Cross-sectional study for derivation of a cut-off value for identification of an early versus delayed diagnosis of endometriosis based on analytical and descriptive research methods.

BACKGROUND: Endometriosis is a benign, hormone-dependent, chronic inflammatory gynecological disease accompanied by cyclic and acyclic pelvic pain and other complaints. The long lists of research recommendations in the AWMF guideline (Burghaus et al., Geburtshilfe Frauenheilkd 81:422-46, 2021) and ESHRE Endometriosis Guideline (ESHRE Endometriosis Guideline Development Group, Endometriosis: Guideline of European Society of Human Reproduction and Embryology, 2022) show that there is still a great need for research in all aspects of the disease. Diagnostic delay, defined as the mean time between symptom onset and confirmed diagnosis, is a particular problem associated with endometriosis. Some quantitative and qualitative studies have investigated possible reasons for this. A range of physician-related (Dixon et al., Br J Gen Pract 71:e668-e676, 2021; van der Zanden and Nap, Reprod Biomed Online 32:527-31, 2016) and patient-related factors (Sayer-Jones and Sherman, Health Psychol Behav Med 9:456-79, 2021) as well as stigmatization of the topic of menstruation by society have been identified (Kruckenberg, Frauenarzt 59:2-5, 2018; Seear, Soc Sci Med 69:1220-7, 2009). The consequences of the disease being diagnosed late (or too late) on the course of disease, the quality of life and the costs of the disease have already been documented in studies (Sims Int J Environ Res Public Health 18(15):8210, 2021; Surrey Adv Ther 37:1087-99, 2020). However, a systematically derived cut-off value that clearly distinguishes between short and long delay is still lacking. Therefore, the aim of our study was to derive a threshold value for the definition of a target corridor for endometriosis diagnosis based on descriptive and analytical methods. METHODS: Since our review of the rather sparse publications on diagnostic delay did not yield satisfactory results, we used descriptive statistics and location parameters to calculate a cut-off value for German population data from the EndoCost study. Statistical methods were used for correlation analysis of shortDD versus longDD (correlation analysis and logistic regression) and group membership (discriminant analysis). RESULTS: Five years was identified as the cut-off value that significantly differentiated between shortDD and longDD based on various disease-related variables. This suggests that endometriosis should be definitively diagnosed within less than five years to minimize the risk of an unfavorable course of the disease. CONCLUSION: Our findings confirmed that an early onset of endometriosis-related symptoms is the most important risk factor for a long diagnostic delay. Consequently, adolescent females should receive increased attention as an especially vulnerable group. Evidently, there is an urgent need to develop adequate concepts to improve the endometriosis education and care among this target group.

The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres.

BACKGROUND: This study aimed to calculate costs and health-related quality of life of women with endometriosis-associated symptoms treated in referral centres. METHODS: A prospective, multi-centre, questionnaire-based survey measured costs and quality of life in ambulatory care and in 12 tertiary care centres in 10 countries. The study enrolled women with a diagnosis of endometriosis and with at least one centre-specific contact related to endometriosis-associated symptoms in 2008. The main outcome measures were health care costs, costs of productivity loss, total costs and quality-adjusted life years. Predictors of costs were identified using regression analysis. RESULTS: Data analysis of 909 women demonstrated that the average annual total cost per woman was €9579 (95% confidence interval €8559-€10 599). Costs of productivity loss of €6298 per woman were double the health care costs of €3113 per woman. Health care costs were mainly due to surgery (29%), monitoring tests (19%) and hospitalization (18%) and physician visits (16%). Endometriosis-associated symptoms generated 0.809 quality-adjusted life years per woman. Decreased quality of life was the most important predictor of direct health care and total costs. Costs were greater with increasing severity of endometriosis, presence of pelvic pain, presence of infertility and a higher number of years since diagnosis. CONCLUSIONS: Our study invited women to report resource use based on endometriosis-associated symptoms only, rather than drawing on a control population of women without endometriosis. Our study showed that the economic burden associated with endometriosis treated in referral centres is high and is similar to other chronic diseases (diabetes, Crohn's disease, rheumatoid arthritis). It arises predominantly from productivity loss, and is predicted by decreased quality of life.

Role of TGF-betas in normal human endometrium and endometriosis.

Endometriosis is characterized by presence of endometrial tissue outside the uterus. Prevalence is estimated at 6-10% in the general female population and many patients experience pain and/or infertility. Diagnosis is achieved by laparoscopic intervention followed by histological confirmation of viable endometriotic tissue. Mild cases are managed medically with contraceptive steroids and non-steroidal anti-inflammatory agents. Surgery provides relief to women in pain but symptoms recur in 75% of cases within 2 years. Starting with menstruation, we have categorized endometriosis into six stages, namely (1) shedding of cells, (2) cell survival, (3) escape from immune surveillance, (4) adhesion to peritoneum, (5) angiogenesis and (6) bleeding. In most of these biological processes, which resemble metastasis, transforming growth factor-beta (TGF-betas) and their high-affinity receptors are involved directly or indirectly. TGF-betas are abundantly and differentially expressed in the endometrium under hormonal control. Although they are preferentially synthesized in the stroma, glands and macrophages also secrete TGF-betas into the uterine fluid, where interaction with preimplantation embryos is suspected. Because mRNA and protein expression of all three TGF-betas is increased around menstruation, we suggest that TGF-betas might be involved in initiation of menstruation. Furthermore, because of high postmenstrual TGF-beta3 levels, we suppose that it might participate in scarless postmenstrual regeneration of endometrium. Our suggestions pave the way to novel routes of investigation into the roles of TGF-betas during menstruation and endometriosis.

Endometriosis and inflammation in infertility.

A wealth of publications proposes that endometriosis and inflammation may have an unfavorable influence on fertility. A recent meta-analysis of assisted reproductive technologies demonstrated that, once confounding factors are controlled for, the pregnancy rate in women with endometriosis is approximately 50% of the rate of women with tubal factor infertility. Peritoneal fluid of women with endometriosis contains elevated amounts of macrophages and their secreted products, such as growth factors, cytokines, and angiogenic factors. Because reproductive organs are bathed in and thus will be influenced by peritoneal fluid, these proinflammatory mediators would affect various aspects of reproduction in women with endometriosis. Advanced stages of endometriosis may have easily understandable factors, such as distortion of the anatomy, causing infertility. On the other hand, in minimal or mild endometriosis mechanisms underlying reproductive failure are subtle and remain controversial. Recent reports suggest that inflammatory factors play a role in this endometriosis-associated reproductive failure. This review provides an overview of recent data on the effects of endometriosis-associated inflammation on fertility.

The diagnosis and treatment of deep infiltrating endometriosis.

BACKGROUND: Endometriosis and adenomyosis uteri are the most common benign disorders affecting girls and women after uterine myomas (fibroids), with a prevalence of roughly 5% to 15%. There have been many advances in diagnostic assessment and in our understanding of the disease over the past decade. Steady improvements in treatment have been accompanied by heightened consciousness of the diagnosis among the affected women and the doctors who care for them. METHODS: A selective literature search was carried out in the Cochrane and PubMed databases using the key words "endometriosis," "deep infiltrating endometriosis," "endometriosis AND diagnostics," "endometriosis AND surgical therapy," "endometriosis AND endocrine treatment," and others. The AWMF and ESHRE guidelines were also taken in account. RESULTS AND CONCLUSION: The main manifestations are primary or secondary dysmenorrhea, bleeding disturbances, infertility, dysuria, pain on defecation (dyschezia), cycle-dependent or (later) cycle-independent pelvic pain, nonspecific cycle-associated gastrointestinal or urogenital symptoms. Cycle-associated problems of urination and/or defecation that are due to endometriosis are most common in young, premenopausal women. Whenever such manifestations are present, endometriosis should be considered in the differential diagnosis, and evidence for it should be sought in the clinical history, physical examination, and ultrasound findings. If endometriosis is histologically confirmed and is of the deeply infiltrating kind, the recommended management today is to refer the patient to an endometriosis center.

DNA-binding ability of NF-kappaB is affected differently by ERalpha and ERbeta and its activation results in inhibition of estrogen responsiveness.

Estrogenic effects involve interactions between estrogen receptors (ERs), response elements, and nuclear proteins. It is hypothesized that interaction between ER and NF-kappa B may affect the regulation of responsive genes. Electrophoretic mobility shift assay (EMSA) was performed to assess if the interaction of ERs and NF- kappaB affect their respective DNA-binding activities, and alkaline phosphatase assay was done to evaluate estrogenic activity. EMSA revealed that ERs inhibit DNA-binding of p50 and p65, whereas p50 did not impair ER alpha binding. Stimulation with estradiol inhibited DNA binding of NF-kappaB in ERalpha-transfected endometrial stromal cells (ESCs). Moreover, activation of NF-kappaB significantly decreased estrogen responsiveness of Ishikawa cells and ERalpha-transfected ESC. Our results suggest that ERs downregulate NF-kappaB-dependent gene activation by directly preventing DNA binding. However, NF-kappaB-mediated inhibition of ER-dependent gene activation may be carried out indirectly rather than through a direct inhibition of ER-DNA binding. These findings offer new insight into the specific role of ERalpha and could eventually help in developing therapeutics for endometriosis.

Combination of CCR1 mRNA, MCP1, and CA125 measurements in peripheral blood as a diagnostic test for endometriosis.

This study investigated the possible use of CCR1 mRNA measurement in peripheral blood leukocytes in combination with measurements of monocyte chemotactic protein-1 (MCP-1) and CA125 protein in serum as a diagnostic test for endometriosis.The expression of CCR1 mRNA in peripheral blood leukocytes was measured by quantitative real-time polymerase chain reaction. MCP-1 and CA125 levels in serum were determined by ELISA and ECLIA.The ratio of CCR1/HPRT mRNA in peripheral blood of patients with endometriosis and adenomyosis was significantly elevated compared with women without endometriosis. Additionally, serum levels of MCP-1 and CA125 were significantly higher in patients with endometriosis. This method showed a sensitivity of 92.2%, a specificity of 81.6%, a negative predictive value of 83.3%, a positive predictive value of 92.3%, a likelihood ratio of a positive test result of 5.017, and a likelihood ratio of a negative test result of 0.096 to predict the presence or absence of endometriosis.The results imply the potential use of CCR1 mRNA, MCP-1, and CA125 protein measurements for the diagnosis or exclusion of endometriosis.