The physical, psychological, and social day-to-day experience of women living with endometriosis compared to healthy age-matched controls — a mixed-methods study

Background: Endometriosis is characterized by lesions of endometrial tissue outside the uterus. Chronic pain is considered as main symptom, but challenges can relate to various physical, mental, and social aspects of the women's lives. The aim of our study was to gain a holistic understanding of the everyday reality of women with endometriosis compared to healthy controls. Methods: The total sample comprised 12 hormone-free endometriosis patients (EP) and 11 age-matched healthy women (HC). A mixed-methods design was used comprising semi-structured interviews, standardized questionnaires and a comprehensive diary to assess pain ratings and various mental and physical symptoms over the course of a menstrual cycle. Interviews were recorded, transcribed, and evaluated according to phenomenological analysis using the MAXQDA software. Results: Interviews showed that living with endometriosis was associated with an impairment in everyday life. Physical strains, especially pain, high levels of psychological distress, and social limitations have been reported. Living with endometriosis affected the patients' personality and they “no longer felt like themselves.” Physical and psychological symptoms were reported to interfere with social interaction and participation. Evaluation of the standardized questionnaires revealed significant impairments in EP compared to HC in regard to anxiety and depression scores (both p < 0.001; Hospital Anxiety and Depression Scale), mental and physical quality of life (both p < 0.001; Short-Form Health Survey-12), stress ratings (p < 0.001; Patient Health Questionnaire-15) and functional well-being (p < 0.001; Functional Well-being-7). The highest levels of mean pelvic pain and dyschezia were observed in EP during menstruation, but mean pain ratings and dyschezia were increased in EPs compared to HP during the whole cycle. EP reported mental symptoms (e.g., depressed mood or anxiety) mainly during menstruation, while HC did not show any mental symptoms during the cycle. In addition, physical symptoms were elevated during the entire cycle in EPs (all p < 0.01). Discussion: The mixed-methods approach enabled to interpret the interviews, the standardized questionnaires, and the symptom diary in a broader context of everyday life. The symptoms do not appear to act independently, but rather influence each other. This leads to a complex interplay of physical, mental, and social impairments, with pain often being the starting point

Control of human endometrial stromal cell motility by PDGF-BB, HB-EGF and trophoblast-secreted factors

Human implantation involves extensive tissue remodeling at the fetal-maternal interface. It is becoming increasingly evident that not only trophoblast, but also decidualizing endometrial stromal cells are inherently motile and invasive, and likely contribute to the highly dynamic processes at the implantation site. The present study was undertaken to further characterize the mechanisms involved in the regulation of endometrial stromal cell motility and to identify trophoblast-derived factors that modulate migration. Among local growth factors known to be present at the time of implantation, heparin-binding epidermal growth factor-like growth factor (HB-EGF) triggered chemotaxis (directed locomotion), whereas platelet-derived growth factor (PDGF)-BB elicited both chemotaxis and chemokinesis (non-directed locomotion) of endometrial stromal cells. Supernatants of the trophoblast cell line AC-1M88 and of first trimester villous explant cultures stimulated chemotaxis but not chemokinesis. Proteome profiling for cytokines and angiogenesis factors revealed neither PDGF-BB nor HB-EGF in conditioned media from trophoblast cells or villous explants, while placental growth factor, vascular endothelial growth factor and PDGF-AA were identified as prominent secretory products. Among these, only PDGF-AA triggered endometrial stromal cell chemotaxis. Neutralization of PDGF-AA in trophoblast conditioned media, however, did not diminish chemoattractant activity, suggesting the presence of additional trophoblast-derived chemotactic factors. Pathway inhibitor studies revealed ERK1/2, PI3 kinase/Akt and p38 signaling as relevant for chemotactic motility, whereas chemokinesis depended primarily on PI3 kinase/Akt activation. Both chemotaxis and chemokinesis were stimulated upon inhibition of Rho-associated, coiled-coil containing protein kinase. The chemotactic response to trophoblast secretions was not blunted by inhibition of isolated signaling cascades, indicating activation of overlapping pathways in trophoblast-endometrial communication. In conclusion, trophoblast signals attract endometrial stromal cells, while PDGF-BB and HB-EGF, although not identified as trophoblast-derived, are local growth factors that may serve to fine-tune directed and non-directed migration at the implantation site

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers