Ovarian Endometriomata Research Articles

Pathophysiology proposed as the basis for modern management of the ovarian endometrioma

Present management of the ovarian endometrioma focuses on the size of the cyst and dictates that surgery should not be performed unless this exceeds 3 cm, which neglects the complex pathology of this condition. Studies of ovaries with the endometrioma in situ show progressive smooth muscle cell metaplasia and fibrosis of the cortical layer as the main ovarian lesion. There is no correlation between the size of the endometrial cyst and the degree of ovarian pathology: it is the mere presence of an ovarian endometrioma that has a detrimental impact on the cortical layer’s follicle reserve. Cystectomy in young patients with an endometrioma may be particularly detrimental to follicle reserve, with the ovarian parenchyma loss at the time of surgery being related to the cyst’s diameter. An underutilized diagnostic procedure, transvaginal hydrolaparoscopy with in-situ inspection of the cyst wall by ovarioscopy, allows careful diagnosis of ovarian pathology and selection of appropriate surgery with minimal invasiveness. Thus, available evidence shows that expectant management may not be the best choice when an endometrioma is suspected. On the contrary, early diagnosis through a minimally invasive technique, followed by early ablative surgery whenever indicated, represents the management of choice to preserve normal ovarian function.Present management of ovarian endometriomata is based on the size of the cyst and dictates that surgery should not be performed unless this exceeds 3cm. We argue that this approach neglects the true pathology of the ovary, since pioneers have studied ovaries with the endometrioma in situ and demonstrated that progressive smooth muscle cell metaplasia and fibrosis in the cortical layer constitute the main features of an endometrioma. There is no correlation between the size of the endometrial cyst and the degree of ovarian pathology: it is in the first place the mere presence of an ovarian endometrioma that has a detrimental impact on follicle reserve. It has been shown that cyst ablation in young patients with an endometrioma may be particularly detrimental to follicle reserve. An underutilized diagnostic procedure, transvaginal needle endoscopy with in-situ inspection after injection of saline suspension into the peritoneal cavity (hydrolaparoscopy) allows careful diagnosis of ovarian cortical pathology by colour changes from pearl-white to dark fibrotic. Thus, available evidence shows that expectant management may not be the best choice when an endometrioma is suspected: the delay in diagnosis causes delay in treatment and progression of the process leading to loss of follicles. On the contrary, early diagnosis through a minimally invasive technique, followed by early ablative surgery whenever indicated, represents the management of choice to preserve normal ovarian function.

MicroRNAs Expression in Endometriosis and Their Relation to Angiogenic Factors

Despite the high prevalence of endometriosis and its incapacitating symptoms, pathogenic mechanisms of this multifactorial disease are unclear. A number of studies have reported that angiogenesis may play an important role in the growth of endometrium outside the uterus. In recent years, microRNAs (miRNAs) have emerged as regulators of gene expression implicated in fundamental biological processes and the pathology of many diseases. Recent studies have suggested that these small (21–22 nucleotide) noncoding RNAs may be important regulators of angiogenesis. Several studies have evaluated possible differential expression of miRNAs in eutopic compared with ectopic endometrium and reported conflicting results. Other angiogenic factors have been implicated in the pathogenesis of endometriosis. Increased levels of vascular endothelial growth factor (VEGF), a potent angiogenic factor, have been reported in endometriosis. Moreover, increased levels of an inhibitor of angiogenesis, thrombospondin-1 (TSP-1) in ovarian endometrioma have been reported. This study investigated several miRNAs implicated in regulation of angiogenesis and their relationship with the angiogenic factors, VEGF-A and TSP-1, comparing their angiogenic activity in endometriotic lesions (ovarian endometrioma, peritoneal lesion, and rectovaginal nodule) and eutopic endometrium from women with endometriosis. The expression of 8 miRNAs (miRNAs-15b, -16, -17-5p, -20a, -21, -125a, -221, and -222).was assessed using TaqMan real-time polymerase chain reaction. Expression of VEGF-A and TSP-1 mRNA were assessed by real-time polymerase chain reaction; protein levels of these 2 angiogenic factors were quantified by ELISA (enzyme-linked immunoadsorbent assay). Study subjects were 58 women with endometriosis; the control group was composed of 38 women without endometriosis. Paired biopsy samples from the eutopic endometrium and ovarian endometriomas of 41 patients with endometriosis were obtained. Compared with eutopic endometrium, paired extracts of ovarian endometriomata showed significantly lower expression of VEGF-A mRNA (P = 0.02) and protein (P = 0.002) and increased expression of antiangiogenic miRNAs (miR-125a [P = 0.003] and miR-222 [P < 0.001]). However, there was an increase in expression of the antiangiogenic factor, TSP-1 and a decrease in the expression of a proangiogenic miRNA (miR-17-5p) in ovarian endometrioma compared with eutopic endometrium (P < 0.001). Significant inverse correlations were observed between miR-222 and VEGF-A protein levels (−0.267, P = 0.018) and between miR-17-5p and TSP-1 protein levels (−0.260, P = 0.022). There were significantly higher VEGF-A protein levels in peritoneal lesions compared with ovarian endometriomata (P < 0.01). These findings suggest that expression of miRNAs regulating angiogenesis may modulate the expression of angiogenic factors and have an important role in the pathogenesis of endometriosis.

Overexpression and Functional Relevance of Somatostatin Receptor-1, -2, and -5 in Endometrium and Endometriotic Lesions

Somatostatin plays a role in physiological and pathological cell proliferation and angiogenesis. Five subtypes of somatostatin receptors have been identified, and the therapeutic use of somatostatin receptor-selective agonists has been reported in several diseases. The aim was to describe the expression and the functional relevance of three human somatostatin receptors (sst1, sst2, and sst5) in tissues of women with and without endometriosis. This pilot study analyzed endometrium, ovarian endometriomata, and peritoneal lesions in 15 patients affected by endometriosis and the endometrium of five women without endometriosis. 111In-pentetreotide scintigraphy was used to detect endometriotic lesions; real-time RT-PCR and immunohistochemistry for sst1, sst2, and sst5 were performed. Migration and proliferation assays were performed on human endometrial stromal cells (ESC) treated with somatostatin and octreotide for 48 h. 111In-pentetreotide scintigraphy was able to correctly identify and locate pelvic endometriotic lesions as confirmed by computed tomography scans. The endometrium of women with endometriosis expressed significantly more sst1, sst2, and sst5 in comparison to that of control women. Moreover, sst1, sst2, and sst5 were highly expressed in ovarian endometriomata and peritoneal lesions. The sst receptor ligand octreotide significantly inhibited ESC migration and proliferation with a maximum effect at 10(-6) m, whereas somatostatin was effective only on ESC growth. This is the first report characterizing the overexpression and functional relevance of somatostatin receptors in eutopic endometrium and lesions of patients affected by endometriosis. Thus, the use of these receptors may provide new strategies for the diagnosis and treatment of endometriosis.

Transvaginal Sonography Guided Aspiration/Sclerosis (TVS-A/S) of Ovarian Endometriomata (OE) Prior to Luteal Phase Gnrha/Controlled Ovarian Hyperstimulation (COH) for IVF-ET

Background and Significance: Laparoscopic resection of OE remains the treatment of choice for patients seeking fertility. Multiple or large OE may adversely affect COH, egg quality and pregnancy outcomes in patients undergoing IVF-ET. In patients having multiple prior surgeries for severe pelvic endometriosis, additional surgeries prior to IVF-ET may add significant risks and cost.

Excisional surgery versus ablative surgery for ovarian endometriomata

Endometriomata are endometriotic deposits within the ovary. The surgical management of these blood filled cysts is controversial. The laparoscopic approach to the management of endometriomata is favoured over a laparotomy approach as it offers the advantage of a shorter hospital stay, faster patient recovery and decreased hospital costs. Currently the commonest procedures for the treatment of ovarian endometriomata are either excision of the cyst capsule or drainage and electrocoagulation of the cyst wall. The objective of this review was to determine the most effective technique of treating an ovarian endometrioma; either excision of the cyst capsule or drainage and electrocoagulation of the cyst wall. The end-points assessed were the relief of pain, recurrence of the endometrioma, recurrence of symptoms and in women desiring to conceive the subsequent pregnancy rate, either spontaneous or as part of fertility treatment. The reviewers searched the Cochrane Menstrual Disorders and Subfertility Group specialised register of trials (searched 3rd March 2007), the Cochrane Register of Controlled Trials (The Cochrane Library, Issue 3, 2007), MEDLINE (1966-August 2007), EMBASE (1980- March 2007) and reference lists of articles, the handsearching of relevant journals and conference proceedings and by contacting leaders in the field of endoscopic surgery throughout the world. The Cochrane Menstrual Disorders and Subfertility Group Trials Register is based on regular searches of MEDLINE, EMBASE, CINHAL and CENTRAL. Randomised controlled trials of excision of the cyst capsule versus drainage and electrocoagulation of the cyst in the management of ovarian endometriomata. Reviewers assessed eligibility and trial quality. No randomised studies of the management of endometriomata by laparotomy were found. Two randomised studies of the laparoscopic management of ovarian endometriomata of greater than 3cm in size, for the primary symptom of pain were included. Laparoscopic excision of the cyst wall of the endometrioma was associated with a reduced recurrence rate of the symptoms of dysmenorrhea (OR 0.15 CI 0.06-0.38), dyspareunia (OR 0.08 CI 0.01-0.51) and non-menstrual pelvic pain (OR 0.10 CI 0.02-0.56), a reduced rate of recurrence of the endometrioma (OR 0.41 CI 0.18-0.93) and with a reduced requirement for further surgery (OR 0.21 CI 0.05-0.79) than surgery to ablate the endometrioma. For those women subsequently attempting to conceive it was also associated with a subsequent increased spontaneous pregnancy rate in women who had documented prior sub-fertility (OR 5.21 CI 2.04-13.29). A further randomised study was identified that demonstrated an increased ovarian follicular response to gonadotrophin stimulation for women who had undergone excsional surgery when compared to ablative surgery (WMD 0.6 CI 0.04-1.16). There is insufficient evidence to favour excisional surgery over ablative surgery with respect to the chance of pregnancy after controlled ovarian stimulation and intra-uterine insemination (OR 1.40 CI 0.47-4.15) . There is good evidence that excisional surgery for endometriomata provides for a more favourable outcome than drainage and ablation with regard to the recurrence of the endometrioma, recurrence of pain symptoms, and in women who were previously subfertile, subsequent spontaneous pregnancy . Consequently this approach should be the favoured surgical approach. However in women who may subsequently may undergo fertility treatment insufficient evidence exists to determine the favoured surgical approach.

Preterm birth, ovarian endometriomata, and assisted reproduction technologies

To report preterm birth and small for gestational age (SGA) rates from assisted reproduction technologies (ART) patients with ovarian endometriomata compared with control groups. Retrospective cohort study. Tertiary university affiliated ART center and Perinatal Data Collection Unit (PDCU). Every woman who had an ART singleton baby born between 1991 and 2004 had her database record assessed (N = 4382). Control groups included 1201 singleton babies from ART patients without endometriosis and 2400 randomly selected women from the PDCU database of 850,000 births. There were 95 singleton ART babies from patients with ovarian endometriomata and 535 ART singleton babies from patients who had endometriosis but no ovarian endometriomata. Preterm birth rates and SGA birth rates. Preterm birth rate increased only in the ovarian endometriomata group when compared with community birth records (n = 850,000). Furthermore, ART patients with ovarian endometriomata had a statistically significantly increased likelihood of having a SGA baby when compared with other forms of endometriosis. Rates of preterm birth and SGA babies doubled in infertility patients with ovarian endometriomata who required ART.

Vascular endothelial growth factor and its soluble receptor in benign and malignant ovarian tumors

An imbalance between pro-angiogenic and anti-angiogenic factors is hypothesized in the pathogenesis of ovarian cystic disease. The aim of the following study was to explore the possible role of free vascular endothelial growth factor receptor 1 (sVEGFR-1), a soluble regulator of vascular endothelial growth factor (VEGF) action, in ovarian cystoadenoma, endometriomata and cystoadenocarcinoma. Forty-eight women, of whom fourteen had ovarian serous cysts, twenty-eight had stage III–IV ovarian endometriomata, and six had stage IIIB–IIIC ovarian carcinoma, were included. Sampling of serum, peritoneal and ovarian cystic fluids and of tumor tissue was performed before, during and following surgery, respectively. Levels of VEGF and sVEGFR-1 were measured in serum, peritoneal and cystic fluid. VEGF and sVEGFR-1 expression was evaluated in tumor tissue. There were no differences in serum VEGF and sVEGFR-1 levels nor in VEGF/VEGFR-1 ratio between study groups. Peritoneal fluid VEGF levels were higher in cystoadenocarcinoma patients than in endometriosis and in cystoadenoma patients, while sVEGFR-1 peritoneal fluid concentrations were significantly higher only in endometriosis-affected women. VEGF/VEGFR-1 ratio was highest in the peritoneal fluid of cancer patients with respect to the other two groups of women. Cystic fluid VEGF and VEGFR-1 concentrations were higher in endometriomata and in cystoadenocarcinomas than in cystadenomas but the VEGF/VEGFR-1 ratio was highest in cancer patients. Western blot evidenced a marked expression of VEGF and soluble VEGFR-1 in endometriosis tissue with respect to benign cyst tissue but a lower expression of both molecules, contrary to that expected, in cancer tissue. In conclusion, all in all, our data indicate that an excess of local VEGF with respect to its soluble receptor VEGFR-1 may be a key factor in the onset and maintenance of pathological neo-angiogenesis in ovarian cyst formation.

Expression of motility-related molecule Cdc42 in endometrial tissue in women with adenomyosis and ovarian endometriomata

To evaluate Cdc42 expression in eutopic and ectopic endometrial tissue in patients with adenomyosis and ovarian endometriotic cysts compared with patients without endometriosis. Experimental retrospective study. University hospital. Twenty-four patients with adenomyosis, 19 with ovarian endometriomata, and 9 with fibroids or benign ovarian cysts. Hysterectomy and bilateral oophorectomy. Immunostaining for Cdc42 of eutopic and ectopic endometrial tissues. In eutopic endometrium of patients with adenomyosis and with fibroids or benign ovarian cysts, the intensity of Cdc42 immunostaining was weaker, especially in the specialized stromal cells, compared with cases with ovarian endometriosis (chi(2) test, P=.003). Expression of Cdc42 in eutopic endometrium showed a trend to be higher in the secretory than in the proliferative phase and in patients with ovarian endometriotic cysts compared with patients with adenomyosis (unpaired t test, P=.005), especially in the proliferative phase. An abnormally high expression of Cdc42 in eutopic endometrium in the secretory phase may contribute to the development of ovarian endometriosis, but it does not seem to be involved in the pathogenesis of adenomyosis.

Transcriptional expression of survivin and its splice variants in endometriosis

Survivin is a novel inhibitor of apoptosis (IAP), and the two splice variants of survivin (survivin-2B and survivin-EX3) have been identified. Gene expression levels of survivin, survivin-2B and survivin-EX3 in 56 ectopic (16 peritoneal red and 16 peritoneal black lesions and 24 ovarian endometriomata) and 13 eutopic endometrial tissues surgically obtained from 42 women with endometriosis (group A) were compared with those in 16 control eutopic endometrium from 16 women without endometriosis (group B) by quantitative RT-PCR analysis. Survivin mRNA expression levels in ectopic endometriotic tissues were significantly higher than those in eutopic endometrium of groups A and B over the whole cycle. Red peritoneal lesions had higher gene expression levels of survivin than black lesions. In contrast, all tissue samples examined showed relatively lower gene expression levels of survivin-2B and survivin-EX3. No cyclic variation was found in survivin and the two splice variants, both in ectopic and in eutopic endometrium. Although there was no significant difference in the ratio of survivin-2B/survivin between ectopic and eutopic endometrium, the ratio of survivin-EX3/survivin in peritoneal endometriotic lesions was significantly higher than that of eutopic endometrium of groups A and B. These results suggest that survivin and survivin-EX3 may be closely linked to escape from apoptosis and the development of endometriosis.

Excisional surgery versus ablative surgery for ovarian endometriomata: a Cochrane Review

The objective of this review was to determine which is the most effective technique for treating an ovarian endometrioma; excision or ablation. A systematic review employing the principles of the Cochrane Menstrual Disorders and Subfertility Group was undertaken. No randomized studies of the management of endometriomata by laparotomy were found. Two randomized studies of the laparoscopic management of ovarian endometriomata of >3 cm in size were included. Laparoscopic excision of the cyst wall of the endometrioma was associated with a reduced rate of recurrence of the endometrioma [odds ratio (OR) 0.41, confidence interval (CI) 0.18-0.93], reduced requirement for further surgery (OR 0.21, CI 0.05-0.79), reduced recurrence rate of the symptoms of dysmenorrhoea (OR 0.15, CI 0.06-0.38), dyspareunia (OR 0.08, CI 0.01-0.51) and non-menstrual pelvic pain (OR 0.10, CI 0.02-0.56). It was also associated with a subsequently increased rate of spontaneous pregnancy in women who had documented prior subfertility (OR 5.21, CI 2.04-13.29). There is some evidence that excisional surgery for endometriomata provides for a more favourable outcome than drainage and ablation, with regard to the recurrence of the endometrioma, recurrence of symptoms and subsequent spontaneous pregnancy in women who were previously subfertile. Consequently this should be the favoured surgical approach. However, we found no data to indicate the best surgical approach in women planning to undergo assisted reproductive techniques.

Sonosclerocystocleisis of recurrent ovarian endometriomata

Recurrent ovarian endometriomata present a frequent challenge in patients with endometriosis. Repeat laparoscopic excision and fulguration becomes technically more difficult because of added adhesive disease, and progressively distorted pelvic anatomy. Noninvasive sonographically guided sclerotherapy of ovarian cysts has received very limited attention in the medical community. The purpose of this report was to prospectively follow patients with recurrent endometriomata who underwent sonosclerocystocleisis. None. Nineteen patients with recurrent endometriomata of the ovaries (1yr–2 cm in size) underwent sonosclerocystocleisis between 1998 and 2002 using vaginal probe sonographically guided needle instillation of 200 mg of Doxycycline, suspended in one ml of solvent. All patients had previous laparoscopic documentation of ovarian endometriomata and peritoneal endometriosis. The procedure was performed under local anesthesia with added intramuscular administration of a narcotic agent. Prior to administration of Doxycycline into the endometriomata, aspiration of the cyst was performed and the cavity was irrigated using 1% lidocaine solution. All recurrent endometriomata were identified during followup of previous endometriosis patients who underwent laparoscopic exploration and treatment of their disease. All 19 patients with recurrent ovarian endometriomata demonstrated chocolate like material during subsequent sonographic aspiration of the ovarian cyst. All patients demonstrated variable postprocedural pain which was manageable using oral analgesics and on occasion, oral narcotic agents. Seventeen (90%) patients demonstrated a less than 5 mm cystic structure in their ovary during a three-month ultrasound followup. Two patients (10%) demonstrated persistence of their previously treated by sclerocystocleisis endometriomata. At one-year followup 12 of of 15 (80%) of the patients demonstrated sonographically undetectable endometriosis of their ovary. The remaining four patients were lost to followup. Of the 9 patients available for a two-year followup, 3 patients demonstrated less than 1 cm recurrent growth of their ovarian endometriomata. Those patients were subjected to repeat sonosclerocystocleisis. They were followed for an additional year without any signs of recurrence. A single patient with recurrent disease underwent three sclerosing procedures during a three-year period with a subsequent re-laparoscopic cystectomy. Sonosclerotherapy of recurrent small ovarian endometriomata is a very simple, inexpensive and effective substitute to laparoscopic reoperation. These remarkable followup results of patients with recurrent ovarian endometriomata suggest that a serious consideration be given to this treatment modality. The ease of performance, lack of peri and postoperative complications and the elimination of recurrent laparoscopic pelvic exploration, make this approach a powerful alternative to surgery. Early sonographic detection of recurrent endometriomata is paramount to a successful sonosclerocystocleisis.

Immunohistochemical analysis of vascular endothelial growth factor cellular expression in ovarian endometriomata

Objective To evaluate the expression of vascular endothelial growth factor (VEGF) in the cell populations of ovarian endometriomata cyst layers. Design Experimental retrospective study. Setting University hospital. Patient(s) Twenty-eight patients with ovarian endometriomata. Intervention(s) Surgical excision of 32 ovarian cysts. Main outcome measure(s) Histologic and VEGF immunohistochemical analysis of cyst layers. Result(s) Though the least represented cell types, macrophages exhibited the highest frequency of strong immunoreactivity, followed by capsular vessel endothelial and subepithelial stromal cells and by epithelial cells and capsular fibroblasts. Endothelia of the subepithelial stroma were the least immunoreactive cells. Diffuse VEGF expression in epithelial cells was associated with cyst diameters greater than 5.4 cm, and high VEGF expression in capsular fibroblasts was associated with bilateral cysts. Conclusion(s) Angiogenesis plays an active role in ovarian endometriosis, especially in the presence of large and bilateral cysts. Expression of VEGF in epithelial cells, capsular fibroblasts, and vessels was found to be related, suggesting that neoangiogenesis might especially affect the outer cyst wall, thus contributing to the fibrosing process of adhesion formation during cyst growth.

Diagnosis of endometriosis: pelvic endoscopy and imaging techniques

Although laparoscopy is the gold standard for the diagnosis of endometriosis, the need for this invasive diagnostic tool is a major stumbling-block in both effective clinical management and for research into this common and debilitating disease. As visual inspection of the pelvis has also major limitations, particularly for the diagnosis of posterior pelvis, bowel and bladder endometriosis, it is not surprising that considerable efforts are being made to improve the diagnosis by imaging techniques. Peritoneal endometriosis and ovarian endometriomata are predominantly haemorrhagic lesions. During laparoscopy, these lesions are readily identified by the presence of old or recent bleeding. Both transvaginal sonography and magnetic resonance (MR) imaging have a low sensitivity for the diagnosis of peritoneal and ovarian implants and adhesions. Transvaginal sonography is useful in the diagnosis of ovarian endometriomata, providing the diameter is larger than 2 cm. As transvaginal sonography costs less than MR imaging, transvaginal sonography might be the preferred method of confirming a sizeable endometrioma. Posterior pelvis endometriosis is an infiltrating adenomyotic lesion with microendometriomata. High-resolution transvaginal ultrasonography, and in particular MR imaging, are increasingly used to diagnose the presence and extent of infiltrating lesions and the involvement of rectosigmoid and ureters.

A systematic review of the accuracy of ultrasound in the diagnosis of endometriosis.

To evaluate transvaginal and transabdominal ultrasound scanning, with or without Doppler, as a diagnostic test for the accurate diagnosis of pelvic endometriosis. The MEDLINE (1966-2001) and EMBASE (1980-2001) databases were searched for relevant studies, published in English. Only studies fulfilling predefined criteria were selected. An assessment of quality was made for each study, and data were then reanalyzed using likelihood ratios to determine the usefulness of the test. In total, 67 papers were identified using the search strategy, of which 17 described relevant studies. Of these, seven fulfilled the inclusion criteria. All seven related to the use of transvaginal gray-scale imaging in the diagnosis of ovarian endometriomata specifically, rather than endometriosis. The positive likelihood ratios ranged from 7.6 to 29.8, and the negative likelihood ratios ranged from 0.1 to 0.4. Confidence intervals were wide. One paper addressed the use of conventional color Doppler with ultrasound: the positive likelihood ratio was 1.2, with a negative likelihood ratio of 0.4. One paper assessed the use of color Doppler energy imaging, and showed a positive likelihood ratio of 33.5 and a negative likelihood ratio of 0.1. Transvaginal ultrasound appears to be a useful test both to make and to exclude the diagnosis of an ovarian endometrioma.

Angiogenesis extent and expression of matrix metalloproteinase-2 and -9 in ovarian endometriomata.

Objective: Angiogenesis and matrix metalloproteinases (MMPs) expression play a central role in development of endometriosis. The purpose of the present study is to study the extent of angiogenesis and MMPs expression in ovarian endometriomata, which represent the highest grade of the disease. Design: Molecular and biological studies in human endometriotic tissue. Materials/Methods: The study has been performed in 44 endometriomata, removed during laparoscopy by stripping technique. Control group was represented by 10 normal parous women, submitted during mid-follicular phase to endometrial biopsy and laparoscopy for infertility. Studies on MMP-2 and -9 expression were performed by in situ hybridization. Angiogenesis was examined by counts of microvessels stained by Factor VIII and CD31 antibodies. The angiogenic capacity of tissues was analyzed by chick embryo chorioallantoic membrane (CAM) system. The significance of changes in microvessels number was assessed by Fisher’s test and Kruskal-Wallis test, corrected by Duncan, Bonferroni and Wilcoxon tests to compare groups two by two. Correlations were examined by linear regression analysis. Results: We described a trend of microvessel counts to increase in endometriotic tissue (both stage 3 and 4) as a whole compared to control tissues (p < 0.001). Simultaneously, there was a trend of vessel count to increase in these tissues together with their higher angiogenic capacity in the CAM. Moreover, we observed a significant increase in the frequency of MMP-2 expression (p < 0.001), MMP-9 expression (p < 0.01) and their co-expression (p < 0.05) over control tissues. In all ovarian endometriomata, MMP-2 was detected in endothelial cells and fibroblasts, whereas MMP-9 was found in a subset of macrophages (evidenced by CD68 staining). In addition, CD31 was more effective than factor VIII in highlighting more immature vessels, thus implying its pivotal role as a prognostic marker in endometriosis. Conclusions: Our data shows that angiogenesis extent, evaluated as microvessel number, and the expression of mRNA for MMP-2 and –9 by ectopic endometrial cells increase in ovarian endometriomata. Since MMP-2 and -9 are also expressed by host stromal cells (microvascular endothelial cells, fibroblasts and macrophages), this suggests that endometriosis gives increased proteolytic and angiogenic activity, therefore there are more opportunities for ovarian endometriomata cells to enter the circulation and spread systemically.

The peritoneal fluid concentration of leptin is increased in women with peritoneal but not ovarian endometriosis.

This study was designed to measure leptin concentrations in the peritoneal fluid (PF) of women with different aspects of pelvic endometriosis. Among 36 consecutive women undergoing laparoscopy, nine were diagnosed as having minimal-mild endometriosis (stage I-II). Among nine other subjects with advanced stage (III-IV) disease, six showed one or more ovarian endometriotic cysts as the only operative finding. The remaining 18 unaffected women constituted the control group. Patients with endometriosis had significantly higher PF leptin concentrations (32.6 +/- 16.2 versus 17.1 +/- 6.6 ng/ml, P = 0.002); this difference remained significant when corrected for body mass index (BMI) (PF leptin/BMI ratio 1.41 +/- 0.67 versus 0.76 +/- 0.28, P = 0.001). Furthermore, the PF leptin/BMI ratio was significantly higher in women with peritoneal implants than in those in whom no implant was found at laparoscopy (1.6 +/- 0.7 versus 0.83 +/- 0.33, P = 0.007). Conversely, patients with one or more ovarian endometriomata as the only finding, had a PF leptin/BMI ratio comparable with that in women where no cyst was found (1.05 +/- 0.4 versus 1.1 +/- 0.65). In women with stage I-II endometriosis, a higher mean PF leptin/BMI ratio was found compared with those affected by stage III-IV (1.78 +/- 0.68 versus 1.05 +/- 0.43, P = 0.01). These results show that during endometriosis the presence of peritoneal disease, and not of ovarian endometriotic cysts, influences leptin concentrations in PF. The data suggest that leptin may play a role in the development of peritoneal endometriosis, and that different biochemical phenomena might be involved in the pathogenesis of the ovarian form of the disease.

Vascular endothelial growth factor and interleukin-8 in ovarian cystic pathology

Objective: To determine the levels of the angiogenic factors vascular endothelial growth factor (VEGF) and interleukin (IL-8) in ovarian cysts. Design: Prospective descriptive study. Setting: University hospital. Patient(s): One hundred women, of whom 9 had ovarian carcinomas, 38 had ovarian endometriomata, 43 had serous ovarian cysts, and 10 had follicular ovarian cysts. Intervention(s): Sampling of serum and ovarian cystic fluid before and during surgery. Main Outcome Measure: Levels of VEGF and IL-8 in cystic fluid and serum. Result(s): Levels of both VEGF and IL-8 were found to be significantly higher in the cystic fluid of ovarian carcinomas and endometriomata than in serous and follicular cysts. In endometriomata fluid, levels of VEGF and IL-8 were found to be directly correlated ( r = 0.68; P=.0074). Serum levels of VEGF were significantly higher in women with ovarian carcinomas and endometriomata than in those with serous and follicular cysts. Ovarian cancers and endometriomata were similar in terms of cystic concentrations of VEGF and IL-8 and in serum levels of VEGF. Conclusion(s): An increase in angiogenic factors that differentiate ovarian carcinomas and endometriomata from other kinds of ovarian pathology is demonstrated.

High concentrations of the vascular endothelial growth factor and interleukin-8 in ovarian endometriomata.

Patients with endometriosis are characterized by the ability of the endometrium to implant and by the peritoneal response to the tissue; angiogenic factors may play a significant role in the aetiology of endometriosis supporting the implantation of ectopic endometrial cells. Vascular endothelial growth factor (VEGF) is a mitogen, morphogen and chemoactractant for endothelial cells and, in vivo, it is a powerful mediator for vessel permeability. Interleukin-8 (IL-8) is a chemoatractant for neutrophils and is a potent angiogenic factor. Women (n = 20) with ovarian endometriomata and 10 women with follicular cysts were enrolled in this study to investigate the role of VEGF and IL-8 in the development and maintenance of ovarian endometriomata. Cystic fluids were collected by laparoscopy, immediately centrifuged and stored until the enzyme-linked immunosorbent assays were performed. The VEGF and IL-8 concentrations were found to be significantly higher in the fluids of the ovarian endometriomata than in those of the follicular cysts of controls (P < 0.001 and P < 0.001 respectively); in addition, a significant inverse correlation between the VEGF cystic fluid concentrations and the diameter of the endometriotic adnexal masses was found (r = -0.56, P = 0.01). The evidence that the high concentrations of VEGF and IL-8 are present in the ovarian endometriomata indicates that angiogenesis could be a specific event both for the progression and maintenance of such cysts.

Tratamento de endometriomas ovarianos com implantes subcutâneos de ST-1435 (Elcometrina)

Objetivos: avaliar o efeito do progestínico ST 1435 (elcometrina) sobre a evolução de endometriomas ovarianos. Métodos: implantes subcutâneos contendo 50 mg da medicação foram administrados a 51 portadoras de endometriomas ovarianos, cujos volumes foram documentados por ultra-sonografia endovaginal antes e a cada intervalo de três meses após o início do tratamento. Um novo implante foi inserido ao fim de seis meses sempre que houvesse necessidade de continuação do tratamento. Resultados: na admissão, 74% das pacientes apresentavam dismenorréia, 57% dor pélvica crônica e 31% dispareunia. A intensidade da dor foi considerada incapacitante ou forte por 82% das pacientes. Um total de 924 meses de observação foi registrado durante os quatro anos de duração do estudo. O alívio da dor foi observado desde o primeiro mês de tratamento e, ao final do primeiro trimestre, nenhuma paciente referia dor incapacitante ou forte. O volume dos endometriomas foi reduzido em 86% das pacientes. Em 45% o volume normal do ovário foi restabelecido. Em 41% a redução de volume foi incompleta e em 14% das pacientes não houve redução do volume ovariano. Setenta e sete por cento das pacientes apresentaram amenorréia durante o tratamento. Os efeitos adversos mais comuns foram redução da libido (21%) e peso nos membros inferiores (14%). Um ano após a suspensão do tratamento, 33% das pacientes mantinham-se assintomáticas, ao passo que 28% tiveram recidivas com menos de três meses após a suspensão. Trinta e nove por cento optaram pela continuidade no uso do implante para prolongar a amenorréia. Conclusão: elcometrina é eficiente em provocar a regressão e reabsorção de endometriomas ovarianos sem apresentar alguns dos efeitos colaterais dos outros tratamentos.

Expression of oestrogen receptor-alpha and -beta in ovarian endometriomata.

The contribution of oestrogen receptor (ER) isoforms, ER-alpha and ER-beta, in oestrogen-dependent development and growth of ovarian endometriomata, is unknown. Therefore, we examined the expression of ER-alpha and ER-beta in ovarian endometriomata and normal uterine endometrium. ER-alpha and ER-beta were shown to be dominantly expressed in the nuclei of the epithelial lining cells of ovarian endometrioma and of the glandular cells of normal uterine endometrium. ER-beta was expressed at a much lower level than ER-alpha in the glandular cells of normal uterine endometrium, while ER-beta was expressed at a slightly lower level than ER-alpha in the epithelial lining cells of ovarian endometrioma. In normal uterine endometrium, ER-beta mRNA was expressed at a much lower level than ER-alpha mRNA, and the expression pattern of ER-beta mRNA during the menstrual cycle was similar to that of ER-alpha mRNA. On the other hand, ER-beta mRNA expression was significantly higher and over a much greater range in ovarian endometriomata (P < 0.05) than in normal uterine endometrium during the menstrual cycle, while ER-alpha mRNA expression was relatively lower and more random. Therefore, in ovarian endometriomata, oestrogen action via ER-alpha cascades seems to be partially damaged, as the expression of ER-alpha mRNA does not respond to endocrinological alterations during the menstrual cycle, while the relative over-expression of ER-beta might be related to a unique oestrogen-dependent growth and spreading of ovarian endometriomata.