Pregnancy and Neonatal Outcomes in Women Treated for Bowel Endometriosis: A Seven-Year Single-Centre Retrospective Matched Cohort Study.

Background/Objectives: Deep infiltrating endometriosis has been linked to worsened maternal and neonatal outcomes. However, reports regarding bowel endometriosis are still scanty. We aimed to evaluate pregnancy, delivery, and newborn adverse outcomes in women after laparoscopic-assisted surgery for bowel endometriosis. Methods: A single-center retrospective cohort study was conducted at a tertiary-care university hospital. From January 2015 to December 2021, pregnant women who were diagnosed and treated for bowel endometriosis were matched using a 1:3 ratio with pregnant women with no history of endometriosis. Patients were matched using the Cox proportional hazards model to determine parity, age, BMI and gestational age-adjusted relative risk (aRR) with a 95% confidence interval (CI). Co-primary outcomes were the incidence of labor abnormalities and cesarean section (CS) rate. Co-secondary outcomes were incidence of complications related to pregnancy, delivery, and newborn. Results: A total of 71 pregnancies among women treated for bowel endometriosis and 213 from healthy controls were included. Patients requiring IVF/ET for getting pregnant were in the bowel endometriosis group relative to controls (43.7% vs. 11.7%; p < 0.001). Increased risk of labor abnormalities was present for bowel endometriosis relative to controls (21.1% vs. 17.4%; p = 0.040; aRR 1.39 [95% CI 1.06-2.05]). Risk of non-cephalic fetal presentation (14.1% vs. 6.1%; p = 0.016; aRR 3.08 [95% CI 2.03-4.68]), CS rate (43.7% vs. 24.9%; p = 0.003; aRR 1.75 [95% CI 1.23-2.49]), and emergent CS rate (19.7% vs. 8.5%; p = 0.009; aRR 2.21 [95% CI 1.55-3.16]) were significantly higher in women treated for colorectal endometriosis compared with controls. Moreover, placenta previa (9.9% vs. 0.0%; p < 0.001; aRR 21.82 [95% CI 2.19-116.40]), second-trimester hemorrhage (5.6% vs. 0.9%; p = 0.017; aRR 6.00 [95% CI 1.12-32.06]), postpartum hemorrhage (15.5% vs. 3.3%; p < 0.001; aRR 4.71 [95% CI 1.90-11.70]), and the need for transfusion during labor (5.6% vs. 0.5%; p = 0.004; aRR 12.00 [95% CI 1.36-105.60]) were increased in treatments vs. controls. Concerning neonatal outcomes, an increased risk for neonatal intensive care unit admission was seen in postsurgical endometriotic women relative to healthy controls (26.0% vs. 6.9%; p < 0.001; aRR 3.75 [2.04-3.86]). Conclusions: Women treated for bowel endometriosis seem more exposed to adverse pregnancy and neonatal outcomes relative to healthy controls. However, additional prospective and comparative studies are needed to validate the available evidence.

Effect of Oral Contraceptive Use in Relation to Fertile Years on the Risk of Endometriosis in Women with Primary Infertility: A Ten-Year Single-Centre Retrospective Analysis.

Background and Objectives: Oral contraceptives (OCs) are usually used to treat endometriosis; however, the evidence is inconsistent about whether OC use in the past, when given to asymptomatic women, is protective against the development of future disease. We aimed to assess the relationship between the use of OCs and the likelihood of discovering endometriosis, considering the length of time under OCs during their fertile age. Materials and Methods: This was a monocentric retrospective cohort study in a tertiary-care University Hospital (Department of Human Reproduction, Division of Gynaecology and Obstetrics, University Medical Centre Ljubljana, Slovenia) carried out from January 2012 to December 2022. Reproductive-aged women scheduled for laparoscopic surgery for primary infertility and subsequent histopathological diagnosis of endometriosis were compared to women without an endometriosis diagnosis. They were classified based on the ratio of years of OC use to fertile years in four subgroups: never, <25%, between 25 and 50%, and >50. Results: In total, 1923 women (390 with and 1533 without endometriosis) were included. Previous OC use was higher in those with endometriosis than controls (72.31% vs. 58.64%; p = 0.001). Overall, previous OC usage was not related to histopathological diagnosis of endometriosis (aOR 1.06 [95% CI 0.87-1.29]). Women who used OCs for less than 25% of their fertile age had reduced risk of rASRM stage III endometriosis (aOR 0.50 [95% CI 0.26-0.95]; p = 0.036) or superficial implants (aOR 0.88 [95% CI 0.58-0.95]; p = 0.040). No significant results were retrieved for other rASRM stages. Using OCs for <25%, between 25 and 50%, or >50% of fertile age did not increase the risk of developing superficial endometriosis, endometriomas, or DIE. Conclusions: When OCs are used at least once, histological diagnoses of endometriosis are not increased. A protective effect of OCs when used for less than 25% of fertile age on superficial implants may be present. Prospective research is needed to corroborate the findings due to constraints related to the study's limitations.

Molecular Mechanism of Resveratrol and Its Therapeutic Potential on Female Infertility.

Resveratrol is a polyphenol present in various plant sources. Studies have reported numerous potential health benefits of resveratrol, exhibiting anti-aging, anti-inflammatory, anti-microbial, and anti-carcinogenic activity. Due to the reported effects, resveratrol is also being tested in reproductive disorders, including female infertility. Numerous cellular, animal, and even human studies were performed with a focus on the effect of resveratrol on female infertility. In this review, we reviewed some of its molecular mechanisms of action and summarized animal and human studies regarding resveratrol and female infertility, with a focus on age-related infertility, polycystic ovary syndrome, and endometriosis.

Oxidative stress markers cannot be used as endometriosis biomarkers in infertile patients.

OBJECTIVES: Endometriosis is a common benign gynaecological disease that significantly compromises the quality of life of patients. To date, invasive surgery is the method of choice to visually and histologically confirm endometriosis. Thus, there is a major interest to develop noninvasive diagnostic tools. Oxidative stress is one of the proposed mechanisms of pathogenesis and may be involved in pelvic pain, dysmenorrhea, dyspareunia, and infertility in endometriosis patients. Thus, markers of oxidative stress may serve as diagnostic biomarkers for endometriosis. DESIGN: This prospective case-control study assessed erythrocyte superoxide dismutase (SOD), erythrocyte glutathione peroxidase (GPX), serum hexanoyl lysine (HEL) and peritoneal fluid HEL. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: We enrolled 86 women with primary infertility; the case group included 57 women with endometriosis, and the control group included 29 women with unexplained primary infertility. All the patients underwent laparoscopy, and the diagnosis was confirmed histologically. RANDOX and RANSEL reagents were used to determine the levels of SOD and GPX, respectively, and ELISA was used to determine the levels of HEL. RESULTS: We found no statistically significant differences in the erythrocyte levels of GPX (p value 0.623) or SOD (p value 0.122) or the serum or peritoneal fluid levels of HEL (p value 0.562 and 0.329 accordingly). CONCLUSIONS: SOD, GPX, and HEL levels most likely do not differ between patients with unexplained infertility and patients with endometriosis.

Risk of Reintervention or Postoperative Bleeding after Laparoscopy for Benign Gynecological Disease: A Clinical Prediction Model.

OBJECTIVE: The objective of the study was to develop a clinically applicable prediction tool to early seek for postoperative major complications after laparoscopic surgery for benign pathologies. DESIGN: Retrospective analysis of prospectively collected data was performed. SETTING: The study was conducted at Tertiary Care University Hospital. PARTICIPANTS: The participants of this study were reproductive-aged women undergoing laparoscopy for benign conditions. METHODS: Anamnestic, intraoperative, and postoperative characteristics from January 2019 to December 2021 were retrospectively reviewed. Patients with postoperative complications (reintervention or postoperative bleeding) were matched in a 1:2 ratio with women with same surgical indications without complications. Cases and controls were matched for preoperative hemoglobin, hematocrit, weight, height, body mass index, age, and blood volume. A prediction model was created by inserting multiple independent modifying factors through logistic regression. The receiver operating characteristic (ROC) curve was used to evaluate the predictive accuracy of the model, and the Hosmer-Lemeshow (H-L) test was carried out to evaluate the goodness-of-fit, and a calibration curve was drawn to confirm the predictive performance. A nomogram was depicted to visualize the prediction model. RESULTS: Thirty-nine complicated procedures were matched with 78 uncomplicated controls. According to the multivariate logistic regression analysis findings, the prediction model was developed using C-reactive protein (CRP), intraoperative blood loss, and 24 h postoperative urinary volume, therefore a nomogram was generated. The area under the ROC curve of the prediction model was 0.879, depicting good accuracy, the sensitivity was 60.00%, while specificity reached 93.59%. The H-L test (χ2 = 4.45, p = 0.931) and the calibration curve indicated a good goodness-of-fit and prediction stability. LIMITATIONS: The retrospective design, moderate sensitivity, and study population limit the generalization of the findings, requiring additional research. CONCLUSIONS: This prediction model based on CRP, intraoperative blood loss, and 24 h postoperative urinary volume might be a potentially useful tool for predicting reintervention and postoperative bleeding in patients undergoing planned gynecological laparoscopy.

TGFBI as a candidate biomarker for non-invasive diagnosis of early-stage endometriosis.

STUDY QUESTION: Can cartilage oligomeric matrix protein (COMP) and transforming growth factor-ß-induced protein ig-h3 (TGFBI) alone or in combination with cancer antigen 125 (CA-125) be considered as potential blood biomarkers of endometriosis? SUMMARY ANSWER: The results of this study indicate that COMP has no diagnostic value. TGFBI has potential as a non-invasive biomarker of the early stages of endometriosis, while TGFBI together with CA-125 has similar diagnostic characteristics as CA-125 alone for all stages of endometriosis. WHAT IS KNOWN ALREADY: Endometriosis is a common, chronic gynecological disease that significantly affects patient quality of life by causing pain and infertility. The gold standard for diagnosis is visual inspection of pelvic organs by laparoscopy, therefore there is an urgent need for discovery of non-invasive biomarkers for endometriosis to reduce diagnostic delays and allow earlier treatment of patients. The potential biomarkers for endometriosis evaluated in this study (COMP and TGFBI) were previously identified by our proteomic analysis of peritoneal fluid samples. STUDY DESIGN, SIZE, DURATION: This is a case-control study divided into a discovery (n = 56 patients) and a validation phase (n = 237 patients). All patients were treated between 2008 and 2019 in a tertiary medical center. PARTICIPANTS/MATERIALS, SETTING, METHOD: Patients were stratified based on the laparoscopic findings. The discovery phase included 32 endometriosis patients (cases) and 24 patients with confirmed absence of endometriosis (controls). The validation phase included 166 endometriosis and 71 control patients. Concentrations of COMP and TGFBI were measured by ELISA in plasma samples, whereas concentration of CA-125 was measured using a clinically validated assay for serum samples. Statistical and receiver operating characteristic (ROC) curve analyses were performed. The classification models were built using the linear support vector machine (SVM) method with the SVM built-in feature ranking method. MAIN RESULTS AND THE ROLE OF CHANCE: The discovery phase revealed significantly increased concentration of TGFBI, but not COMP, in plasma samples of patients with endometriosis compared to controls. In this smaller cohort, univariate ROC analysis showed fair diagnostic potential of TGFBI, with an AUC value of 0.77, sensitivity of 58%, and specificity of 84%. The classification model built using linear SVM and combining TGFBI and CA-125 showed an AUC value of 0.91, sensitivity of 88% and specificity of 75% in distinguishing patients with endometriosis from controls. The validation phase results revealed similar diagnostic characteristics of the SVM model combining TGFBI and CA-125, with an AUC value of 0.83, sensitivity of 83% and specificity of 67% and CA-125 alone with AUC value of 0.83, sensitivity of 73% and specificity of 80%. TGFBI exhibited good diagnostic potential for early-stage endometriosis (revised American Society for Reproductive Medicine stage I-II), with an AUC value of 0.74, sensitivity of 61% and specificity of 83% compared to CA-125, which had an AUC value of 0.63, sensitivity of 60% and specificity of 67%. An SVM model combining TGFBI and CA-125 showed a high AUC value of 0.94 and sensitivity of 95% for diagnosing moderate-to-severe endometriosis. LIMITATIONS, REASONS FOR CAUTION: The diagnostic models were built and validated from a single endometriosis center, and thus further validation and technical verification in a multicenter study with a larger cohort is needed. Additional limitation was lack of histological confirmation of disease for some patients in the validation phase. WIDER IMPLICATIONS OF THE FINDINGS: This study revealed for the first time increased concentration of TGFBI in plasma samples of patients with endometriosis, particularly those with minimal-to-mild endometriosis, compared to controls. This is the first step in considering TGFBI as a potential non-invasive biomarker for the early stages of endometriosis. It also opens a path for new basic research to investigate the importance of TGFBI in the pathophysiology of endometriosis. Further studies are needed to confirm the diagnostic potential of a model based on TGFBI and CA-125 for the non-invasive diagnosis of endometriosis. STUDY FUNDING/COMPETING INTEREST(S): The preparation of this manuscript was supported by grant J3-1755 from the Slovenian Research Agency to T.L.R and EU H2020-MSCA-RISE project TRENDO (grant 101008193). All authors declare that they have no conflicts of interest. TRIAL REGISTRATION NUMBER: NCT0459154.

Uterine rupture in pregnancy after hysteroscopic septum resection: a 20-year retrospective analysis.

INTRODUCTION: In this study, we reviewed the cases of uterine rupture in our setting, identified which of them had previously undergone hysteroscopic septum resection (HSR), and evaluated the main clinical characteristics for each case. MATERIAL AND METHODS: We retrospectively analyzed (ClinicalTrial ID: NCT04449640) the delivery outcomes from the National Perinatal Information System of the National Institute of Public Health of the Republic of Slovenia of the last 20 years (1 January 1999 - 31 December 2019) and cross-linked the patients with surgical data from our electronic database. We collected baseline characteristics, surgical details and obstetrical outcomes. We excluded women who had undergone previous myomectomy or cesarean section (CS) and described the clinical course of each case since no statistical analysis was performed. RESULTS: We found four patients who had uterine rupture in pregnancy after HSR. Median time to pregnancy was 17 months (range 1-60), all the women underwent CS and fetal-maternal outcomes were acceptable in half of the cases. Symptoms were nonspecific and included pain, fetal distress and vaginal bleeding. CONCLUSION: Uterine rupture in pregnancy after a previous HSR is a very rare, but life-threatening event. Prompt diagnosis can ensure successful management and avoid adverse maternal-fetal outcomes.

Does Hysteroscopic Dissection of Partial Uterine Septum Represent a Risk Factor for Placental Abnormalities in Subsequent Pregnancy Compared with Controls Undergoing Other Hysteroscopic Surgery? Results from a Large Case-Control Analysis.

BACKGROUND: Hysteroscopic septum dissection (HSD) is thought to improve fertility and pregnancy outcomes. However, the available literature suggests that uterine surgery can cause placental abnormalities in subsequent pregnancies. METHODS: A case-control study was performed at the University Medical Center of Ljubljana, Department of Human Reproduction, from 1 January 2016 to 31 December 2018. The primary outcome was the association between HSD and the occurrence of placental abnormalities. We included women who underwent HSD due to infertility. Age-matched women who underwent hysteroscopic surgery for other issues were considered as controls. In addition, we divided the groups according to conception method. Only singleton pregnancies and first delivery were considered. RESULTS: A total of 1286 women (746 who underwent HSD and 540 controls) were included in the analysis. HSD had no influence on placental abnormalities since the ratio was comparable regardless of the method of conception (113/746 vs. 69/540; p = 0.515). Infertile women who conceived naturally after HSD had a normal placentation rate comparable to women who did not undergo HSD (380/427 vs. 280/312; p = 0.2104). The rate of placental abnormalities in women who achieved pregnancy with IVF/ICSI procedures following HSD was comparable to that of women who did not undergo HSD (52/319 vs. 33/228; p = 0.5478). Placenta previa occurred significantly more often in infertile women without HSD after IVF/ICSI compared to natural conception (2/312 vs. 7/228; p = 0.0401). CONCLUSIONS: HSD was not associated with higher rate of placental abnormalities in the first singleton pregnancy compared with other hysteroscopic procedures. A higher rate of placenta previa in pregnancies following IVF/ICSI procedures, which was shown by our research, is corroborated by previous research findings.

Reproductive outcomes after laparoscopic surgery in infertile women affected by ovarian endometriomas, with or without in vitro fertilisation: results from the SAFE (surgery and ART for endometriomas) trial.

We performed a retrospective cohort study, namely "Surgery and ART for Endometriomas" (SAFE) trial (Clinical Trial ID: NCT03717870), including women who underwent laparoscopic cystectomy for endometrioma before first IVF and compared their reproductive outcomes with the ones of women without endometriosis and with unexplained infertility, tubal factor or male factor infertility. We found that women who underwent previous laparoscopic cystectomy for endometrioma had higher FSH and LH levels between the 2nd and 5th day of the cycle before IVF, required higher doses of gonadotrophins for ovarian stimulation and had a lower number of retrieved oocytes compared with other types of infertility. Nevertheless, pregnancy and delivery rates remain comparable to other causes of infertility. In addition, differences in ovarian stimulation parameters between endometriosis and other types of infertility lost significance with the increase of women's age. These pieces of information can be considered useful to make adequate counselling about reproductive outcomes for infertile women with ovarian endometriomas and allow a proper decision-making approach shared with the patient.IMPACT STATEMENTWhat is already known on this subject? Although endometriomas are common findings in infertile women, whether they should be surgically removed before an in vitro fertilisation (IVF) is a long-lasting debate, and current evidence does not offer a robust background to draw firm recommendations.What do the results of this study add? Women who underwent previous laparoscopic cystectomy for endometrioma need higher doses of gonadotrophins for ovarian stimulation and have a lower number of retrieved oocytes, compared with other types of infertility. Pregnancy and delivery rates remain comparable to other causes of infertility.What are the implications of these findings for clinical practice and/or further research? These pieces of information can help to make adequate counselling about reproductive outcomes for infertile women with ovarian endometriomas and allow a proper decision-making approach shared with the patient.

Perinatal outcome of in vitro fertilization pregnancies in women with polycystic ovary syndrome by pregravid BMI.

OBJECTIVES: Given the adverse effects of either polycystic ovary syndrome (PCOS) or overweight/obesity, one could speculate that patients with both would fare worse than others. We sought to evaluate the relationship between pregravid BMI and pregnancy complications in PCOS patients conceived by assisted reproductive techniques (ART). METHODS: Maternal and fetal/neonatal outcomes of singleton pregnancies after assisted reproduction in women with and without PCOS were compared by pregravid body mass index (BMI, <24.9 vs. ≥25 kg/cm2). RESULTS: The study population comprised 185 with a BMI <24.9 kg/cm2 including 39 (21%) with PCOS and 146 (79%) without. We also included 84 patients with BMI ≥25 kg/cm2, involving 34 (40.5%) with PCOS and 50 (59.5%) without. PCOS (total 73 patients) was significantly more common among overweight/obese patients, OR 2.5 (95% CI 1.4, 4.4). Neonates >4,000 g were born only to the overweight/obese mothers in the PCOS group. A higher incidence of gestational diabetes, chronic hypertension, and gestational hypertension was related to pregravid overweight/obesity rather than PCOS. CONCLUSIONS: In this specific subgroup of patients conceived after assisted reproduction, pregravid BMI>25 kg/cm2 rather than PCOS itself appears to be associated with GDM and hypertensive disorders.

Preterm delivery risk in infertile women who conceived after reproductive surgery: natural conception versus IVF/ICSI.

STUDY QUESTION: Is preterm delivery an infertility treatment-related adverse outcome in infertile women who conceived after reproductive surgery? SUMMARY ANSWER: Compared with matched fertile women, preterm delivery appears to be a modest infertility treatment-related adverse outcome in infertile women who have reproductive surgery then conceived naturally or after IVF/ICSI. WHAT IS KNOWN ALREADY: Most observational studies have shown that women who receive any infertility treatment are more likely to deliver preterm than do fertile women. However, studies on the outcome of pregnancies in infertile women who conceive naturally after reproductive surgery are scarce. STUDY DESIGN, SIZE, DURATION: This was a single-centre historical two-part study: cohort and matched cohort study. Anonymized data of 761 infertile women who conceived after reproductive surgery and 758 fertile women were obtained by linking three computerized databases from 1 July 2012 to 31 December 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: In the cohort study, we evaluated the association between the mode of conception and preterm delivery <37 and <32 gestational weeks in 703 infertile women, with a singleton pregnancy who conceived after reproductive surgery, using logistic regression adjusted for relevant co-variates to calculate the adjusted odds ratio with a 95% CI. In the matched cohort study, we evaluated preterm delivery as infertility treatment-related adverse outcome using the propensity score (PS) method. The matched cohort comprised 758 infertile women and 758 fertile women with a twin or singleton pregnancy. Infertile women conceived after reproductive surgery either naturally or through IVF/ICSI. Infertile and fertile women were matched using PS matching. Infertile and fertile women were matched for pre-defined risk factors for preterm delivery. Three infertile women out of an original 761 were not included in the analysis because they lacked all required matching variables. We performed a 1:1 matching with an optimal matching algorithm with a caliper width of the linear predictor of 0.1 standard deviations. The effect of reproductive surgery on preterm delivery was evaluated in the PS-matched sample using Pearson's χ2 test and presented as the odds ratio (OR) with 95% CI. All women delivered at the Department of Perinatology, University Medical Centre Ljubljana, Slovenia. MAIN RESULTS AND THE ROLE OF CHANCE: Among 761 infertile women who conceived after reproductive surgery, 428 (56.2%) women conceived naturally and 333 (43.8%) conceived after IVF/ICSI. The incidence of twin pregnancies was significantly lower after natural conception (2.6% vs 14.1%). Among the 703 infertile women with a singleton pregnancy, 417 (59.3%) conceived naturally and 286 (40.7%) conceived after IVF/ICSI. Adjusted for maternal age and parity in infertile women with singleton pregnancies, IVF/ICSI showed a moderate association with preterm delivery <32 weeks. Compared with natural conception after reproductive surgery, the odds for preterm delivery after IVF/ICSI was 1.07 (95% CI 0.63-1.81) <37 weeks and 2.25 (95% CI 0.80-6.34) <32 weeks. Preterm delivery appears to be a modest infertility treatment-related adverse outcome. Compared with fertile women in the PS-matched sample, infertile women who conceived after reproductive surgery either naturally or after IVF/ICSI the odds of preterm delivery <37 weeks were 1.31 (95% CI 0.97-1.78) and odds of preterm delivery <32 weeks were 1.57 (95% CI 0.78-3.18). However, none of the estimations were statistically significant. LIMITATIONS, REASONS FOR CAUTION: The main limitations of the study were the retrospective design, the heterogeneity of the types of reproductive surgery performed and underlying reproductive pathologies. The low number of preterm deliveries in the present study might influence the precision of estimations. WIDER IMPLICATIONS OF THE FINDINGS: The present study aims to alter the prevailing opinion that reproductive surgery should only be considered preceding IVF to increase implantation and pregnancy rates after IVF. It implies that in selected infertile women who have had reproductive surgery, a high rate of natural conception, a low rate of multiple pregnancies, and a modest infertility treatment-related effect on preterm delivery should be the reasons to encourage natural conception after reproductive surgery. Furthermore, by allowing for natural conception, we can avoid a high-cost invasive medical procedure. STUDY FUNDING/COMPETING INTEREST(S): The study received no funding. We have no competing interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Effect of hysteroscopic septum resection on preterm delivery rate in singleton pregnancies.

INTRODUCTION: Uterine septum is the most common uterine anomaly and is often found during the work-up in primary infertile women. In this study, we aimed to evaluate the potential effect of hysteroscopic septum resection (HSR) on preterm delivery (PTD) in primary infertile women who had singleton pregnancies. MATERIAL AND METHODS: We analyzed 420 singleton pregnancies after primary infertility treatment and compared the PTD rates in women who underwent previous HSR (cases) and women who did not undergo previous operative hysteroscopy or cervical dilation (controls), regardless of the modality of conception (spontaneous or by in vitro fertilization). RESULTS: We did not find significant differences between cases and controls for the incidence of overall PTD rate (p = .237), PTD before 32 gestational weeks (p = .848), and between 32 and 37 gestational weeks (p = .324), premature rupture of membranes (p = .419), and neonatal birth weight (p = .129). Overall, the risk of spontaneous PTD <37 gestational weeks after HSR was not found to be significantly higher compared to controls (RR 1.29, 0.61-2.73 95% CI; p = .561). CONCLUSION: According to our results, previous HSR could be not considered a risk factor for PTD in singleton pregnancies, regardless of the modality of conception (spontaneous or by in vitro fertilization).

Evaluation of M1 and M2 macrophages in ovarian endometriomas from women affected by endometriosis at different stages of the disease.

Endometriosis is an estrogen-dependent disease defined by the presence and growth of functional endometrial-like tissue, glands and stroma, outside the uterine cavity. Macrophages are broadly classified into pro-inflammatory M1 macrophages, and M2 macrophages, which have selective anti-inflammatory and pro-fibrotic activities and are able to induce immunotolerance and angiogenesis. Based on these elements, the aim of our study was to evaluate CD14+CD68+CD197+CD80+ M1 and CD14+CD68+CD163+CD206+ M2 macrophages in tissue samples from ovarian endometriomas of women affected by endometriosis at different stages of the disease. For each patient, we collected a biological sample of the cyst (ovarian endometriomas for cases and ovarian functional cyst for controls) during laparoscopy. We found that the number of both M1 and M2 macrophages was significantly higher in endometriosis group than controls, regardless of stage (p < .0001 for each stage versus controls). Moreover, our data analysis shows a trend in progressive decrease of M1 macrophages from stage I to stage IV; on the contrary, M2 macrophages show a specular trend compared to M1 macrophages, with a progressive increase from stage I to stage IV. This may contribute to the pro-inflammatory microenvironment in the early stages of the disease, and to the pro-fibrotic activity of the advanced stages.

Fasting as possible complementary approach for polycystic ovary syndrome: Hope or hype?

Polycystic ovary syndrome (PCOS) is a common endocrine system disorder among women of reproductive age. In several cases, PCOS women show infertility or subfertility and other metabolic alteration, such as insulin resistance (InsR), dyslipidaemia, hyperinsulinemia and obesity. Despite the aetiology of the syndrome is still far from be elucidated, it could be considered the result of concurrent endocrine modifications, lifestyle factors and genetic background. In particular, accumulating evidence suggests that InsR and compensatory hyperinsulinemia play a pivotal pathogenic role in the hyperandrogenism of many PCOS phenotypes, which in turn have a clear detrimental effect on chronic anovulation. Different forms of fasting, such as intermittent fasting (IF, including alternate day fasting, or twice weekly fasting, for example) and periodic fasting (PF, lasting several days or longer every 2 or more weeks) are currently being tested in several in vitro and in vivo studies. Changes in the circulating levels of Insulin Growth Factor-1 (IGF-1), Insulin-like Growth Factor-Binding Protein 1 (IGFBP1), glucose and insulin are typical effects of fasting which may play a key role on aging and metabolic homeostasis. Considering the paramount importance of InsR and compensatory hyperinsulinemia, different fasting regimens can reduce IGF-1, IGFBP1, glucose and insulin levels and consequently have beneficial effects on ovarian function, androgen excess and infertility in PCOS women.

Spontaneous pregnancy rates after reproductive surgery.

With the development of IVF procedures, the role of reproductive surgery in the management of infertile couples has been questioned. Pregnancy rates (PR) after IVF procedures are well known, but recent data on spontaneous PR after reproductive surgery are scarce. This study aimed to prospectively evaluate how often fertility is restored by reproductive surgery and to identify which independent factors influence spontaneous pregnancy after reproductive surgery. Eight hundred eighty-eight infertile women who underwent surgery for infertility were prospectively included. Women who were referred to IVF after surgery, ceased to plan pregnancy and were lost to follow-up were excluded. Spontaneous PR was analysed for 519 women. A total of 252 (48.6%) women, including 30 treated with clomiphene citrate, conceived spontaneously in the 12-18 months observation period following surgery. Multivariate logistic regression showed that woman's age (OR 0.95, 95% CI 0.90-0.99) and duration of infertility (OR 0.86, 95% CI 0.74-0.99) significantly influence spontaneous PR. Each year of infertility lowers spontaneous PR following surgery by 14% and each year of woman's age by 5%. The study shows a relatively high percentage of women conceived spontaneously after reproductive surgery. The role of reproductive surgery in the management of infertility should be re-evaluated.

Unus pro omnibus, omnes pro uno: A novel, evidence-based, unifying theory for the pathogenesis of endometriosis.

The theory of retrograde menstruation as aetiopathogenesis of endometriosis formulated by John Sampson in 1927 shows clear shortcomings: this does not explain why retrograde menstruation is a physiological process that affects 90% of women, while endometriosis occurs in only 10% of cases; it also does not explain the endometriotic foci distant from the pelvis, nor explains the cases of endometriosis in male patients. The immunological alterations of the peritoneal fluid explains the effects of disease, such as the inhibition of the physiological processes of cytolysis, but does not explain the cause. There is evidence to support the hypothesis that ectopic müllerian remnants of the endometrium, endocervix and endosalpinx are items from the genital ridge leaked during organogenesis. It is known that tissues derived from coelomatic epithelial and mesenchymal cells have the potential to metaplastically differentiate into epithelium and stroma. In addition, the phenotype of the ectopic endometrial cells is significantly different from those ectopic. There is scientific evidence that, during organogenesis, the genes of the Homeobox and Wingless family play a fundamental role in the differentiation of the ducts of Muller and development of the anatomical structure of the urogenital tract. We present here a hypothesis that deregulation of genes and the Wnt signaling pathway Wnt/ß-catenin leads to aberrations and deregulation within the mesoderm, thus, may cause aberrant placement of stem cells. In addition, immune cells, adhesion molecules, extracellular matrix metalloproteinase and pro-inflammatory cytokines activate/alter peritoneal microenvironment, creating the conditions for differentiation, adhesion, proliferation and survival of ectopic endometrial cells.

Anxiety and depression in patients with endometriosis: impact and management challenges.

Endometriosis is one of the most common gynecological diseases and affects ~10% of women in reproductive age. The most common clinical signs of endometriosis are menstrual irregularities, chronic pelvic pain (CPP), dysmenorrhea, dyspareunia and infertility. Symptoms of endometriosis often affect psychological and social functioning of patients. For this reason, endometriosis is considered as a disabling condition that may significantly compromise social relationships, sexuality and mental health. Considering this point, the aim of this narrative review is to elucidate the impact of anxiety and depression in the management of women with endometriosis. Psychological factors have an important role in determining the severity of symptoms, and women who suffer from endometriosis report high levels of anxiety, depression and other psychiatric disorders. In addition, endometriosis is one of the most important causes of CPP; women with endometriosis suffer from a wide range of pelvic pain such as dysmenorrhea, dyspareunia, nonmenstrual (chronic) pelvic pain, pain at ovulation, dyschezia and dysuria. Several studies have underlined the influence of CPP on quality of life and psychological well-being of women with endometriosis. Data suggest that the experience of pelvic pain is an important component of endometriosis and may significantly affect emotive functioning of affected women. It has been demonstrated that high levels of anxiety and depression can amplify the severity of pain. Further studies are needed to better understand the relationship between psychological factors and perception of pain. Treatment of endometriosis may be hormonal or surgical. Surgery is the primary treatment for more severe forms of endometriosis. There are few data in the literature about the influence of psychological factors and psychiatric comorbidities on the effectiveness of treatments. It is important to evaluate the presence of previous psychiatric diseases in order to select the most appropriate treatment for the patient.

The effect of LED on blood microcirculation during chronic wound healing in diabetic and non-diabetic patients-a prospective, double-blind randomized study.

Chronic wounds, especially in diabetic patients, represent a challenging health issue. Since standard treatment protocols often do not provide satisfactory results, additional treatment methods-like phototherapy using low-level light therapy-are being investigated. The aim of our study was to evaluate the effect of phototherapy with light-emitting diodes on chronic wound treatment in diabetic and non-diabetic patients. Since a sufficient blood supply is mandatory for wound healing, the evaluation of microcirculation in the healthy skin at a wound's edge was the main outcome measure. Forty non-diabetic patients and 39 diabetics with lower limb chronic wounds who were referred to the University Medical Center Ljubljana between October 2012 and June 2014 were randomized to the treated and control groups. The treated group received phototherapy with LED 2.4 J/cm2 (wavelengths 625, 660, 850 nm) three times a week for 8 weeks, and the control group received phototherapy with broadband 580-900 nm and power density 0.72 J/cm2. Microcirculation was measured using laser Doppler. A significant increase in blood flow was noted in the treated group of diabetic and non-diabetic patients (p = 0.040 and p = 0.033), while there was no difference in the control groups. Additional Falanga wound bed score evaluation showed a significant improvement in both treated groups as compared to the control group. According to our results, phototherapy with LED was shown to be an effective additional treatment method for chronic wounds in diabetic and non-diabetic patients.