Women with Endometriosis-Who Is at Risk for Complications Associated with Pregnancy and Childbirth? A Retrospective Case-Control Study.

Women with endometriosis (EM), particularly the manifestations of adenomyosis (AM) and deep infiltrating endometriosis (DIE), suffer from pain and sterility. DIE also appears with several specific obstetric complications. To determine the risk profile, we designed a retrospective case-control study. Primary outcomes were defined as the risk of preterm birth and caesarean delivery (CD). Primiparous singleton pregnancies in women with DIE were compared with controls without EM. We matched for mode of conception and maternal age. A total of 41 women diagnosed with DIE and 164 controls were recruited. A total of 92.7% of the cases were also diagnosed with AM. Preterm birth occurred in 12.2% of cases and in 6.7% of controls. The difference was not statistically significant (OR: 1.932; 95% CI: 0.632-5.907). The rate of CD was similar in both groups. Remarkably, placental implantation disorders in the form of placenta praevia were eight times more frequent in women with DIE (9.8%) than in controls (1.2%, OR: 8.757; 95% CI: 1.545-49.614). Neonatal outcome was similar in both groups. Four out of fourteen cases reported abdominal wall endometriosis after CD. Women with DIE/AM and with placenta praevia are at risk of bleeding complications. After CD, they can develop abdominal wall EM. We therefore suggest evaluating the birth mode in each woman with DIE/AM.

Physical and psychosocial factors are crucial for maintaining physical and mental health in endometriosis: a longitudinal analysis.

OBJECTIVE: To test the associations of physical and psychosocial factors with physical and mental health in individuals living with endometriosis (EM) by means of cross-sectional and longitudinal analyses. METHODS AND MEASURES: Data were gathered via an online survey between February and August 2021. At survey date t1, sociodemographic, EM-related and psychosocial factors as well as physical and mental health of people with EM were assessed. At survey date t2 three months later, physical and mental health was reassessed. The sample consisted of n_t1 = 723 (30.60 ± 6.31 years) and n_t2 = 216 (30.56 ± 6.47 years) cis women with EM. Statistical analyses included bivariate and partial correlation analyses and hierarchical regression analyses. RESULTS: The participants' physical health was within the average range and their mental health was below-average at t1 and t2. Cross-sectional analyses revealed that worse health was associated with longer diagnostic delay, more surgeries, greater pelvic pain and lower sense of coherence, self-efficacy, sexual satisfaction and satisfaction with the gynecological treatment. In longitudinal analyses, pelvic pain and participants' satisfaction with the gynecological treatment remained significantly associated with health. CONCLUSION: Treatment should address both pelvic pain and psychosocial factors to improve long-term physical and mental health in EM.

Multicenter evaluation of blood-based biomarkers for the detection of endometriosis and adenomyosis: A prospective non-interventional study.

OBJECTIVE: To evaluate blood-based biomarkers to detect endometriosis and/or adenomyosis across nine European centers (June 2014-April 2018). METHODS: This prospective, non-interventional study assessed the diagnostic accuracy of 54 blood-based biomarker immunoassays in samples from 919 women (aged 18-45 years) with suspicion of endometriosis and/or adenomyosis versus symptomatic controls. Endometriosis was stratified by revised American Society for Reproductive Medicine stage. Symptomatic controls were "pathologic symptomatic controls" or "pathology-free symptomatic controls". The main outcome measure was receiver operating characteristic-area under the curve (ROC-AUC) and Wilcoxon P values corrected for multiple testing (q values). RESULTS: CA-125 performed best in "all endometriosis cases" versus "all symptomatic controls" (AUC 0.645, 95% confidence interval [CI] 0.600-0.690, q < 0.001) and increased (P < 0.001) with disease stage. In "all endometriosis cases" versus "pathology-free symptomatic controls", S100-A12 performed best (AUC 0.692, 95% CI 0.614-0.769, q = 0.001) followed by CA-125 (AUC 0.649, 95% CI 0.569-0.729, q = 0.021). In "adenomyosis only cases" versus "symptomatic controls" or "pathology-free symptomatic controls", respectively, the top-performing biomarkers were sFRP-4 (AUC 0.615, 95% CI 0.551-0.678, q = 0.045) and S100-A12 (AUC 0.701, 95% CI 0.611-0.792, q = 0.004). CONCLUSION: This study concluded that no biomarkers tested could diagnose or rule out endometriosis/adenomyosis with high certainty.

Shedding Light on the Interaction Between Rif1 and Telomeres in Ovarian Cancer.

Ovarian cancer, more precisely high-grade serous ovarian cancer, is one of the most lethal age-independent gynecologic malignancies in women worldwide, regardless of age. There is mounting evidence that there is a link between telomeres and the RIF1 protein and the proliferation of cancer cells. Telomeres are hexameric (TTAGGG) tandem repeats at the tip of chromosomes that shorten as somatic cells divide, limiting cell proliferation and serving as an important barrier in preventing cancer. RIF1 (Replication Time Regulation Factor 1) plays, among other factors, an important role in the regulation of telomere length. Interestingly, RIF1 appears to influence the DNA double-strand break (DSB) repair pathway. However, detailed knowledge regarding the interplay between RIF1 and telomeres and their degree of engagement in epithelial ovarian cancer (EOC) is still elusive, despite the fact that such knowledge could be of relevance in clinical practice to find novel biomarkers. In this review, we provide an update of recent literature to elucidate the relation between telomere biology and the RIF1 protein during the development of ovarian cancer in women.

Rare Clinical Presentation of Postmenopausal Endometriosis: A New Perspective.

Endometriosis affects 2-5 % of postmenopausal women with menopause hormone therapy and is less common in women without treatment with exogenous estrogen or tamoxifen. Postmenopausal endometriosis has more unknown aspects in its pathogenesis and clinical manifestation than in the case of premenopausal patients. The aim of this review was to summarize the clinical presentation of rare cases of endometriosis, including deep infiltrating (DIE) and extragenital endometriosis, in women. The symptoms of endometriosis in the post-reproductive age are more heterogeneous than in women of childbearing age, often resembling symptoms of gastrointestinal tumors or urinary tract diseases. We summarize cases of endometriosis of the intestines, liver, pancreas, and stomach, as well as endometriosis of the urinary tract and skin, with non-gynecological manifestations. We also describe the pathogenesis of endometrial tissue activity in the context of reduced estrogen levels after menopause, which is also not clear, and demands more molecular and genetic studies. NAD+-dependent deacetylases called Sirtuins are metabolic sensors for maintaining body homeostasis. In the context of endometriosis, Sirtuins are being studied for their potential role in modulating inflammation, cell proliferation, and sex hormone sensitivity, but their role in postmenopausal endometriosis is not well researched. Treatment in postmenopausal women includes mostly for now surgery, depending on the location of the lesion, and aromatase inhibitors. The complete genetic and epigenetic profile in women post-reproductive age is needed to propose target therapy, especially in severe cases such as endometriosis that is deeply infiltrating and located outside the pelvis.

Endo Belly: What Is It and Why Does It Happen?-A Narrative Review.

Endometriosis is a chronic inflammatory disease where endometrial-like lesions settle outside the uterus, resulting in extensive inflammatory reactions. It is a complex disease that presents with a range of symptoms, with pain and infertility being the most common. Along with severe dysmenorrhea, cyclic and acyclic lower abdominal pain, cyclic dysuria and dyschezia, dyspareunia, and infertility, there are also nonspecific complaints that can cause confusion and make endometriosis the chameleon among gynecological diseases. These symptoms include unspecific intestinal complaints, cyclic diarrhea, but also constipation, nausea, vomiting, and stomach complaints. It appears that in addition to general bowel symptoms, there are also specific symptoms related to endometriosis such as cyclic bloating of the abdomen, known as endo belly. During the second half of the menstrual cycle leading up to menstruation, the abdomen becomes increasingly bloated causing discomfort and pain due to elevated sensitivity of the intestinal wall. Patients with endometriosis exhibit a reduced stretch pain threshold of the intestinal wall. Here, we review the endo belly, for the first time, pathophysiology and the influence of other diseases (such as irritable bowel syndrome-IBS), microbiome, hormonal levels, inflammation, and diet on the presentation of this condition.

ARID1a Gene as a Potential Early Marker to Tackle Endometriosis-Associated Ovarian Cancer.

The worries of women with endometriosis - a chronic gynecological disease affecting approximately 10% of women of childbearing age - about the increased risk of ovarian cancer are present worldwide. Endometriosis is a common, often painful, but benign gynecological disease that affects women. However, the pathogenesis remains elusive but is certainly multifactorial. Interestingly, endometriosis shares similarities with cancer. Therefore, women suffering from endometriosis fear an increased risk of ovarian cancer. In addition, these patients suffer from anxiety and depression. Previous studies have provided evidence that epithelial mutations in endometriosis or in the endometrium include certain inactivating mutations responsible for ovarian cancer, such as in the ARID1A gene.

Pelvic floor hypertension: possible factors for pelvic floor tenderness in endometriosis patients-a pilot study.

PURPOSE: Chronic pelvic pain (CPP) is one of the main problems of endometriosis, leading to a significant impairment of quality of life. Understanding the pain mechanisms and the pelvic floor muscles (PFM) changes in these patients is essential to integrate additional therapeutic strategies. We hypothesize that endometriosis patients have changes in PFM and that targeted vaginal electrostimulation can be a treatment option for CPP in this disease. METHODS: Fifteen patients with endometriosis and chronic acyclical pelvic pain were included. PFM electromyography with the Multiple Array Probe Leiden (MAPLe) was performed. Mapping of PFM was utilized and targeted electrostimulation of the hypertensive muscles was conducted. Control electromyography was performed afterward to evaluate the electrostimulation therapeutic effect. RESULTS: In 12/15 (80%) patients, the myofascial trigger point could be localized by digital examination. The most frequently affected muscle was the puborectalis (10/15-66.7%). Most of the patients showed serious changes in the average resting tone (aRT) of PFM. aRT was significantly increased in all patients and decreased after stimulation, whereby the difference prior to and after stimulation was not significant (p = 0.064). The detailed separated analysis of the hypertensive muscles showed a significant (p = 0.026) reduction in their resting tone (hRT), after targeted stimulation. CONCLUSION: Vaginal electrostimulation is a promising and feasible complementary treatment option for CPP in endometriosis patients. Targeted treatment of pelvic floor dysfunction should be included in clinical trials.

[Holistic treatment of endometriosis]. / Ganzheitliche Behandlung der Endometriose.

BACKGROUND: The pain phenomena caused by endometriosis are manifold. In addition to nociceptive pain there is also a nociplastic reaction with central sensitization. Atypical symptoms, such as acyclic lower abdominal pain, radiating pain, nonspecific bladder and intestinal complaints or even depression increasingly occur in addition to the classical cyclic complaints, such as severe dysmenorrhea, cyclic lower abdominal pain, dyspareunia, dysuria and dyschezia. Due to the diffuse range of symptoms, affected patients often consult not just gynecologists but also specialists from other disciplines (internal medicine, gastroenterology, orthopedics, pain therapy, psychology etc.). OBJECTIVE: The complexity of endometriosis is presented. The resulting approaches to multimodal interdisciplinary holistic treatment are described. RESULTS: Interdisciplinary concepts should be involved in the optimal treatment of endometriosis patients along with hormonal and surgical treatment, mostly under the supervision of a gynecologist and pain management, dietary changes, psychological support and physiotherapeutic management should also be included. This article provides an overview of possible treatment strategies for chronic symptomatic endometriosis. CONCLUSION: Based on multimodal treatment strategies and regarding the complex pathophysiological alterations of this disease, the complex complaints that significantly impair the quality of life of endometriosis patients can be greatly improved.

Mechanisms of peripheral sensitization in endometriosis patients with peritoneal lesions and acyclical pain.

PURPOSE: Endometriosis (EM) is one of the most frequent differential diagnoses concerning chronic pelvic pain. Women under hormonal therapy (HT) often benefit from it but sometimes suffer a setback and develop acyclical pelvic pain. Due to the assumption that mechanisms of neurogenic inflammation are involved in the generation of chronic pelvic pain, we aimed to investigate the expression of sensory nerve markers in EM-associated nerve fibers of patients with/without HT. METHODS: Laparoscopically excised peritoneal samples from 45 EM and 10 control women were immunohistochemically stained for: PGP9.5, Substance P (SP), NK1R, NGFp75, TRPV-1, and TrkA. Demographics and severity of pain were documented. RESULTS: EM patients showed a higher nerve fiber density (PGP9.5 and SP) and increased expression of NGFp75, TRPV1, TrkA, and NK1R in blood vessels and immune cells compared with controls. Patients with HT have cycle-dependent pelvic pain but suffer from acyclical pelvic pain. Interestingly, reducing NK1R expression in blood vessels under HT was observed. A correlation between dyspareunia severity and nerve fibers density and between NGFRp75 expression in blood vessels and cycle-dependent pelvic pain severity was observed. CONCLUSION: Patients under HT have no ovulation and no (menstrual) bleeding, which correlate with inflammation and cyclical pain. However, acyclical pain seems to be due to peripheral sensitization once it is present under treatment. Neurotransmitters, like SP and their receptors, are involved in mechanisms of neurogenic inflammation, which are relevant for pain initiation. These findings indicate that in both groups (EM with/without HT), neurogenic inflammation is present and responsible for acyclical pain.

Nociceptin/Orphanin FQ Opioid Peptide-Receptor Expression in the Endometriosis-Associated Nerve Fibers-Possible Treatment Option?

Endometriosis (EM) is a chronic inflammatory disease affecting millions of women worldwide. Chronic pelvic pain is one of the main problems of this condition, leading to quality-of-life impairment. Currently, available treatment options are not able to treat these women accurately. A better understanding of the pain mechanisms would be beneficial to integrate additional therapeutic management strategies, especially specific analgesic options. To understand pain in more detail, nociceptin/orphanin FQ peptide (NOP) receptor expression was analyzed in EM-associated nerve fibers (NFs) for the first time. Laparoscopically excised peritoneal samples from 94 symptomatic women (73 with EM and 21 controls) were immunohistochemically stained for NOP, protein gene product 9.5 (PGP9.5), substance P (SP), calcitonin gene-related peptide (CGRP), tyrosine hydroxylase (TH), and vasoactive intestinal peptide (VIP). Peritoneal NFs of EM patients and healthy controls were positive for NOP and often colocalized with SP-, CGRP-, TH-, and VIP-positive nerve fibers, suggesting that NOP is expressed in sensory and autonomic nerve fibers. In addition, NOP expression was increased in EM associate NF. Our findings highlight the potential of NOP agonists, particularly in chronic EM-associated pain syndromes and deserve further study, as the efficacy of NOP-selective agonists in clinical trials.

Sox-2 positive cells identified in lymph nodes from endometriosis patients may play a role in the disease pathogenesis.

OBJECTIVE: This study aimed to characterize Sox-2 in sentinel lymph nodes and randomly obtained lymph nodes from endometriosis (EM) patients for the first time. STUDY DESIGN: This prospective study analyzed tissue samples from surgical specimens collected from May until December 2007 in the Endometriosis Center Charité, Berlin. Lymph node samples from 38 women aged between 22 and 49 years who underwent laparoscopy due to symptomatic EM were analyzed. The material was obtained either randomly or, in the case of deep infiltrating endometriosis, detected using 4 cc Patent Blue®, labeled intraoperatively, which made the sentinel lymph nodes available for histological examination. Together with hematoxylin and eosin staining, the sections were evaluated by immunohistochemistry with antibodies against estrogen and progesterone receptors and Sox-2. Using double-immunofluorescence microscopy, the colocalization of Sox-2 and estrogen receptors were evaluated. RESULTS: Sox-2-positive cells were identified in the lymph nodes' cortical and medullary zones, with a higher expression in the medullary layer. Occasionally, Sox-2 positive stained cell groups, called cell nests, could also be detected. The number of Sox-2 positive cells in the sentinel lymph nodes was almost three times higher than in the random lymph nodes (p = 0.031). A significant five-fold increase (p = 0.0013) in Sox-2 expression was seen in the estrogen and progesterone receptor (ER/PR) positive patient group compared to the progesterone receptor positive group or hormone receptor negative patients. Identical hormone-related Sox-2 expression was also detected separately for the sentinel lymph node group (p = 0.0174). Sox-2 showed pronounced colocalisation with estrogen receptors. CONCLUSION: The lymphatic involvement in EM is evidence of a systemic disease manifestation and provides evidence of an immune system failure. In recent years, many theories have been studied, but there is no single theory that could explain all aspects of EM. The future concept of EM is likely to incorporate the elements from all the pathogenetic theories already described. Through this study, stem cells and lymphatic metastasis theories were incorporated.

Transcranial direct current stimulation to reduce chronic pelvic pain in endometriosis: phase II randomized controlled clinical trial.

BACKGROUND: It is known that various chronic pain conditions lead to maladaptive changes in the central nervous system. Endometriosis is frequently associated with chronic pelvic pain (CPP). Its sufficient treatment remains a clinical challenge. Transcranial direct current stimulation (tDCS) has been shown to be a powerful method to reduce chronic pain. Therefore, this study aimed to investigate pain reduction via anodal tDCS in patients with endometriosis and CPP. METHODS: This clinical phase II, placebo-controlled, randomized, parallel-design study included 36 patients with endometriosis and CPP. All patients had CPP, defined as a score of ≥3/10 on the visual analog scale for ≥3 months in the prior 6 months. Anodal or placebo tDCS (18 patients per arm) was applied over the primary motor cortex for 10 days. The primary outcome measure was the pressure pain threshold (objective pain measure), and secondary outcomes were the numerical rating scale score (subjective pain measure), Von Frey monofilaments, and disease- and pain-related questionnaires. Data were collected at baseline, after the 10-day stimulation, and at a follow-up session, which took place 1 week after the tDCS had ended. Statistical analyses were performed with analyses of variance and t tests. RESULTS: Significant decreased pain perception in both pain measurements (pressure pain threshold and numerical rating scale score) was found for the active tDCS group compared with the placebo group. This proof-of-concept study shows that tDCS is a helpful supporting pain therapy for patients with endometriosis and CPP. Moreover, further analyses revealed that 1 week after the stimulation had ended, pain reduction as indexed by pressure pain threshold remained significantly decreased, which indicates possible long-term analgesic effects. CONCLUSION: The present study provides evidence that tDCS is an effective therapy for pain reduction in endometriosis-associated CPP. The results support the notion that CPP is developed and maintained in the central nervous system, making a multimodal pain therapy necessary. TRIAL REGISTRATION: www.ClinicalTrials.gov ID: NCT05231239.

Endometriosis and Opioid Receptors: Are Opioids a Possible/Promising Treatment for Endometriosis?

Endometriosis (EM), defined as the presence of endometrial-like tissue with surrounding smooth muscle cells outside the uterus, is a disregarded gynecological disease reported to affect 6-10% of women of reproductive age, with 30-50% of them suffering from chronic pelvic pain and infertility. Since the exact pathogenic mechanisms of EM are still unclear, no curative therapy is available. As pain is an important factor in EM, optimal analgesia should be sought, which to date has been treated primarily with non-steroidal anti-inflammatory drugs (NSAIDs), metamizole or, in extreme cases, opioids. Here, we review the pain therapy options, the mechanisms of pain development in EM, the endogenous opioid system and pain, as well as the opioid receptors and EM-associated pain. We also explore the drug abuse and addiction to opioids and the possible use of NOP receptors in terms of analgesia and improved tolerability as a target for EM-associated pain treatment. Emerging evidence has shown a promising functional profile of bifunctional NOP/MOP partial agonists as safe and nonaddictive analgesics. However, until now, the role of NOP receptors in EM has not been investigated. This review offers a thought which still needs further investigation but may provide potential options for relieving EM-associated pain.

Chronic Pelvic Pain in Endometriosis: Cross-Sectional Associations with Mental Disorders, Sexual Dysfunctions and Childhood Maltreatment.

The aim of this cross-sectional study was to compare the rates of mental disorders, sexual dysfunctions and childhood maltreatment (CM) in women with endometriosis with either chronic pelvic pain (CPP) or minimal to no pelvic pain. Additionally, two models to predict a current mental disorder were tested, including pelvic-pain-related or psychosocial predictor variables. We examined 100 women with confirmed endometriosis (group CPP, n = 50; group NOPAIN, n = 50). Participants responded to a comprehensive questionnaire and the Childhood Trauma Questionnaire. The Diagnostic Interview for Mental Disorders was used to assess mental disorders according to DSM-5 and to screen for sexual dysfunctions. The mean age was 28.8 ± 5.6 (CPP)/2.7 ± 6.3 (NOPAIN). Participants with CPP had higher rates of current mental disorders (p = 0.019), lifetime mental disorders (p = 0.006) and sexual dysfunctions (p < 0.001), but not CM (p = 0.074). In two binary-logistic regression analyses, a greater need for pain relief (aOR = 4.08, p = 0.026) and a sexual dysfunction (aOR = 2.69, p = 0.031) were significant predictors for a current mental disorder. Our findings confirmed the crucial role of pelvic pain for mental and sexual well-being in endometriosis. They highlight the need for pain relief and interdisciplinary care in the treatment of endometriosis.

Endometriosis, an Ongoing Pain-Step-by-Step Treatment.

Endometriosis is a disease that is becoming more and more challenging for the medical community. The current therapeutic concepts (surgical therapy and/or hormonal therapies) often do not lead to sufficient pain control, and late diagnosis and high recurrence rates mean that women affected by the disease can suffer for decades before receiving proper treatment. Although the introduction of certified endometriosis centers has created contact points for surgical therapies performed by endometriosis experts, these centers are not sufficient to offer the affected patients the all-encompassing long-term support they need. In recent years, new findings regarding the pathogenesis and correlations of the pain phenomena caused by endometriosis have shown that conventional therapy strategies are not adequate and individual long-term concepts must be developed. Not only can endometriosis cause nociceptive pain, but it can also lead to a nociplastic reaction with central sensitization. Hence, aside from the classic cyclic complaints, patients increasingly suffer from atypical pain. Due to the high number of affected patients who are treated inadequately, it is necessary for gynecologists in private practices to become familiar with multimodal treatment concepts since they are the central point of contact of their patients. The following article will provide an overview of treatment strategies for chronic symptomatic endometriosis.

Neurogenic Inflammation in the Context of Endometriosis-What Do We Know?

Endometriosis (EM) is an estrogen-dependent disease characterized by the presence of epithelial, stromal, and smooth muscle cells outside the uterine cavity. It is a chronic and debilitating condition affecting ~10% of women. EM is characterized by infertility and pain, such as dysmenorrhea, chronic pelvic pain, dyspareunia, dysuria, and dyschezia. Although EM was first described in 1860, its aetiology and pathogenesis remain uncertain. Recent evidence demonstrates that the peripheral nervous system plays an important role in the pathophysiology of this disease. Sensory nerves, which surround and innervate endometriotic lesions, not only drive the chronic and debilitating pain associated with EM but also contribute to a growth phenotype by secreting neurotrophic factors and interacting with surrounding immune cells. Here we review the role that peripheral nerves play in driving and maintaining endometriotic lesions. A better understanding of the role of this system, as well as its interactions with immune cells, will unearth novel disease-relevant pathways and targets, providing new therapeutics and better-tailored treatment options.

Pathogenesis of Endometriosis: The Origin of Pain and Subfertility.

Endometriosis (EM) and adenomyosis (AM) are common conditions with pain and infertility as the principal symptoms. The pathophysiology of pain in EM and AM comprises sensory and somatoform pain mechanisms. Over time, these may aggravate and lead to individual complex disease patterns if not diagnosed and treated. Despite the known facts, several years often pass between the onset of symptoms and diagnosis. Chronic pain disorders with changes on a neuronal level frequently arise and are linked to depressive disorders, with the process becoming a vicious cycle. Additionally, women with EM and AM suffer from sub- and infertility. Low fecundity rates are caused by anatomical changes in combination with behavioral changes in the sexual activity of women with chronic pain as well as local proinflammatory factors that not only decrease implantation rates but also promote early abortions.

Functional changes of immune cells: signal of immune tolerance of the ectopic lesions in endometriosis?

RESEARCH QUESTION: What is the potential role of immune cells and their inflammatory cytokines in the pathogenesis, development and establishment of endometriosis? DESIGN: Peritoneal fluid from 59 women (43 with endometriosis and 16 controls) who had undergone laparoscopic surgery was analysed. Changes in the population of innate and adaptive immune cells, cytokines, chemokines and growth factor expression were measured by flow cytometry, Luminex Technology and enzyme-linked immunosorbent assay. RESULTS: No differences were found in the frequencies of the innate and adaptive immune cells between women with and without endometriosis. In the peritoneal fluid of women with endometriosis, IL-1ß, IL-1RN, IL-2, IL-4, IL-8, IL-10, IL-12 (p70), IL-17α, FGF2, G-CSF, MCP-1, MIP-1α and TNF-α were significantly increased compared with controls. A correlation between IL-2, MCP-1, MIP-1α, TNF-α and the severity of endometriosis was observed. The concentration of neopterin, a possible biomarker for this disease, was increased in women with endometriosis compared with controls. CONCLUSIONS: The functional activity of immune cells seemed to be reduced despite their numbers remaining unchanged. The data indicate that a shift of TH cytokine profile occurs, which increases the TH1-TH2 ratio. This is driven by the increased levels of the cytokines (TNF-α and IL-2) in women with severe endometriosis.