a control group. This group was matched
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alongside the former group in terms of sex, race, body mass index, and age, as shown in table
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1.
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Table 1 – Analysis of the clinical numerical variable and, measurements of the reproductive device and of
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gestation according to the group.
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The members of the control group were selected based the following criteria: no
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history of gynaecological diseases and absence of the main symptoms of endometriosis, such
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The endometriosis patients had a much higher frequency of ovarian varices compared with the controls (80% vs. 26.1%, respectively). This elevation in the percentage of ovarian
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varices in the patients was highly significant, with a difference of 53.9% and a 95%
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confidence interval of 30% to 78%. We used a threshold of 5 mm, and the mean diameter of
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the right ovarian veins with reflux found in our sample was 6.2 mm (p=0.016), while that of
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the left ovarian veins was 5.8 mm (p=0.0001) , as shown in Fig 1a e 1b. In addition, the
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endometriosis patients had a significantly larger left ovarian vein diameter of ≥ 5 mm
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(p<0.0001), larger right ovarian vein diameter of ≥5 mm (p<0.0001), increased left vein
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reflux (p=0.023), pelvic pain (p=0.0003), dysmenorrhea (p=0.036), dyspareunia (p=0.001)
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and intestinal constipation (p=0.018) compared with the control patients without
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endometriosis. Other categorical variables did not present any significant differences at the
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level of 5% between the groups. The endometriosis patients also exhibited an increased
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tendency of mild/strong pain in the lumbar region compared with the controls (p=0.097), as
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shown in table 2.
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Table 2 – Analysis of the categorical variables according to group.
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The results of our study confirm the high prevalence of ovarian varices in
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Discussion
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endometriosis patients, as they were found at a frequency of 80% in the patients compared
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with 26.1% of the controls.
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Similar prevalences as those determined in the present study have been previously
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reported in the medical literature, including reports of 12.2% pelvic varicose veins in the
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general population [6, 15], 50% in patients with chronic pelvic pain (a group suspected to
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have endometriosis and/or ovarian varices) [14, 20, 37] and 100% in patients with
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endometrioma in the left ovary [38]. Matalliotakis et al. have suggested a new mechanical
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theory of implication, the female varicocele theory, suggesting that these veins may play a
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fundamental role in the development of ovarian endometriosis [38]. We identified varicose
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veins beside the endometrioma in our research, as shown below in Figure 2. Carolina Wassong et al. [39] have described a 13-year-old child with endometriosis
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associated with ovarian varices. Ghosh et al. [40] performed video-laparoscopy to treat an
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endometriosis patient and found ovarian varices, which were then treated. Three months after
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this treatment, the patient became pregnant [40]. In our study, we found endometriotic
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patients with ovarian varices of 5 to 8 mm. There is no agreement in the literature concerning
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the ideal threshold for the correlation between the adnexal vein diameter measured by
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transvaginal Doppler ultrasound and the presence of reflux. Moreover, many threshold values
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have been reported in a variety of studies, ranging from 5 to 8 mm [15, 16, 34, 35]. Two
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recent studies have shown that oxidative stress (OS) is greater in varicose veins with
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insufficient valves [41, 42]. OS is the result of an imbalance between pro-oxidants and
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antioxidants [43]. This ratio can be altered by the following factors: increased levels of
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reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) or decreased activity
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of antioxidant defence mechanisms [44, 45]. Varicose veins are considered common
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manifestations of venous insufficiency and venous hypertension, and they may provoke
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chronic venous insufficiency in the lower limbs [46]. Venous hypertension in the lower limbs
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may cause increases in the plasmatic level of VEGF [32], endothelial activation by leucocyte
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adhesion, and OS and altered skin microcirculation [2, 41-43].
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Studies have found that patients with “a high level of OS” and varicose veins may be
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treated by surgery, namely long saphenous vein stripping or therapy with compression socks,
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which have been demonstrated to reduce the levels of local reactive oxygen metabolites in
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patients with venous disease of the lower limbs [32, 33].
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Ovarian varices may provoke alterations in the ovaries that are similar to those of
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varicoceles beside the testicles, resulting in OS, DNA damage, infertility, and changes in
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hormonal production with alterations in the hypothalamic-pituitary-testis (HPT) axis. The
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treatment of varicoceles by surgery, sclerotherapy, or embolization normally results in
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improvements in the integrity of sperm DNA and OS and increases fertility and the chance of
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pregnancy by intrauterine insemination [47]. Moreover, in adolescents, if surgery is
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performed before damage becomes severe and irreversible, the testicles resume growth [48].
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Studies have shown that not all patients with a varicocele develop infertility, suggesting that
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other factors are involved in this process [49]. The increased DNA damage in spermatozoa,
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oocytes and embryos seems to be responsible for the numerous fertilization and implantation
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failures experienced by endometriotic patients [50].
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A medical team treating “hypofunctional ovaries due to varicosities of the ovarian veins “with embolization of the pelvic veins has reported that after treatment, of 19 patients
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considered to be infertile, 14 later became pregnant [51].
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embolization of pelvic varices in the medical literature [16, 40, 51-55]. An association among endometriosis, hyperprolactinaemia and luteal insufficiency
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We found 23 cases of pregnancy in women with a confirmed history of infertility after
has been described as a possible cause of infertility due to ovulatory dysfunction [56].
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Up to 50% of women with ovarian varicose veins have polycystic ovaries, which
could play a role in the development of ovulatory dysfunction [17]. Data have shown that functional disturbances in the ovaries and testicles in relation to
the hypothalamic-pituitary axis are associated with various diseases [57, 58]. Premature ovarian insufficiency manifests through disturbances in the functioning of
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the hypothalamic-pituitary-ovarian axis, ovulatory dysfunction, and infertility [57], and it has
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been associated with several endocrine (thyroid, adrenal, and hypoparathyroid disorders,
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diabetes and hypophysitis) and non-endocrine diseases (systemic lupus erythematous,
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rheumatoid arthritis, autoimmune haemolytic anaemia and others) [57-59].
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Research has shown high rates of autoimmune and endocrine disorders, including hypothyroidism, chronic fatigue syndrome, systemic lupus erythematous, rheumatoid arthritis
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and multiple sclerosis, in women with endometriosis [60].
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In addition, the majority of male subjects with multiple sclerosis have abnormal functioning of the HPT-axis and impaired fertility [60].
Pacheco et al. [52] have reported a patient with deep endometriosis and infertility who
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became pregnant at 4 months after the treatment of ovarian varices by embolization and
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sclerotherapy. Three days after the procedure, the patient reported that her chronic pelvic
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pain, which she had been experiencing for ten years, had disappeared. In addition, she stated
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that she was no longer experiencing intestinal constipation, which had lasted for 8 days, and
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that she was having regular bowel movements and intestinal functioning [52]. In our study,
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we found that 44% of the endometriosis patients complained of intestinal constipation,
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whereas only 13% of the controls reported this symptom (p=0.018). Studies have shown an
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association of varicoceles and ovarian varices with chronic intestinal constipation [61, 62].
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Increasing evidence suggests that a combination of hormonal, genetic, environmental,
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anatomical, and immunological factors play crucial roles in the pathogenesis of endometriosis
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[63, 64]. OS has been reported to play an important role in the promotion of angiogenesis, in
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endometriotic implantation and in increased VEGF production. OS can cause genetic and
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molecular alterations and contribute to the pathogenesis of “endometriosis with associated
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infertility “[65].
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ROS can directly disrupt endothelial cell functioning and cellular interactions, thereby
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promoting microvascular thrombosis and organ dysfunction [66]. Furthermore, ovarian
257
dysfunction is associated with endometriosis and infertility [67]. Venous hypertension causes
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distension and OS in endothelial cells and as a result, the expression of numerous genes may
259
become altered [31]. Therefore, we postulate that OS present in varices located beside the
260
ovary triggers dysfunctional microcirculation in the ovary itself. Previous reports in the
261
literature have indicated that the treatment of varices may relieve OS. Various authors have
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shown that the treatment of pelvic varices with embolization confers positive results and a
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low risk of complications [16, 34, 68]. Medical suppression of ovarian function and
264
hysterectomy with or without bilateral salpingo-oophorectomy have also been mentioned as
265
possible alternatives [14, 69, 70] however, these procedures are not commonly practiced.
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Open surgical division of the ovarian veins is not widely performed due to the associated
267
complications, but laparoscopic division has been performed with positive results [71]. Case
268
reports have shown that the lack of treatment of ovarian varices may lead to complications
269
that evolve into venous thrombosis and pulmonary embolism [72, 73]. There are two
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principal objectives in the treatment of endometriosis: the alleviation of pelvic pain and
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successful achievement of pregnancy in infertile patients [74].
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Just as positive results have been demonstrated for the treatment of varicose veins in
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the lower limbs, ovarian varices, and varicoceles [16, 33, 34, 47, 48, 69] success can also be
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obtained in the treatment of ovarian varicose veins in some patients with endometriosis and
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endometriosis-associated infertility.
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Conclusions
Varices in the lower limbs are associated with OS, leucocyte adhesion, and
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endothelial dysfunction, and they can cause alterations in skin microcirculation, resulting in
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chronic venous insufficiency with hyperpigmentation, eczema, lipodermatosclerosis and
281
ulcerations [2]. Tissue damage may also be provoked by varices in the scrotal sack.
282
Varicoceles in men are associated with OS, endothelial dysfunction, DNA fragmentation in
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283
sperm, altered hormone production, altered functioning of the HPT axis and even testicular
284
atrophy [47, 48].
285
It is possible that ovarian varices also provoke OS, endothelial dysfunction, and alterations in the formation of follicles and oocytes, causing an imbalance in the genetic,
287
hormonal, and immunological composition of the ovaries. Our finding of the high prevalence
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of ovarian varices in the endometriosis patients warrants further studies of the roles of pelvic
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varicose veins in infertility and endometriosis.
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Disclosures
This paper resulted from research performed at the Pedro Ernesto University Hospital
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(UERJ-Brasil) with the purpose of obtaining a master’s degree at the Universidade Federal do
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Rio Grande do Sul in Brasil. The abstract of this study will be presented during the poster
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session at the SEOUL UIP 2015.
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The authors declare that there are no conflicts of interest with respect to the authorship and/or publication of this paper.
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Conflicts of interest
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Acknowledgements
The authors wish to thank Dr. Rodolfo Acatauassú Nunes for his valuable
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contributions and permission to collect and examine patients of the gynaecological service of
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the University Hospital Pedro Ernesto – UERJ - Brasil in this study.
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Authors Contribution:
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KGP – Performed the research
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MRFO – She examined the patients with ultrasound
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GBBP – Advisor Search
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AHP – Co-advisor Search
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