The Known, the Unknown and the Future of the Pathophysiology of Endometriosis.

Endometriosis is one of the most common causes of chronic pelvic pain and infertility, affecting 10% of women of reproductive age. A delay of up to 9 years is estimated between the onset of symptoms and the diagnosis of endometriosis. Endometriosis is currently defined as the presence of endometrial epithelial and stromal cells at ectopic sites; however, advances in research on endometriosis have some authors believing that endometriosis should be re-defined as "a fibrotic condition in which endometrial stroma and epithelium can be identified". There are several theories on the etiology of the disease, but the origin of endometriosis remains unclear. This review addresses the role of microRNAs (miRNAs), which are naturally occurring post-transcriptional regulatory molecules, in endometriotic lesion development, the inflammatory environment within the peritoneal cavity, including the role that cytokines play during the development of the disease, and how animal models have helped in our understanding of the pathology of this enigmatic disease.

Extracellular vesicle-associated VEGF-C promotes lymphangiogenesis and immune cells infiltration in endometriosis.

Endometriosis is a highly prevalent gynecological disease with severe negative impacts on life quality and financial burden. Unfortunately, there is no cure for this disease, which highlights the need for further investigation about the pathophysiology of this disease to provide clues for developing novel therapeutic regimens. Herein, we identified that vascular endothelial growth factor (VEGF)-C, a potent lymphangiogenic factor, is up-regulated in endometriotic cells and contributes to increased lymphangiogenesis. Bioinformatic analysis and molecular biological characterization revealed that VEGF-C is negatively regulated by an orphan nuclear receptor, chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII). Further studies demonstrated that proinflammatory cytokines, via suppression of COUP-TFII level, induce VEGF-C overexpression. More importantly, we show that functional VEGF-C is transported by extracellular vesicles (EVs) to enhance the lymphangiogenic ability of lymphatic endothelial cells. Autotransplanted mouse model of endometriosis showed lenvatinib treatment abrogated the increased lymphatic vessels development in the endometriotic lesion, enlarged retroperitoneal lymph nodes, and immune cells infiltration, indicating that blocking VEGF-C signaling can reduce local chronic inflammation and concomitantly endometriosis development. Evaluation of EV-transmitted VEGF-C from patients' sera demonstrates it is a reliable noninvasive way for clinical diagnosis. Taken together, we identify the vicious cycle of inflammation, COUP-TFII, VEGF-C, and lymphangiogenesis in the endometriotic microenvironment, which opens up new horizons in understanding the pathophysiology of endometriosis. VEGF-C not only can serve as a diagnostic biomarker but also a molecular target for developing therapeutic regimens.

Quinagolide Treatment Reduces Invasive and Angiogenic Properties of Endometrial Mesenchymal Stromal Cells.

Endometrial mesenchymal stromal cells (E-MSCs) extensively contribute to the establishment and progression of endometrial ectopic lesions through formation of the stromal vascular tissue, and support to its growth and vascularization. As E-MSCs lack oestrogen receptors, endometriosis eradication cannot be achieved by hormone-based pharmacological approaches. Quinagolide is a non-ergot-derived dopamine receptor 2 agonist reported to display therapeutic effects in in vivo models of endometriosis. In the present study, we isolated E-MSCs from eutopic endometrial tissue and from ovarian and peritoneal endometriotic lesions, and we tested the effect of quinagolide on their proliferation and matrix invasion ability. Moreover, the effect of quinagolide on E-MSC endothelial differentiation was assessed in an endothelial co-culture model of angiogenesis. E-MSC lines expressed dopamine receptor 2, with higher expression in ectopic than eutopic ones. Quinagolide inhibited the invasive properties of E-MSCs, but not their proliferation, and limited their endothelial differentiation. The abrogation of the observed effects by spiperone, a dopamine receptor antagonist, confirmed specific dopamine receptor activation. At variance, no involvement of VEGFR2 inhibition was observed. Moreover, dopamine receptor 2 activation led to downregulation of AKT and its phosphorylation. Of interest, several effects were more prominent on ectopic E-MSCs with respect to eutopic lines. Together with the reported effects on endometrial and endothelial cells, the observed inhibition of E-MSCs may increase the rationale for quinagolide in endometriosis treatment.

Fibrin clot properties among women with endometriosis and the impact of ovarian stimulation.

RESEARCH QUESTION: Is there a difference in fibrin clot phenotype in women with endometriosis before and after ovarian stimulation? DESIGN: Prospective study including 73 infertile women in two age-matched groups: (i) with confirmed endometriosis (n = 29); (ii) without endometriosis (n = 44). Assessments of plasma fibrin clot permeability (Ks), efficiency of fibrinolysis using clot lysis time (CLT), along with thrombin generation (prothrombin fragments 1+2 [F1+2] and endogenous thrombin potential [ETP]) and fibrinolysis inhibitors were performed together with clinical pregnancy rate. RESULTS: Endometriosis was associated with increased thrombin generation, reflected by both higher F1+2 (+96.1%, P = 0.005) and ETP (+14.2%, P = 0.014) along with unfavourably altered fibrin clot properties represented by lower Ks (-31%, P < 0.001) and prolonged CLT (+13.5%, P = 0.02), compared with the non-endometriosis group. Moreover, women with endometriosis had higher plasminogen activator inhibitor-1 (PAI-1; +272%, P = 0.004) concentrations and alpha-2-antiplasmin activity (+39.9%, P < 0.001) in contrast to the other group. Ovarian stimulation led to reduction in F1+2 (-48.1%, P < 0.001), improvement of fibrin clot phenotype reflected by higher Ks (+25.9%, P < 0.001) and shortened CLT (-11.9%, P < 0.001), along with lower PAI-1 (-54%, P = 0.016) compared with the baseline in women with endometriosis. CONCLUSIONS: Endometriosis is associated with the prothrombotic fibrin clot phenotype and increased thrombin generation. Ovarian stimulation favourably alters fibrin clot properties and leads to comparable pregnancy outcomes to those in women without endometriosis.

Diet quality and perceived effects of dietary changes in Dutch endometriosis patients: an observational study.

RESEARCH QUESTION: What is the current diet of women with endometriosis, in terms of adherence to dietary guidelines and use of diets, and what are the perceived effects of dietary modifications? DESIGN: In this online explorative observational study, the Dutch Healthy Diet 2015 index (DHD-15) and quality of life (QoL) with the Endometriosis Health Profile-30 questionnaire (EHP-30) were used to assess diet quality. RESULTS: The questionnaires were completed by 157 participants. Many participants made one or more dietary adaptations for their endometriosis, in the form of a specific diet (46.5%), with the use of dietary supplements (56.1%), with other dietary adjustments (64.3%), or all. Endometriosis patients had a significantly lower DHD-15 score, indicating a lower diet quality than a healthy reference group (P = 0.004). In the endometriosis group, diet users had a significantly higher total DHD-15 score than non-diet users (P < 0.0001). Diet quality was not correlated with QoL (Pearson's r = -0.010, P = 0.904). Many specific dietary adjustments (71.3%), however, were reported to reduce endometriosis pain-related symptoms. The removal of gluten, dairy or soy, as well as the addition of vegetables, showed the greatest perceived reductions of symptoms in participants. CONCLUSIONS: Although no specific dietary adjustment was found to increase QoL, endometriosis patients do feel that dietary adjustments have a beneficial effect on their symptoms. Therefore, more research is needed to gain evidence about the specific effects of nutrients on endometriosis symptoms.

Exosomes and their cargo are important regulators of cell function in endometriosis.

Endometriosis is a chronic oestrogen-dependent gynaecological disorder characterized by non-menstrual pelvic pain, infertility and the extrauterine growth of endometrial-like glands and stroma. It has been noted that the eutopic endometrium of women with endometriosis is functionally distinct from that of women without endometriosis. Moreover, ectopic endometrial implants are functionally different from the eutopic endometrium of women with endometriosis. However, the mechanisms directing these differences are ill-defined. It is proposed here that small membrane-bound extracellular vesicles called exosomes are important vehicles in the protection and transport of signalling molecules central to the dysregulation of endometrial function in women with endometriosis. Therefore, a critical review of the literature linking exosomes and their cargo to the pathobiology of endometriosis was conducted. Circulating peritoneal fluid and endometrial cell exosomes contained long non-coding RNA, miRNA and proteins involved in histone modification, angiogenesis and immune modulation that differed significantly in women with endometriosis compared with controls. Moreover, experimental evidence supports a role for exosomes and their cargo in angiogenesis, neurogenesis, immune modulation and endometrial stromal cell invasion. It is therefore suggested that exosomes play an important role in the pathophysiology of endometriosis.

Ovarian reserve and recurrence 1 year post-operatively after using haemostatic sealant and bipolar diathermy for haemostasis during laparoscopic ovarian cystectomy.

RESEARCH QUESTION: Is there a difference in the ovarian reserve 1 year post-operatively in those who used a haemostatic sealant or bipolar diathermy for haemostasis during laparoscopic ovarian cystectomy for ovarian endometriomas? DESIGN: This was an extended follow-up observational study of a previous randomized controlled trial where women aged 18 to 40 years with 3-8 cm unilateral or bilateral endometriomas were randomized to receive haemostasis by a haemostatic sealant or bipolar diathermy following ovarian cystectomy. The primary outcome was the ovarian reserve as assessed by antral follicle count (AFC) 1 year post-operatively. Secondary outcomes included the recurrence rate of ovarian endometrioma, the change in anti-Müllerian hormone (AMH) and FSH concentrations, and reproductive outcomes. RESULTS: The significant increase in AFC at 3 months after initial surgery (P = 0.025) in the haemostatic sealant group compared with the diathermy group was sustained at 1 year (P = 0.024) but there was no difference in AMH or FSH concentrations between the groups throughout the follow-up period. The recurrence rate in the FloSeal group was 7.7% (n = 3/39) compared with 22.2% (n = 8/36) in the diathermy group (P = 0.060). The recurrence rate in women who had bilateral lesions was significantly higher than those with unilateral lesions (risk ratio 5.33, interquartile range 1.55-18.38). No difference in reproductive outcomes was found between the two groups. CONCLUSIONS: Applying haemostatic sealant after laparoscopic cystectomy of ovarian endometriomas produces a significantly greater improvement in AFC, which was apparent at 3-month follow-up, and was sustained at 1-year follow-up without compromising the recurrence rate.

Evaluation of Bowel Function After Surgical Treatment for Intestinal Endometriosis: A Prospective Study.

BACKGROUND: Defecation symptoms related to intestinal deep infiltrative endometriosis are caused by anatomical and functional disorders and are probably linked to the course of the disease and surgical treatment. OBJECTIVE: The primary aim of this study was to assess bowel function before and after intestinal deep infiltrative endometriosis surgery. Secondarily, we sought to correlate defecatory symptoms with preoperative risk factors. DESIGN/SETTINGS: This is a single-center prospective cohort study, using the low anterior resection syndrome score to evaluate bowel function 4 weeks before, as well as at 6 months and 1 year after surgery. The Wilcoxon signed-rank test and logistic multiple regression analyses were performed to compare preoperative and postoperative scores. The level of significance was set at <0.05 for all comparisons. PATIENTS: Thirty-seven adult female patients who underwent intestinal resection for deep infiltrative endometriosis between 2015 and 2017 were included. MAIN OUTCOME MEASURES: The primary outcome was bowel function appraisement in deep infiltrative endometriosis intestinal surgery. RESULTS: During the preoperative evaluation, 48.6% of patients reported low anterior resection syndrome score ≥21. This group presented a mean score of 17.9 ± 13.7, with a median of 20 and a range of 5 to 30. After 1 year, the mean score was decreased to 9.6 ± 11.1, with a median of 4 and a range of 0 to 22. A significant difference was detected when comparing the post- and preoperative scores (p = 0.0006). Improvements in defecatory symptoms such as reduced fecal incontinence for flatus (p = 0.004) and liquid stools (p = 0.014) were also reported. The clustering of stools (p = 0.005) and fecal urgency (p = 0.001) also improved 1 year after surgery. The preoperative multiple logistic regression showed that dyschezia was the only independent variable associated with bowel symptoms. LIMITATIONS: This is a well-documented prospective study, but the data presented have a relatively small population. CONCLUSIONS: This study provides evidence that intestinal deep infiltrative endometriosis surgery improves bowel function and has a positive impact on evacuation symptoms. See Video Abstract at http://links.lww.com/DCR/B534. EVALUACIN DE LA FUNCIN INTESTINAL DESPUS DEL TRATAMIENTO QUIRRGICO PARA LA ENDOMETRIOSIS INTESTINAL UN ESTUDIO PROSPECTIVO: ANTECEDENTES:Se considera que los síntomas defecatorios relacionados con la endometriosis intestinal infiltrativa profunda, son causados por trastornos anatómicos y funcionales, y probablemente estén relacionados con el curso de la enfermedad y tratamiento quirúrgico.OBJETIVO:El objetivo principal fue evaluar la función intestinal antes y después de la cirugía por endometriosis intestinal infiltrativa profunda. En segundo lugar, correlacionar los síntomas defecatorios con los factores de riesgo preoperatorios.DISEÑO / AJUSTES:Es un estudio de cohorte prospectivo de un solo centro, utilizando la puntuación del síndrome de resección anterior baja (LARS Score) para evaluar la función intestinal 4 semanas antes, 6 meses y un año después de la cirugía. Se realizaron pruebas de rango firmado de Wilcoxon y análisis de regresión logística múltiple para comparar puntuaciones preoperatorias y postoperatorias. Para todas las comparaciones, el nivel de significancia se estableció en <0.05.ENTORNO CLINICO:Se incluyeron 37 mujeres adultas sometidas a resección intestinal por endometriosis infiltrativa profunda entre 2015 y 2017.PRINCIPALES MEDIDAS DE VALORACION:El resultado principal, fue la evaluación de la función intestinal en cirugía de endometriosis infiltrativa profunda intestinal.RESULTADOS:Durante la evaluación preoperatoria, el 48,6% de los pacientes reportaron Síndrome de Resección Anterior Baja ≥ 21. Este grupo presentó una puntuación media de 17,9 ± 13,7, con una mediana de 20 y un rango de 5 a 30. Después de un año, la puntuación media se redujo a 9,6 ± 11,1, con una mediana de 4 y un rango de 0 a 22 Se detectó una diferencia significativa al comparar las puntuaciones postoperatorias y preoperatorias (p = 0,0006). Se informó de mejoras en los síntomas defecatorios como la reducción de la incontinencia fecal por flatos (p = 0,004) y heces líquidas (p = 0,014). La agrupación de heces (p = 0,005) y la urgencia fecal (p = 0,001) presentaron mejoría a un año después de la cirugía. La regresión logística múltiple preoperatoria mostró que la disquecia fue la única variable independiente asociada con los síntomas intestinales.LIMITACIONES:A pesar de que es un estudio prospectivo bien documentado, los datos presentados son de una población relativamente pequeña.CONCLUSIONES:El estudio proporciona evidencia de que la cirugía intestinal por endometriosis infiltrativa profunda, mejora la función intestinal y tiene un impacto positivo en los síntomas de evacuación. Consulte Video Resumen en http://links.lww.com/DCR/B534.

Is primary dysmenorrhea a precursor of future endometriosis development?

Primary dysmenorrhea (PD) is the most common gynecologic disorder during adolescence and it is characterized by crampy lower abdominal pain that occurs during menstruation. Secondary dysmenorrhea, in contrast, has the same clinical features but occurs in women with a disease that could account for their symptoms (endometriosis, adenomyosis, uterine fibroids, pelvic inflammatory disease). Endometriosis is the most common cause of secondary dysmenorrhea and it should be considered in patients with persistent and clinically significant dysmenorrhea despite treatment. It is often diagnosed after a long delay, increasing the likelihood of pain chronicity and fertility problems at a later age. Women who suffer from dysmenorrhea in adolescence have higher risk of endometriosis in future. The open question is if endometriosis was already present at the onset of dysmenorrhea but undiagnosed or if PD favors subsequent development of endometriosis-associated pain. Since PD is associated with higher risk for developing chronic pain state and shares some of the same pain pathways of endometriosis (prostaglandins overproduction, inflammation, peripheral sensitization, central sensitization and abnormal stress responses), a correlation between PD and endometriosis is suggested. To know whether it is a risk factor for the development of endometriosis-associated pain may provide an opportunity for early intervention and prevention. The present review aims to investigate the clinical and pathogenetic features of PD and endometriosis in order to identify a possible association between the two conditions.

Dienogest vs GnRH agonists as postoperative therapy after laparoscopic eradication of deep infiltrating endometriosis with bowel and parametrial surgery: a randomized controlled trial.

BACKGROUND: The recurrence of deep infiltrating endometriosis (DIE) after its surgical excision is a big problem: postoperative treatment is crucial. OBJECTIVE: To compare two postoperative treatments: Dienogest and GnRH agonists. DESIGN: Prospective Randomized Controlled Trial (RCT). PATIENTS: 146 women submitted to laparoscopic eradication of DIE with bowel and parametrial surgery. INTERVENTIONS: Patients were randomized into two groups. Group A (n = 81) received Triptorelin or Leuprorelin 3.75 mg every 4 weeks for 6 months. Group B (n = 65) received Dienogest 2 mg/day for at least 6 months. A first interview made after six months valued compliance to therapy, treatment tolerability, pain improvement, and side effects. A second interview at 30 ± 6 months valued pain relapse, imaging relapse, and pregnancy rate. MAIN OUTCOMES: The primary outcome was to demonstrate the non-inferiority of Dienogest about the reduction in pain recurrence. Secondary outcomes were differences in terms of treatment tolerability, side effects, imaging relapse rate, and pregnancy rate. RESULTS: Both Dienogest and GnRH agonists were associated with a highly significant reduction of pain at 6 and 30 months, without any significant difference (p < .001). About treatment tolerability, a more satisfactory profile was reported with Dienogest (p = .026). No difference in terms of clinical relapse, imaging relapse, and live births was found. CONCLUSIONS: Dienogest has proven to be as effective as GnRH agonists in preventing recurrence of DIE and associated pelvic pain after surgery. Also, it is better tolerated by patients.

The effect of vitamin D supplementation on clinical symptoms and metabolic profiles in patients with endometriosis.

BACKGROUND: To our knowledge, data on the effects of vitamin D supplementation on clinical symptoms and metabolic profiles in patients with endometriosis are limited. This study was conducted to determine the effects of vitamin D supplementation on clinical symptoms and metabolic profiles in patients with endometriosis. METHODS: The current randomized, double-blind, placebo-controlled trial was conducted among 60 patients (aged 18-40 years old) with endometriosis. Participants were randomly allocated into two groups (30 participants each group) to receive either 50,000 IU vitamin D or placebo each 2 weeks for 12 weeks. RESULTS: Vitamin D supplementation significantly decreased pelvic pain (ß - 1.12; 95% CI, -2.1, -0.09; p=.03) and total-/HDL-cholesterol ratio (ß - 0.29; 95% CI, -0.57, -0.008; p=.04) compared with the placebo. Moreover, vitamin D intake led to a significant reduction in high-sensitivity C-reactive protein (hs-CRP) (ß - 0.64 mg/L; 95% CI, -0.97, -0.30; p<.001) and a significant increase in total antioxidant capacity (TAC) (ß 47.54 mmol/L; 95% CI, 19.98, 75.11; p=.001) compared with the placebo. CONCLUSIONS: Overall, our study demonstrated that vitamin D intake in patients with endometriosis resulted in a significant improvement of pelvic pain, total-/HDL-cholesterol ratio, hs-CRP and TAC levels, but did not affect other clinical symptoms and metabolic profiles.

Estradiol/nomegestrol acetate as a first-line and rescue therapy for the treatment of ovarian and deep infiltrating endometriosis.

PURPOSE: Estradiol valerate/nomegestrol acetate (E2V/NOMAC) is a new combined oral contraceptive with a good tolerability profile and low drop-out rates, which was shown to improve menstrual-related symptoms. This study aims to evaluate its effectiveness in the control of symptoms and progression of disease in women with ovarian endomestriomas and deep infiltrating endometriosis (DIE). METHODS: This was a retrospective cohort study on 39 women with pelvic endometriosis treated with E2V/NOMAC. We assessed for each patient, at the beginning of treatment and after 6 months, the painful symptoms, through a global VAS (Visual Analogue Scale) index and the size of the greatest ovarian and/or deep infiltrating endometriotic lesions. RESULTS: After 6 months of treatment, a significant reduction was observed for the global VAS score for pain symptoms and for the mean size of ovarian endometriomas, whereas DIE lesions did not present significant changes in mean size. CONCLUSIONS: E2/NOMAC was effective in reducing pain symptoms associated with pelvic endometriosis and the size of ovarian endometriomas, whereas DIE lesions remained stable. This therapy could provide good results in the control of symptoms and disease progression in women with pelvic endometriosis.

Novel Technology to Capture Objective Data from Patients' Recovery from Laparoscopic Endometriosis Surgery.

STUDY OBJECTIVE: To assess the feasibility of a noncontact radio sensor as an objective measurement tool to study postoperative recovery from endometriosis surgery. DESIGN: Prospective cohort pilot study. SETTING: Center for minimally invasive gynecologic surgery at an academically affiliated community hospital in conjunction with in-home monitoring. PATIENTS: Patients aged above 18 years who sleep independently and were scheduled to have laparoscopy for the diagnosis and treatment of suspected endometriosis. INTERVENTIONS: A wireless, noncontact sensor, Emerald, was installed in the subjects' home and used to capture physiologic signals without body contact. The device captured objective data about the patients' movement and sleep in their home for 5 weeks before surgery and approximately 5 weeks postoperatively. The subjects were concurrently asked to complete a daily pain assessment using a numeric rating scale and a free text survey about their daily symptoms. MEASUREMENTS AND MAIN RESULTS: Three women aged 23 years to 39 years and with mild to moderate endometriosis participated in the study. Emerald-derived sleep and wake times were contextualized and corroborated by select participant comments from retrospective surveys. In addition, self-reported pain levels and 1 sleep variable, sleep onset to deep sleep time, showed a significant (p <.01), positive correlation with next-day-pain scores in all 3 subjects: r = 0.45, 0.50, and 0.55. In other words, the longer it took the subject to go from sleep onset to deep sleep, the higher their pain score the following day. CONCLUSION: A patient's experience with pain is challenging to meaningfully quantify. This study highlights Emerald's unique ability to capture objective data in both preoperative functioning and postoperative recovery in an endometriosis population. The utility of this uniquely objective data for the clinician-patient relationship is just beginning to be explored.

Relationship between Cyst Fluid Concentrations of Iron and Severity of Dysmenorrhea in Patients with Ovarian Endometrioma.

OBJECTIVES AND DESIGN: Endometriosis-related pain can be caused by anatomical distortions as well as environmental factors such as inflammation and oxidative stress. The aim of this study is to investigate the relationship between the severity of dysmenorrhea in patients with ovarian endometrioma (OMA) and cyst fluid (CF) concentrations of irons, including total iron, heme iron, and free iron. METHOD: Eighty-three patients who were histologically diagnosed with OMA were enrolled in the Department of Gynecology, Nara Medical University Hospital, between 2013 and 2019. The patients were divided into 4 groups according to the severity of dysmenorrhea: no pain, mild, moderate, and severe. Iron concentration was measured by the inductively coupled plasma optical emission spectrometry method. RESULTS: There were no significant differences among the 4 groups in variables such as age at diagnosis, preoperative CA125, preoperative CA19-9, cyst size, and tumor laterality (unilateral or bilateral). There was a positive correlation between the severity of dysmenorrhea and total iron (p < 0.001) and heme iron (p = 0.016) concentrations. Multiple regression analyses revealed that the CF concentration of total iron (hazard ratio 18.75, 95% confidence interval: 2.26-155.35, p = 0.007) was a significant independent variable associated with the severity of dysmenorrhea. A receiver operating characteristic curve analysis showed that a total iron exceeding 290.8 mg/L was associated with severe dysmenorrhea with a sensitivity of 90.9% and a specificity of 65.7%. LIMITATIONS: This study excluded patients with adenomyosis, superficial endometriosis, or deep endometriosis, resulting in a smaller number of cases. Iron levels could not be compared to the endometriosis stage using the r-ASRM score. CONCLUSIONS: There is no clear evidence that iron predicts the severity of endometriosis-related pain. However, iron may be closely associated with dysmenorrhea.

FSH dose is negatively correlated with number of oocytes retrieved: analysis of a data set with ~650,000 ART cycles that previously identified an inverse relationship between FSH dose and live birth rate.

PURPOSE: To evaluate whether total FSH dose was negatively correlated with number of oocytes retrieved in a large data set where previously, a negative correlation between FSH dose and live birth rate was identified. METHODS: Data from 650,637 fresh autologous in vitro fertilization (IVF) cycles reported to the Society for Assisted Reproductive Technology between 2004 and 2012 were included. Logistic regression analysis was performed to determine if the relationship between total FSH dose used during ART with number of oocytes retrieved was impacted by the patient's health prognosis, age, BMI, ovarian stimulation protocol, or infertility diagnosis. RESULTS: The number of oocytes retrieved was negatively correlated with FSH dose (P < 0.0001). Regardless of patient prognosis, age, BMI, ovarian stimulation protocol, and infertility diagnosis, the highest number of oocytes retrieved was in the 1001-2000 IU FSH group, and was 36-51% lower in the > 5000 IU compared with the optimal, 1001-2000 IU, FSH groups. Overall, ~80% of patients received FSH doses outside of the optimal FSH dose. Moreover, 61% of good prognosis patients (excludes individuals likely prescribed higher FSH doses) received doses exceeding the optimal dose range. CONCLUSION: The inverse relationship between FSH dose and the number of oocytes retrieved independent of patient age or health implies that excessive FSH doses during ART may be detrimental to oocyte retrieval.

Carbon dioxide (CO2) laser ablation of symptomatic vaginal endometriosis: a pilot study.

Deep dyspareunia affects almost half of the women with endometriosis and is associated with vaginal endometriotic lesions. Our pilot study's objective is to assess the feasibility and effectiveness of CO2-laser ablation under colposcopic guidance for the treatment of symptomatic vaginal endometriosis. A non-comparative pilot study has been performed. Only women with histologically proven vaginal endometriosis, who declared the presence of moderate or severe deep dyspareunia, resistant to at least 6 months of conventional hormonal treatment, were deemed eligible for the study. All treatments were performed in an outpatient setting with a colposcopic-guided, hand-directed CO2-laser. Variation in pain symptoms was measured with a 0- to 10-point numerical rating scale (NRS), in sexual functioning with the Female Sexual Function Index (FSFI), in psychological status with the Hospital Anxiety and Depression Scale (HADS), and in quality of life with the Short Form-12 questionnaire (SF-12). Satisfaction with treatment was evaluated according to a five-category scale (very satisfied, satisfied, neither satisfied nor dissatisfied, dissatisfied, very dissatisfied). Nineteen women were enrolled. No complications occurred. At 12-month follow-up, significant improvements were observed in deep dyspareunia and dyschezia scores, in FSFI, HADS, and in the physical component summary scores of SF-12, whereas the mental component score of SF-12 did not vary substantially. Most women (84%) were satisfied with the treatment received. CO2-laser ablation for vaginal endometriosis could represent a valuable alternative option for women with symptomatic lesions, both in terms of amelioration of pain symptoms and improvement in quality of life and sexual function.

Molecular Basis of Endometriosis and Endometrial Cancer: Current Knowledge and Future Perspectives.

The human endometrium is a unique tissue undergoing important changes through the menstrual cycle. Under the exposure of different risk factors in a woman's lifetime, normal endometrial tissue can give rise to multiple pathologic conditions, including endometriosis and endometrial cancer. Etiology and pathophysiologic changes behind such conditions remain largely unclear. This review summarizes the current knowledge of the pathophysiology of endometriosis and its potential role in the development of endometrial cancer from a molecular perspective. A better understanding of the molecular basis of endometriosis and its role in the development of endometrial pathology will improve the approach to clinical management.

BMI-1 Expression Heterogeneity in Endometriosis-Related and Non-Endometriotic Ovarian Carcinoma.

BMI-1 is a key component of stem cells, which are essential for normal organ development and cell phenotype maintenance. BMI-1 expression is deregulated in cancer, resulting in the alteration of chromatin and gene transcription repression. The cellular signaling pathway that governs BMI-1 action in the ovarian carcinogenesis sequences is incompletely deciphered. In this study, we set out to analyze the immunohistochemical (IHC) BMI-1 expression in two different groups: endometriosis-related ovarian carcinoma (EOC) and non-endometriotic ovarian carcinoma (NEOC), aiming to identify the differences in its tissue profile. METHODS: BMI-1 IHC expression has been individually quantified in epithelial and in stromal components by using adapted scores systems. Statistical analysis was performed to analyze the relationship between BMI-1 epithelial and stromal profile in each group and between groups and its correlation with classical clinicopathological characteristics. RESULTS: BMI-1 expression in epithelial tumor cells was mostly low or negative in the EOC group, and predominantly positive in the NEOC group. Moreover, the stromal BMI-1 expression was variable in the EOC group, whereas in the NEOC group, stromal BMI-1 expression was mainly strong. We noted statistically significant differences between the epithelial and stromal BMI-1 profiles in each group and between the two ovarian carcinoma (OC) groups. CONCLUSIONS: Our study provides solid evidence for a different BMI-1 expression in EOC and NEOC, corresponding to the differences in their etiopathogeny. The reported differences in the BMI-1 expression of EOC and NEOC need to be further validated in a larger and homogenous cohort of study.

Fibronectin Molecular Status in Plasma of Women with Endometriosis and Fertility Disorders.

The diagnosis of endometriosis and fertility disorders is difficult; therefore, it is necessary to look for reliable biomarkers. Analysis of the molecular status of fibronectin as a key player in repair and wound healing processes, as well as in coagulation and fibrinolysis pathways, is justified. ELISA and SDS-agarose immunoblotting were applied to determine the fibronectin concentration and presence and occurrence of soluble FN-fibrin complexes in the blood plasma of women with endometriosis (n = 38), fertility disorders (n = 28) and the healthy group (n = 25). The concentration of fibronectin in the blood plasma of women with endometriosis (292.61 ± 96.17 mg/L) and fertility disorders (287.53 ± 122.68 mg/L) was significantly higher than in the normal group (226.55 ± 91.98 mg/L). The presence of FN-fibrin complexes of 750, 1000, 1300, 1600 and 1900 kDa in the plasma of women with endometriosis and fertility disorders was shown. The presence of FN-fibrin complexes with a molecular mass of more than 1300 kDa in women with endometriosis and infertility and the complete absence of these complexes in healthy women may indicate an increased and chronic activation of coagulation mechanisms in these patients. The presence of complexes of high molecular mass may be one of the biomarkers of fertility disorders in women.

Exosomes as Biomarkers for Female Reproductive Diseases Diagnosis and Therapy.

Cell-cell communication is an essential mechanism for the maintenance and development of various organs, including the female reproductive system. Today, it is well-known that the function of the female reproductive system and successful pregnancy are related to appropriate follicular growth, oogenesis, implantation, embryo development, and proper fertilization, dependent on the main regulators of cellular crosstalk, exosomes. During exosome synthesis, selective packaging of different factors into these vesicles happens within the originating cells. Therefore, exosomes contain both genetic and proteomic data that could be applied as biomarkers or therapeutic targets in pregnancy-associated disorders or placental functions. In this context, the present review aims to compile information about the potential exosomes with key molecular cargos that are dysregulated in female reproductive diseases which lead to infertility, including polycystic ovary syndrome (PCOS), premature ovarian failure (POF), Asherman syndrome, endometriosis, endometrial cancer, cervical cancer, ovarian cancer, and preeclampsia, as well as signaling pathways related to the regulation of the reproductive system and pregnancy outcome during these pathological conditions. This review might help us realize the etiology of reproductive dysfunction and improve the early diagnosis and treatment of the related complications.