Discovery and validation of peritoneal endometriosis biomarkers in peritoneal fluid and serum.

RESEARCH QUESTION: What are the potential biomarkers for peritoneal endometriosis in peritoneal fluid and serum? DESIGN: Case-control studies composed of independent discovery and validation sets were conducted. In the discovery set, untargeted liquid chromatography-mass spectrometry (LC-MS/MS) metabolomics, multivariable and univariable analyses were conducted to generate global metabolomic profiles of peritoneal fluid for endometriosis and to identify potential metabolites that could distinguish peritoneal endometriosis (n = 10) from controls (n = 31). The identified metabolites from the discovery set were validated in independent peritoneal fluid (n =19 peritoneal endometriosis and n = 20 controls) and serum samples (n = 16 peritoneal endometriosis and n = 19 controls) using targeted metabolomics. The area under the receiver-operating characteristics curve (AUC) analysis was used to evaluate the diagnostic performance of peritoneal endometriosis metabolites. RESULTS: In the discovery set, peritoneal fluid phosphatidylcholine (34:3) and phenylalanyl-isoleucine were significantly increased in peritoneal endometriosis groups compared with control groups, with AUC 0.77 (95% CI 0.61 to 0.92; P = 0.018) and AUC 0.98 (95% CI 0.95 to 1.02; P < 0.001), respectively. In the validation set, phenylalanyl-isoleucine retained discriminatory performance to distinguish peritoneal endometriosis from controls in both peritoneal fluid (AUC 0.77, 95% CI 0.61 to 0.92; P = 0.006) and serum samples (AUC 0.81, 95% CI 0.64 to 0.99; P = 0.004), with notably stronger discrimination between peritoneal endometriosis and controls in proliferative phase. CONCLUSION: Our preliminary results propose phenylalanyl-isoleucine as a potential biomarker of peritoneal endometriosis, which may be used as a minimally invasive diagnostic biomarker of peritoneal endometriosis.

The potentialities of oxytocin receptor inhibitors for endometriosis therapy.

OBJECTIVE: Genital endometriosis (GE) is a widespread gynecological disease which requires its further pathogenesis investigation and search for new effective treatments. The known data of oxytocin receptor presence in endometrioid heterotopy smooth muscle cells give some grounds to assume oxytocin participation in the pathogenesis of endometriosis. The present study objective was to evaluate oxytocin level in peripheral blood (PB) in patients with endometriosis associated pain syndrome and to estimate the efficacy of oxytocin receptor inhibitors (IOXTR) administration based on animal endometriosis model. MATERIALS AND METHODS: The basic group comprised 61 patients with endometriosis associated pain syndrome, while 21 patients formed the control group. VAS, MPQ, and BBS objective tests were applied for pain syndrome evaluation. Oxytocin level in PB was measured by immunoenzyme method. After confirmation of endometriosis experimental model formation in rats and further randomization, a daily IOXTR intra-abdominal injection was performed in a dose of 0.35 mg/kg/24 h in the basic group (n = 12) or saline solution administration in the control (n = 12). On the final stage, endometrioid heterotopy size measuring was performed along with histological examination. RESULTS: Oxytocin level in PB was authentically higher in patients with GE compared to the control: 51.45 (35.54-62.76) pg/mL and 27.64 (23.23-34.12) pg/mL, respectively (p<.001). Positive correlation between oxytocin PB level and pain syndrome expression was established in patients with GE: VAS (r = 0.76; p<.001), MPQ (r = 0.52; p<.001), and BBS (r = 0.57; p<.001). Based on the experimental disease model authentical decrease of endometrioid heterotopy average area was observed after IOXTR therapy compared to the control (7.3 ± 1.8 mm2 and 22.2 ± 1.2 mm2, respectively, p<.05). CONCLUSIONS: The obtained results confirm the oxytocin role in the pathogenesis of endometrioid associated pain syndrome. The high efficacy of IOXTR administration based on animal model of surgically induced endometriosis allows viewing this method as a perspective therapy.

High Levels of Anti-GM-CSF Antibodies in Deep Infiltrating Endometriosis.

Endometriosis is a chronic hormono-dependent inflammatory gynecological disease. Endometriosis can be subdivided into three forms: superficial peritoneal implants, endometrioma, and deep infiltrating endometriosis (DIE). Inflammation is a typical feature of endometriosis with overproduction of prostaglandins, chemokines, and cytokines, like granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is a hematopoietic growth factor and immune modulator which belongs to the group of cytokines that actively participate in inflammatory reactions. GM-CSF autoantibodies (Ab) are described in inflammatory diseases such as Crohn disease and ulcerative colitis where high concentrations of anti-GM-CSF Ab are correlated with severity, complications, and relapses. We have evaluated the presence of anti-GM-CSF Ab in the serum of 106 patients with endometriosis and 92 controls using a home-made enzyme-linked immunosorbent assay (ELISA) and correlated the results with the form and severity of the disease. We found that anti-GM-CSF Ab level is significantly increased in the sera of patients with endometriosis compared to controls and is associated with the severity of the disease especially in patients with deep endometriosis (p < 0.0001) with the highest number of lesions (p = 0.0034), including digestive involvement (p = 0.0041). We also found a correlation between these levels of anti-GM-CSF Ab and the number of lesions in DIE patients (r = 0.913). In this way, searching anti-GM-CSF Ab in endometriosis patient sera could be of value for patient follow-up and put further insight into the role of inflammation and of GM-CSF in endometriosis pathogenesis.

AA amyloidosis associated with Castleman disease: A case report and review of the literature.

RATIONALE: AA amyloidosis (AA) is caused by a wide variety of inflammatory states, but is infrequently associated with Castleman disease (CD). CD describes a heterogeneous group of hematologic disorders that share characteristic lymph node histopathology. CD can present with a solitary enlarged lymph node (unicentric CD, UCD) or with multicentric lymphadenopathy (MCD), constitutional symptoms, cytopenias, and multiple organ dysfunction due to an interleukin-6 driven cytokine storm. PATIENT CONCERNS: We are reporting a case of a 26-year-old woman with no significant past medical history who presented with a 3-month history of fatigue and an unintentional 20-pound weight loss. DIAGNOSIS: A CT-scan of the abdomen and pelvis revealed hepatosplenomegaly and a mesenteric mass. Congo Red staining from a liver biopsy showed apple-green birefringence and serum markers were suggestive of an inflammatory process. Post-excision examination of the resected mass revealed a reactive lymph node with follicular hyperplasia with kappa and lambda stains showing polyclonal plasmacytosis consistent with CD. INTERVENTIONS: The patient underwent surgery to remove the affected lymph node. OUTCOMES: IL-6, anemia, leukocytosis, and thrombocytosis resolved or normalized 2 weeks after resection; creatinine normalized 9 months postsurgery. Twenty two months post-surgery her IFN-γ normalized, her fatigue resolved, her proteinuria was reduced by >90% and she had returned to her baseline weight. LESSONS: Our case and literature review suggest that patients presenting with UCD or MCD along with organ failure should prompt consideration of concurrent AA amyloidosis.

CCR5/CCR5 ligand-induced myeloid-derived suppressor cells are related to the progression of endometriosis.

RESEARCH QUESTION: Immunological disorders have been reported to promote the progression of endometriosis. Several recent studies have shown that myeloid-derived suppressor cells (MDSC) drive the progression of endometriosis. The aim of this case-control study was to test whether CCR5 and its ligands drive MDSC accumulation and play a role in the progression of endometriosis. DESIGN: Thirty-six endometriosis patients and 20 controls were recruited. All subjects underwent laparoscopy. An ELISA kit was used to define CCR5 ligands in plasma and peritoneal fluid from endometriosis patients; flow cytometry was then used to characterize CCR5+MDSC in peripheral blood and peritoneal fluid. RESULTS: Data showed that endometriosis patients displayed a significantly higher production of plasma CCL3 (P = 0.046) and peritoneal fluid CCL3/5 (P = 0.042/0.036) compared with those from the uterine leiomyoma group. Furthermore, the concentrations of peritoneal fluid CCL5 were elevated in late stage patients compared with those from the uterine leiomyoma group. Accumulation of blood CCR5+Mo-MDSC was detected in endometriosis patients compared with those from both the ovarian dermoid cysts and uterine leiomyoma groups. Endometriosis patients also showed an elevation of CCR5+MDSC and CCR5+Mo-MDSC in peritoneal fluid samples compared with uterine leiomyoma samples. It was also found that enrichment of CCR5+MDSC (r = 0.6807; P < 0.0001) and CCR5+Mo-MDSC (r = 0.6893; P < 0.0001) were correlated with enhanced production of CCL5 in peritoneal fluid from endometriosis patients. CONCLUSIONS: This study showed that CCR5 and its ligands could drive the progression of endometriosis by enhancing the accumulation of MDSC. These findings might produce a promising treatment that targets CCR5+MDSC for endometriosis patients.

Differential Levels of Regulatory T Cells and T-Helper-17 Cells in Women With Early and Advanced Endometriosis.

CONTEXT: Regulatory T (Treg) cells and T-helper-17 (Th17) cells may be involved in endometriosis. Information on the pattern of change in the percentages of Treg and Th17 cells in the peripheral blood (PB) and peritoneal fluid (PF) of women with early and advanced endometriosis is unclear. OBJECTIVE: To investigate the pattern of change in the percentages of Treg and Th17 cells in the PB and PF of women with early and advanced endometriosis. METHODS: We recruited 31 women with laparoscopically and histologically confirmed, revised American Society of Reproductive Medicine stage I-II endometriosis, 39 women with stage III-IV endometriosis, and 36 control subjects without visible endometriosis. PB and PF samples were collected and T-cell subpopulations analyzed by flow cytometry using specific monoclonal antibodies recognizing CD4+, CD25+, FOXP3+, and IL-17A+ markers. PF concentrations of TGF-ß and IL-17 were measured by ELISA. RESULTS: The percentages of CD25+FOXP3+ Treg cells within the CD4+ T-cell population were significantly higher in the PF of women with advanced endometriosis than in either early endometriosis or in control subjects (P < 0.05 for both). A persistently lower percentage of CD4+IL-17A+ Th17 cells was found in both PB and PF of women with early and advanced endometriosis. Compared with IL-17 levels, PF levels of TGF-ß were significantly higher in women with endometriosis (P = 0.01). CONCLUSION: Our findings reconfirmed the current speculation that endometriosis is related to alteration of Treg and Th17 cells in the pelvis causing survival and implantation of ectopic endometrial lesions.

Prolactin concentration in various stages of endometriosis in infertile women.

OBJECTIVE: The relation between excessive prolactin and endometriosis-related infertility is debatable. Anovulation or defective luteal phase occurs frequently due to hyperprolactinemia in subfertile women. In this investigation, we evaluated the association between serum prolactin levels and the severity of endometriosis. METHODS: This retrospective cohort study carried out at the Babol Infertility Research Center looked into the baseline serum prolactin levels of 114 infertile women with endometriosis and compared them to the levels seen in 101 infertile women without endometriosis (controls). Statistical analysis included independent t-test, chi-square, Welch test and ROC curve analysis. RESULTS: Infertile women with endometriosis had significantly higher serum prolactin levels than infertile women without endometriosis (p=0.003). A significant difference was detected between controls and individuals with endometriosis stages III/IV (p-value=0.009). Prolactin was found to have diagnostic value to detect endometriosis stages III/IV vs. stages I/II in AUC=0.65, 95% CI (0.55, 0.76). Prolactin values with a cut off set at 20.08 ng/mL had a sensitivity of 0.74 and specificity of 0.54 in detecting disease stages III/IV vs. I/II. The prognostic capability of prolactin in detecting endometriosis in cases vs. controls by ROC curve analysis had an AUC=+0.67, 95% CI (0.60, 0.74). Prolactin values with a cut off set at 17.5 ng/mL had a sensitivity of 0.64 and specificity of 0.63 in segregating subjects with and without endometriosis. CONCLUSION: Higher prolactin levels were observed in infertile women with more severe endometriosis when compared to infertile women without endometriosis. Prolactin levels act as a probable prognostic biomarker to detect endometriosis stages III/IV vs. I/II and segregate infertile women with endometriosis from subjects without endometriosis.

A high level of TGF-B1 promotes endometriosis development via cell migration, adhesiveness, colonization, and invasiveness†.

Endometriosis is a prevalent gynecological disorder that eventually gives rise to painful invasive lesions. Increased levels of transforming growth factor-beta 1 (TGF-B1) have been reported in endometriosis. However, details of the effects of high TGF-B1 on downstream signaling in ectopic endometrial tissue remain obscure. We induced endometriotic lesions in mice by surgical auto-transplantation of endometrial tissues to the peritoneal regions. We then treated endometriotic (ectopic and eutopic endometrial tissues) and nonendometriotic (only eutopic endometrial tissues) animal groups with either active TGF-B1 or PBS. Our results demonstrate that externally supplemented TGF-B1 increases the growth of ectopically implanted endometrial tissues in mice, possibly via SMAD2/3 activation and PTEN suppression. Adhesion molecules integrins (beta3 and beta8) and FAK were upregulated in the ectopic endometrial tissue when TGF-B1 was administered. Phosphorylated E-cadherin, N-cadherin, and vimentin were enhanced in the ectopic endometrial tissue in the presence of TGF-B1 in the mouse model, and correlated with epithelial-mesenchymal transition (EMT) in ovarian endometriotic cells of human origin. Furthermore, in response to TGF-B1, the expression of RHOGTPases (RAC1, RHOC, and RHOG) was increased in the human endometriotic cells (ovarian cyst derived cells from endometriosis patient) and tissues from the mouse model of endometriosis (ectopic endometrial tissue). TGF-B1 enhanced the migratory, invasive, and colonizing potential of human endometriotic cells. Therefore, we conclude that TGF-B1 potentiates the adhesion of ectopic endometrial cells/tissues in the peritoneal region by enhancing the integrin and FAK signaling axis, and also migration via cadherin-mediated EMT and RHOGTPase signaling cascades.

Selected Case From the Arkadi M. Rywlin International Pathology Slide Club: Peritoneal Lipofuscinosis and Deciduosis in Pregnancy.

Peritoneal lipofuscinosis is a very rarely recognized condition occurring during pregnancy characterized by brown pigmentation of the omentum and peritoneum, a decidual reaction and benign mesothelial cells. The iron negative pigment, which is likely to be confused with hemosiderin in the hematoxylin and eosin stain, is lipofuscin. The seminar case, apparently the third published, arose in a 37-year-old woman who presented in October 2015 at 24 weeks pregnancy with abdominal pain. Investigations revealed a ruptured left ovarian cyst and rising serum carcinoembryonic antige levels. At laparotomy, there was no free intraperitoneal blood but the omentum and uterine serosa were black. Histology showed lipofuscinosis and a decidual reaction. The patient delivered a normal baby in February 2016 and was clinically well after delivery. A left ovarian endometriotic cyst was removed in February 2017. The patient made a good recovery with no clinically apparent symptoms from the liposuscinosis. We postulate that the endometriotic cyst had ruptured and released blood into the peritoneal cavity in 2015. The iron from the red cells breakdown was then rapidly resorbed because of the pregnancy requirements for iron, leaving lipofuscin in peritoneal macrophages.

Coagulation Status in Women With Endometriosis.

Subtle alterations in coagulation and fibrinolysis have been recently reported in patients with endometriosis supporting a potential hypercoagulable status associated with the disease. This cross-sectional study aimed at evaluating some variables of coagulation status and inflammatory markers in women with endometriosis. A total of 314 women who underwent surgery were considered. The case group (n = 169) included patients with a surgical diagnosis of endometriosis, at any stage of disease. The control group (n = 145) included women with a surgical diagnosis of benign gynecologic pathology. No difference was found for thrombin time, International Normalized Ratio (INR), platelet count, neutrophil count, lymphocyte count, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio (PLR) between women with endometriosis and controls. Conversely, patients with endometriosis had significantly shortened activated partial thromboplastin time (APTT) when compared to controls (1.08 ± 0.06 and 1.12 ± 0.19, respectively; P < .01). In the subgroup analysis, women with ovarian endometriosis had significantly shortened APTT values in comparison to women without this form and women with stage I to II endometriosis had significantly shorter APTT values and higher PLR than those with stage III to IV disease. In multivariate logistic regression analysis, after controlling for potential confounders, a shortened APTT remained associated with the disease. Activated partial thromboplastin time is shorter in women with endometriosis but still in the normal range. The evidence is insufficient to foresee a possible use of APTT as a diagnostic marker and to claim a crucial role of a systemic hypercoagulable state in the origin of the disease. A role of the local coagulation system in the pathogenesis of the disease cannot be excluded.

Plasma urocortin-1 as a preoperative marker of endometriosis in symptomatic women.

Accurate noninvasive diagnostic tests for endometriosis are still missing. This study evaluated the predictive value of the neuropeptide urocortin 1 (Ucn1) to detect pelvic endometriosis in symptomatic women. We enrolled prospectively 97 consecutive women submitted to gynecologic laparoscopy for chronic or acute pelvic pain, infertility or adnexal mass. Preoperative blood samples were assayed for Ucn1 using enzyme immunoassay. Patients with endometriosis had higher plasma Ucn1 levels compared to patients with no lesions (median 59 vs. 34 pg/ml, p < .01, Dunn's test). Elevated plasma Ucn1 levels were found among all endometriosis phenotypes (superficial peritoneal lesions, ovarian endometrioma, and deep infiltrating endometriosis, p < .05 vs. no lesions). Receiver operating characteristics curve analysis identified plasma Ucn1 > 46 pg/mL as the best cutoff point to detect endometriosis vs. no lesions, with 76% sensitivity and 88% specificity (area under the curve [AUC] 0.827, 95% confidence interval [CI] 0.695 - 0.959), but no cutoff could accurately distinguish endometriosis from other pathological conditions (AUC 0.593 [95% CI 0.474 - 0.711]). In women with chronic pelvic pain, infertility, or both symptoms, the probability of endometriosis (positive predictive value) increased consistently with the increase of plasma Ucn1 levels. The present findings suggest that high plasma Ucn1 levels increase the likelihood of endometriosis in symptomatic women.

Hematoma retroperitoneal espontáneo concurrente con una atonía uterina poscesárea / Concurrent Spontaneous Retroperitoneal Hematoma with Uterine Atony Post Cesarean

El hematoma retroperitoneal espontáneo durante el embarazo es una complicación infrecuente definido como el sangrado en el espacio retroperitoneal que ocurre sin historia de trauma reciente, tratamiento anticoagulante o enfermedad vascular. El objetivo del trabajo es presentar un caso grave poco usual en que el hematoma retroperitoneal coexistió en una paciente con atonía uterina. Se presenta una gestante de 21 años y 39 semanas que acudió al Cuerpo de Guardia del Hospital Ginecobstétrico de Guanabacoa en noviembre 2016 por presentar dolor abdominal. Se ingresa en Cuidados perinatales. Los exámenes complementarios, físico y la cardiotocografía fueron normales. Cuatro horas después aqueja dolor lumbar y se detectó dolor a la palpación en región intercostal posterior derecha sin otro hallazgo ni alteraciones hemodinámicas. No hay dinámica uterina y frecuencia fetal 140 latidos/minuto. Dos horas después, presentó un cuadro que el familiar informa como una "convulsión", no observada por personal médico o de enfermería. No hay toma de conciencia y los signos vitales normales, se comprueba una bradicardia fetal que motiva la indicación de cesárea de urgencia. La hemoglobina descendió a 70 g/L. Se repone volumen y se extrae un neonato con Apgar 1-3. Se produce atonía uterina que no cedió al tratamiento medicamentoso y/o masaje. Se realiza técnica de B- Lynch para la hemostasia que se logra. Se comprueba hematoma retroperitoneal no activo desde borde superior hepático hasta flanco derecho. Se estabiliza hemodinámicamente. El neonato fallece a las 72 horas. El diagnóstico y tratamiento precoz del hematoma retroperitoneal contribuye a disminuir la morbilidad y mortalidad materna.

Spontaneous retroperitoneal hematoma during pregnancy is an uncommon complication defined as bleeding in the retroperitoneal space that occurs without a history of recent trauma, anticoagulant treatment or vascular disease. The objective of this study is to present an unusual case in which the retroperitoneal hematoma coexisted in a patient with uterine atony. A 21 year old pregnant woman of 39 weeks who went to the Emergency Room at Guanabacoa Gynecobstetric Hospital in November 2016, due to abdominal pain. The patient is admitted to perinatal care. Complementary studies and physical examination were normal, including cardiotocography. Four hours later, she suffered back pain, which was detected on palpation in the right posterior intercostal region without any other finding or hemodynamic changes. There were no uterine dynamics and fetal frequency was 140 beats / minute. Two hours later, this patient presented a "seizure," according to her family member that was not observed by medical or nursing staff. There was no loss of consciousness and her vital signs were normal. A fetal bradycardia is verified that motivates the indication of emergency caesarean section. Hemoglobin decreased to 70 g / L. Volume was replaced and an Apgar 1-3 neonate was extracted. There was uterine atony that did not yield to drug treatment and massage. The B-Lynch technique was performed for the hemostasis that was achieved. A non-active retroperitoneal hematoma was found from the superior border of the liver to the right flank. The patient was hemodynamically stabilized. The neonate died at 72 hours. The diagnosis and early treatment of retroperitoneal hematoma help to reduce maternal morbidity and mortality.

Hematoma retroperitoneal espontáneo concurrente con una atonía uterina poscesárea / Concurrent Spontaneous Retroperitoneal Hematoma with Uterine Atony Post Cesarean

El hematoma retroperitoneal espontáneo durante el embarazo es una complicación infrecuente definido como el sangrado en el espacio retroperitoneal que ocurre sin historia de trauma reciente, tratamiento anticoagulante o enfermedad vascular. El objetivo del trabajo es presentar un caso grave poco usual en que el hematoma retroperitoneal coexistió en una paciente con atonía uterina. Se presenta una gestante de 21 años y 39 semanas que acudió al Cuerpo de Guardia del Hospital Ginecobstétrico de Guanabacoa en noviembre 2016 por presentar dolor abdominal. Se ingresa en Cuidados perinatales. Los exámenes complementarios, físico y la cardiotocografía fueron normales. Cuatro horas después aqueja dolor lumbar y se detectó dolor a la palpación en región intercostal posterior derecha sin otro hallazgo ni alteraciones hemodinámicas. No hay dinámica uterina y frecuencia fetal 140 latidos/minuto. Dos horas después, presentó un cuadro que el familiar informa como una "convulsión", no observada por personal médico o de enfermería. No hay toma de conciencia y los signos vitales normales, se comprueba una bradicardia fetal que motiva la indicación de cesárea de urgencia. La hemoglobina descendió a 70 g/L. Se repone volumen y se extrae un neonato con Apgar 1-3. Se produce atonía uterina que no cedió al tratamiento medicamentoso y/o masaje. Se realiza técnica de B- Lynch para la hemostasia que se logra. Se comprueba hematoma retroperitoneal no activo desde borde superior hepático hasta flanco derecho. Se estabiliza hemodinámicamente. El neonato fallece a las 72 horas. El diagnóstico y tratamiento precoz del hematoma retroperitoneal contribuye a disminuir la morbilidad y mortalidad materna(AU)

Spontaneous retroperitoneal hematoma during pregnancy is an uncommon complication defined as bleeding in the retroperitoneal space that occurs without a history of recent trauma, anticoagulant treatment or vascular disease. The objective of this study is to present an unusual case in which the retroperitoneal hematoma coexisted in a patient with uterine atony. A 21 year old pregnant woman of 39 weeks who went to the Emergency Room at Guanabacoa Gynecobstetric Hospital in November 2016, due to abdominal pain. The patient is admitted to perinatal care. Complementary studies and physical examination were normal, including cardiotocography. Four hours later, she suffered back pain, which was detected on palpation in the right posterior intercostal region without any other finding or hemodynamic changes. There were no uterine dynamics and fetal frequency was 140 beats / minute. Two hours later, this patient presented a "seizure," according to her family member that was not observed by medical or nursing staff. There was no loss of consciousness and her vital signs were normal. A fetal bradycardia is verified that motivates the indication of emergency caesarean section. Hemoglobin decreased to 70 g / L. Volume was replaced and an Apgar 1-3 neonate was extracted. There was uterine atony that did not yield to drug treatment and massage. The B-Lynch technique was performed for the hemostasis that was achieved. A non-active retroperitoneal hematoma was found from the superior border of the liver to the right flank. The patient was hemodynamically stabilized. The neonate died at 72 hours. The diagnosis and early treatment of retroperitoneal hematoma help to reduce maternal morbidity and mortality(AU)

Revisiting the wandering womb: Oxytocin in endometriosis and bipolar disorder.

Hippocrates attributed women's high emotionality - hysteria - to a 'wandering womb'. Although hysteria diagnoses were abandoned along with the notion that displaced wombs cause emotional disturbance, recent research suggests that elevated levels of oxytocin occur in both bipolar disorder and endometriosis, a gynecological condition involving migration of endometrial tissue beyond the uterus. We propose and evaluate the hypothesis that elevated oxytocinergic system activity jointly contributes to bipolar disorder and endometriosis. First, we provide relevant background on endometriosis and bipolar disorder, and then we examine evidence for comorbidity between these conditions. We next: (1) review oxytocin's associations with personality traits, especially extraversion and openness, and how they overlap with bipolar spectrum traits; (2) describe evidence for higher oxytocinergic activity in both endometriosis and bipolar disorder; (3) examine altered hypothalamic-pituitary-gonadal axis functioning in both conditions; (4) describe data showing that medications that treat one condition can improve symptoms of the other; (5) discuss fitness-related impacts of endometriosis and bipolar disorder; and (6) review a pair of conditions, polycystic ovary syndrome and autism, that show evidence of involving reduced oxytocinergic activity, in direct contrast to endometriosis and bipolar disorder. Considered together, the bipolar spectrum and endometriosis appear to involve dysregulated high extremes of normally adaptive pleiotropy in the female oxytocin system, whereby elevated levels of oxytocinergic activity coordinate outgoing sociality with heightened fertility, apparently characterizing, overall, a faster life history. These findings should prompt a re-examination of how mind-body interactions, and the pleiotropic endocrine systems that underlie them, contribute to health and disease.

Total circulating microparticle levels are increased in patients with deep infiltrating endometriosis.

STUDY QUESTION: Are the levels of total circulating cell-derived microparticles (cMPs) and circulating tissue factor-containing microparticles (cMP-TF) increased in patients with endometriosis? SUMMARY ANSWER: The levels of total cMP, but not cMP-TF, were higher in patients with endometriosis, and these were attributed to higher levels in patients with deep infiltrating endometriosis (DIE). WHAT IS KNOWN ALREADY: Previous studies have reported elevated levels of total cMP in inflammatory conditions as well as higher levels of other inflammatory biomarkers in endometriosis. Increased expression of tissue factor (a transmembrane receptor for Factor VII/VIIa) in eutopic and ectopic endometrium from patients with endometriosis has been described. There is no previous data regarding total cMP and cMP-TF levels in patients with endometriosis. STUDY DESIGN, SIZE, DURATION: A prospective case-control study including two groups of patients was carried out. The E group included 65 patients with surgically confirmed endometriosis (37 with DIE lesions) and the C group comprises 33 women without surgical findings of any form of endometriosis. Patients and controls were recruited during the same 10-month period. Controls were the next patient without endometriosis undergoing surgery, after including two patients with endometriosis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Venous blood samples for total cMP and cMP-TF determinations were obtained at the time of surgery, before anesthesia at a tertiary care center. To assess total cMP, an ELISA functional assay was used and cMP-TF activity in plasma was measured using an ELISA kit. MAIN RESULTS AND THE ROLE OF CHANCE: Total cMP levels in plasma were higher in the E group compared with the C group (P < 0.0001). The subanalysis of endometriosis patients with DIE or with ovarian endometriomas without DIE showed that total cMP levels were higher in the DIE group (P = 0.001). There were no statistically significant differences in cMP-TF levels among the groups analyzed. LIMITATIONS, REASONS FOR CAUTION: This is a preliminary study in which the sample size was arbitrarily decided, albeit in keeping with previous studies analyzing cMP in other inflammatory diseases and other biomarkers in endometriosis. The control group included patients with other pathologies as well as healthy controls, and blood samples were taken at different phases of the cycle. WIDER IMPLICATIONS OF THE FINDINGS: Elevated total cMP levels in DIE patients may reflect an inflammatory and/or procoagulant systemic status in these patients. Further studies are warranted to confirm our findings and to assess the role of cMP levels in the pathophysiology of DIE. STUDY FUNDING/COMPETING INTERESTS: This study was supported in part by a grant from FIS-PI11/01560 and FIS-PI11/00977 within the 'Plan Nacional de I + D + I' and co-funded by the 'ISCIII-Subdirección General de Evaluación' and 'Fondo Europeo de Desarrollo Regional (FEDER)' and by the grant 'Premi Fi de Residència Emili Letang 2015' from the Hospital Clínic of Barcelona. The authors have no competing interests to disclose.

Alteration of Lysophosphatidylcholine-Related Metabolic Parameters in the Plasma of Mice with Experimental Sepsis.

Plasma concentration of lysophosphatidylcholine (LPC) was reported to decrease in patients with sepsis. However, the mechanisms of sepsis-induced decrease in plasma LPC levels are not currently well known. In mice subjected to cecal ligation and puncture (CLP), a model of polymicrobial peritoneal sepsis, we examined alterations in LPC-related metabolic parameters in plasma, i.e., the plasma concentration of LPC-related substances (i.e., phosphatidylcholine (PC) and lysophosphatidic acid (LPA)), and activities or levels in the plasma of some enzymes that can be involved in the regulation of plasma LPC concentration (i.e., secretory phospholipase A2 (sPLA2), lecithin:cholesterol acyltransferase (LCAT), acyl-CoA:lysophosphatidylcholine acyltransferase (LPCAT), and autotaxin (ATX)), as well as plasma albumin concentration. We found that levels of LPC and albumin and enzyme activities of LCAT, ATX, and sPLA2 were decreased, whereas levels of PC, LPA, and LPCAT1-3 were increased in the plasma of mice subjected to CLP. Bacterial peritonitis led to alterations in all the measured LPC-related metabolic parameters in the plasma, which could potentially contribute to sepsis-induced decrease in plasma LPC levels. These findings could lead to the novel biomarkers of sepsis.

Effects of alpha lipoic acid on intra-abdominal adhesion: an experimental study in a rat model.

BACKGROUND: This study was performed to determine the effect of alpha lipoic acid, a powerful antioxidant, on intra-abdominal adhesion formation. METHODS: Twenty-four female Wistar Albino rats weighing 250-300 g were used in this study conducted on three groups consisting of the alpha lipoic acid group (Group I, n=8), control group (Group II, n=8), and sham group (Group III, n=8). After performing laparotomy with a midline incision under general anesthesia, the adhesion model was created on the antimesenteric side of the caecum in Group I and Group II. 50 mg/kg alpha-lipoic acid was administered intraperitoneally (IP) in Group I while the surgical procedure was performed but no drugs administered in Group II. Only laparotomy was performed in Group III. Rats were sacrificed at the end of the tenth day. RESULTS: Macroscopic scoring was performed, tissue samples were obtained and subjected to biochemical and histopathological evaluation. The degree of adhesion and malondialdehyde level decreased (p<0.01), and glutathione levels had increased (p<0.01) in Group I compared to Group II in macroscopic scoring. CONCLUSION: Alpha lipoic acid was found to significantly decrease (p<0.01) intra-abdominal adhesion when administered IP compared to the control group.

Regression of experimental endometriotic implants in a rat model with the angiotensin II receptor blocker losartan.

AIM: Endometriosis is a common disease in women of reproductive age, and many different treatments have been developed, although none has provided a cure. In this study, the efficacy of losartan, an angiotensin II type 1 receptor blocker and an antiangiogenic and anti-inflammatory agent, on regression of experimental endometriotic implants in a rat model was investigated. METHODS: Peritoneal endometriosis was surgically induced in 16 mature female Sprague-Dawley rats. The peritoneal endometriotic implant was confirmed after 28 days, and the animals were divided randomly into two groups. The control group (n = 8) was given 4 mL/day tap water by oral gavage, and the losartan group (n = 8) was given 20 mg/kg per day losartan p.o. We compared endometriotic implant size, extent and severity of adhesion, as well as plasma and peritoneal lavage fluid cytokine levels including vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF)-α, plasma inflammatory factor pentraxin-3 (PTX-3) and C-reactive protein (CRP) between the treatment groups. RESULTS: Mean surface endometriotic area, histological score of implants, adhesion formation, plasma VEGF, TNF, PTX-3 and CRP levels were significantly lower in the losartan group compared with control (P < 0.05). Furthermore, the peritoneal VEGF level was lower in the losartan group than in the control group (P < 0.001), but peritoneal TNF-α was similar in both groups (P > 0.05). CONCLUSION: Losartan suppressed the implant surface area of experimental endometriosis in rats and reduced the levels of plasma VEGF, TNF-α, PTX-3 and CRP.