Coexistence of Endometriosis and Thyroid Autoimmunity in Infertile Women: Impact on in vitro Fertilization and Reproductive Outcomes.

OBJECTIVES: The objective of the study was to evaluate the prevalence and impact of impaired thyroid-stimulating hormone (TSH) levels on the reproductive outcomes of in vitro fertilization patients diagnosed with endometriosis and compared to controls without endometriosis. DESIGN: This is a retrospective cohort study on prospectively collected data. SETTING: The study was conducted at tertiary care university hospital. PARTICIPANTS: Participants were infertile women with histopathological diagnosis of endometriosis. METHODS: For 12 months (January 2018 to January 2019), women were deemed suitable and subsequently divided according to serum TSH levels above or below 2.5 mIU/L and compared to patients without endometriosis. Needed sample size was at least 41 patients for each cohort of women. Co-primary outcomes were the live birth rate (LBR), clinical pregnancy rate (CPR), and pregnancy loss rate (PLR). RESULTS: Overall, 226 women (45 with endometriosis and 181 controls without endometriosis) were included. Diagnoses of Hashimoto thyroiditis were significantly more frequent in women with rather than without endometriosis (14/45 [31.1%] vs. 27/181 [14.9%]; p = 0.012). Similarly, in women with endometriosis, Hashimoto diagnosis rates were higher with TSH ≥2.5 mIU/L compared to TSH <2.5 mIU/L (9/15 [60%] vs.5/30 [16.6%]; p = 0.001) so were the Hashimoto diagnosis rates in control group (women without endometriosis) with TSH ≥2.5 mIU/L compared to TSH <2.5 mIU/L (17/48 [35.4%] vs. 10/133 [7.5%], respectively; p = 0.001). Effect size analysis confirmed an increased risk of Hashimoto thyroiditis in women with endometriosis and TSH ≥2.5 mIU/L compared to women with endometriosis and TSH <2.5 mIU/L (risk ratio [RR] 3.60 [95% CI 1.46-8.86]) and in women with endometriosis and TSH ≥2.5 mIU/L compared to non-endometriotic euthyroid patients (RR 7.98 [95% CI 3.86-16.48]). Dysmenorrhea risk was higher in endometriotic euthyroid women compared to euthyroid patients with no endometriosis (RR 1.87 [95% CI 1.21-2.87]). The risk was still increased in euthyroid women with endometriosis relative to dysthyroid women with no endometriosis (RR 1.97 [95% CI 1.11-3.50]). There were no significant differences between the four groups for CPR, LBR, PLR and retrieved oocytes, immature oocytes, degenerated and unfertilized oocytes, cultured blastocysts, embryos and transferred embryos. LIMITATIONS: Limitations of the study were retrospective design, limited sample size, and use of different ovarian stimulation protocol. CONCLUSIONS: Thyroid autoimmunity seems more common in women with endometriosis and TSH over 2.5 mIU/L. However, there was no significant impact on in vitro fertilization and reproductive outcomes related to the coexistence of endometriosis, Hashimoto disease, and higher TSH levels. Due to limitations of the study, additional evidence is required to validate the abovementioned findings.

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.

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.

Sperm Cryopreservation Today: Approaches, Efficiency, and Pitfalls.

The cryopreservation of human spermatozoa has been an option for patients undergoing chemo or radiotherapies since the late 1950s. Presently, there are different techniques for the cryopreservation of spermatozoa. The most commonly used techniques are programmable slow freezing and freezing on liquid nitrogen vapors, while the use of vitrification is still not accepted as clinically relevant. Although there have been many improvements, the ideal technique for achieving better post-thaw sperm quality continues to be a mystery. A major obstacle during cryopreservation is the formation of intracellular ice crystals. Cryodamage generated by cryopreservation causes structural and molecular alterations in spermatozoa. Injuries can happen because of oxidative stress, temperature stress, and osmotic stress, which then result in changes in the plasma membrane fluidity, motility, viability, and DNA integrity of the spermatozoa. To prevent cryodamage as much as possible, cryoprotectants are added, and in some clinical trial cases, even antioxidants that may improve post-thaw sperm quality are added. This review discusses cryopreservation techniques, cryodamage on molecular and structural levels, and cryoprotectants. It provides a comparison of cryopreservation techniques and describes recent advances in those techniques.

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.

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.

Pathology of the Placenta in Singletons after Assisted Reproductive Technology Compared to Singletons after Spontaneous Conception: A Systematic Review.

Background: We reviewed the literature comparing the pathological characteristics of singleton births conceived after assisted reproductive technology (ART) with those after spontaneous conception. Methods: We reviewed PubMed, EMBASE, Ovid MEDLINE, Google Scopus, Scholar, Cochrane Central Register of Controlled Trials and the Web of Science for the previous 10 years, up to November 2022. Results: Four eligible studies included 3445 placentas, 806 after ART (IVF/ICSI). Placentas after ART differed in frequency of retroplacental and marginal hematomas (p = 0.04), increased thickness (p = 0.02), higher overall occurrences of vascular and anatomical pathology (p < 0.001) and more frequent marginal (p = 0.001) and membranous (p = 0.02) umbilical cord insertion than placentas from non-ART pregnancies. Conclusion: Further research is needed to determine the extent to which these placental changes in ART pregnancies alter its function and pregnancy outcome.

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.

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.

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.

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.

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.

The effect of transcutaneous application of gaseous CO2 on diabetic chronic wound healing-A double-blind randomized clinical trial.

Chronic wounds in diabetics are difficult to treat, therefore, adjuvant therapies have been investigated. Bathing in CO2 -rich water (spa therapy) has been known in Europe for decades for its positive effect on peripheral vascular disorders. Recently, much effort has been invested in developing optimal application methods of CO2 . Uses include subcutaneous injections of CO2 , bathing in CO2 -enriched water, and transcutaneous application of CO2 . To verify the effect of transcutaneous application of gaseous CO2 on the healing of chronic diabetic wounds, a randomized double-blind clinical research was designed. The research included 30 and 27 wounds in the study and control groups, respectively. In addition to standard treatment, patients in the study group received 20 therapies with medical-grade CO2 gas and the control group received the same treatment with air. Results showed significantly faster healing in the study group: 20 of the 30 wounds in the study group were healed compared with none in the control group. Mean wound surface and volume in the study group was reduced significantly (surface: 96%, P = .001, volume: 99%, P = .003) compared with a small reduction in the control group (surface: 25%, P = .383, volume: 27%, P = .178). Considering our results, transcutaneous application of gaseous CO2 is an effective adjuvant therapy in diabetic chronic wound treatment.

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.

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.

Dienogest as preoperative treatment of submucous myomas for hysteroscopic surgery: a prospective, randomized study.

The aim of this single-center, prospective, randomized, parallel-group study was to compare Dienogest and Danazol as endometrial preparation in patients who have to undergo hysteroscopic surgery for submucous myomas. We enrolled 80 consecutive eligible patients, in reproductive age, affected by submucous myomas. Pre- and posttreatment characterization of endometrium was performed by hysteroscopic visual observation and histologic confirmation. The enrolled patients were randomly assigned to two groups: 40 were treated with 2 mg of Dienogest/die, 40 with 100 mg of Danazol/die, both orally for 5 weeks, starting on day 1 of menstruation. Posttreatment comparison of endometrial patterns showed a significant more marked effect of Dienogest, respect to Danazol, in atrophying endometrium ("normotrophic non-responders" versus "hypotrophic"-"atrophic", p = 0.028). Intraoperative data showed no significant difference between the two groups for cervical dilatation time (p = 0.326), while in the Dienogest group, we found a significant reduction of operative time (p = 0.001), infusion volume (p = 0.001), and severity of bleeding (p = 0.042). Moreover, Dienogest caused less side effects (p = 0.008). According to our data analysis, Dienogest, respect to Danazol, is more effective for the preparation of the endometrium in patients who have to undergo hysteroscopic surgery for submucous myomas, and causes less side effects.

Natural Killer T cell subsets in eutopic and ectopic endometrium: a fresh look to a busy corner.

PURPOSE: Invariant Natural Killer T cells (iNKT) are a specialized subset of T cells that use their T cell receptor to recognize self and foreign lipids presented by CD1d as cognate antigens. iNKT have been shown to have either protective or harmful roles in many pathological states, including microbial infection, autoimmune disease, allergic disease and cancer. Accumulating evidence seems to suggest that this unique T cell subset combines both classically innate and adaptive immunologic characteristic. Considering these recent data, the aim of work was to review the current knowledge about iNKT in eutopic and ectopic endometrium. METHODS: Narrative overview, synthesizing the findings of literature retrieved from searches of computerized databases. RESULTS: Currently, the immune paradigm of reproduction is gradually changing shape: recent data confirmed that cytokine milieu influences the development and plasticity of different subtype of mononuclear cells, and in turn it can be influenced by the cytokine production of the latter. Among the different NKT cell populations, the recently characterized iNKT seems to share actions typical both of innate and adaptive immunity, being capable of secreting Th1 as well as Th2 cytokine pattern. Moreover, several subtypes of iNKT were identified, who partially express the same master transcription factors of the corresponding T cells counterpart. CONCLUSIONS: Although the data about iNKT's actions in eutopic and ectopic endometrium are still scarce, it is possible to hypothesize that future investigation can shed light on this point, thus allowing a better knowledge about the regulation of these two microenvironments.

Photobiomodulation with light-emitting diodes improves sperm motility in men with asthenozoospermia.

Sperm motility is an important parameter of male fertility and depends on energy consumption. Photobiomodulation with light-emitting diode (LED) is known to stimulate respiratory chain in mitochondria of different mammalian cells. The aim of this research was to evaluate the effect of photobiomodulation with LED on sperm motility in infertile men with impaired sperm motility-asthenozoospermia. Thirty consecutive men with asthenozoospermia and normal sperm count who visited the infertility clinic of University Medial Centre Ljubljana between September 2011 and February 2012 were included in the study. Semen sample of each man was divided into five parts: one served as a non-treated (native) control and four parts were irradiated with LED of different wavelengths: (1) 850 nm, (2) 625, 660 and 850 nm, (3) 470 nm and (4) 625, 660 and 470 nm. The percentage of motile sperm and kinematic parameters were measured using a Sperm Class Analyser system following the WHO recommendations. In the non-treated semen samples, the average ratio of rapidly progressive sperms was 12% and of immotile sperm 73%. Treating with LED significantly increased the proportion of rapidly progressive sperm (mean differences were as follows: 2.83 (1.39-4.28), 3.33 (1.61-5.05), 4.50 (3.00-5.99) and 3.83 (2.31-5.36) for groups 1-4, respectively) and significantly decreased the ratio of immotile sperm (the mean differences and 95% CI were as follows: 3.50 (1.30-5.70), 4.33 (2.15-6.51), 5.83 (3.81-7.86) and 5.50 (2.98-8.02) for groups 1-4, respectively). All differences were highly statistically significant. This finding confirmed that photobiomodulation using LED improved the sperm motility in asthenozoospermia regardless of the wavelength.