Endometriosis as a Comorbid Condition in Chronic Fatigue Syndrome (CFS): Secondary Analysis of Data From a CFS Case-Control Study.

Background: Endometriosis (EM) is a recognized co-morbid condition in women with chronic fatigue syndrome (CFS). This analysis evaluates the impact of EM on the health of women with CFS by comparing selected health characteristics and laboratory parameters in women with CFS with and without EM (CFS+EM and CFS-only). Methods: This secondary analysis included all 36 women with CFS from a cross-sectional study of CFS in Wichita, KS, conducted between 2002 and 2003. The health characteristics and laboratory parameters of interest included functioning, fatigue, CFS-related symptoms, gynecologic history, routine laboratory parameters, inflammatory markers, cortisol levels, allostatic load, and sleep parameters (overnight polysomnography). We used parametric or non-parametric tests to compare group differences in the selected health characteristics and laboratory parameters. For examining the association between EM and variables of interest, logistic regression models were performed and odds ratios (OR) with 95% confidence intervals (CI) were reported for the magnitude of associations. Statistical significance was set at 0.05 (two-sided). Results: The mean age of this study sample was 50.9 years. Of women with CFS, 36.1% reported having EM. Age and body mass index (BMI) did not differ between CFS+EM and CFS-only groups. When examining the impact of EM, compared to women with CFS-only, women with both CFS and EM were more likely to report chronic pelvic pain [OR = 9.00 (95% CI, 1.47-55.25)] and hysterectomy [OR = 10.3 (1.82-58.39)], had more CFS symptoms (6.8 ± 0.3 vs. 5.5 ± 0.3, p = 0.02), younger mean age at menopause onset (36.4 ± 3.0 vs. 47.0 ± 2.7 years, p = 0.03), higher mean number of obstructive apnea episodes per hour (20.3 vs. 4.4, p = 0.05) and reported more negative life events (15.8 vs. 4.4, p = 0.05). Other parameters did not differ significantly between the two groups. Conclusions: We found more than a third of women with CFS reported endometriosis as a comorbid condition. The endometriosis comorbidity was associated with chronic pelvic pain, earlier menopause, hysterectomy, and more CFS-related symptoms. However, endometriosis in women with CFS did not appear to further impact functioning, fatigue, inflammatory markers, or other laboratory parameters. Further investigations including younger women are warranted.

Early life abuse and risk of endometriosis.

STUDY QUESTION: Is there an association between physical and sexual abuse occurring in childhood or adolescence and risk of laparoscopically-confirmed endometriosis? SUMMARY ANSWER: Early life sexual and physical abuse was associated with an increased risk of endometriosis. WHAT IS KNOWN ALREADY: Previous studies have reported that physical and sexual abuse are associated with chronic pelvic pain (CPP). However, only one study has examined the association between childhood physical abuse and laparoscopically-confirmed endometriosis, and did not observe an association with endometriosis risk. STUDY DESIGN, SIZE, DURATION: Prospective cohort study using data collected from 60 595 premenopausal women from 1989 to 2013 as part of the Nurses' Health Study II cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants completed an exposure to violence victimization questionnaire in 2001. Cases were restricted to laparoscopically-confirmed endometriosis. Cox proportional hazards models were used to calculate rate ratios (RR) and 95% confidence intervals (CI). MAIN RESULTS AND THE ROLE OF CHANCE: Three thousand three hundred and ninety-four cases of laparoscopically-confirmed endometriosis were diagnosed during 24 years of follow-up. Compared to those reporting no physical or sexual abuse, the risk of endometriosis was greater among those who experienced severe physical abuse (RR = 1.20; 95% CI = 1.06, 1.37) or severe sexual abuse (RR = 1.49; 95% CI = 1.24, 1.79). There was a 79% increased risk of laparoscopically-confirmed endometriosis for women reporting severe-chronic abuse of multiple types (95% CI = 1.44, 2.22). The associations between abuse and endometriosis were stronger among women presenting without infertility, a group that was more likely to have been symptomatic with respect to pain. LIMITATIONS, REASONS FOR CAUTION: The violence exposure was recalled by the study participants and thus is subject to misclassification as well as recall bias for the cases who were diagnosed prior to 2001. However, our results were similar in a sensitivity analysis including only endometriosis cases incident after their violence history report. In addition, residual or unmeasured confounding is a possibility; however, we were able to adjust for a variety of potential early life confounders. Finally, selection bias is also a possibility if those who chose to return the violence questionnaire did so based jointly on abuse history and endometriosis risk. WIDER IMPLICATIONS OF THE FINDINGS: Early life sexual and physical abuse was associated with an increased risk of endometriosis. Severity, chronicity and accumulation of types of abuse were associated with greater risk. Understanding the mechanisms underlying these relations may better define the biologic impacts of abuse and the related pathophysiology of endometriosis. STUDY FUNDING/COMPETING INTEREST(s): This work was supported by National Institute of Child Health and Human Development [Grant numbers HD48544, HD52473, HD57210 and CA50385] and the Atlanta Clinical and Translational Science Institute [Grant number ULRR025008]. The Nurses' Health Study II is supported by the National Institutes of Health grant UM1 CA176726 from the National Cancer Institute. H.R.H. is supported by the National Cancer Institute, National Institutes of Health [Grant number K22 CA193860]. Authors report no conflict of interest.

Cathepsin Protease Inhibition Reduces Endometriosis Lesion Establishment.

Endometriosis is a gynecologic disease characterized by the ectopic presence of endometrial tissue on organs within the peritoneal cavity, causing debilitating abdominal pain and infertility. Current treatments alleviate moderate pain symptoms associated with the disorder but exhibit limited ability to prevent new or recurring lesion establishment and growth. Retrograde menstruation has been implicated for introducing endometrial tissue into the peritoneal cavity, but molecular mechanisms underlying attachment and invasion are not fully understood. We hypothesize that cysteine cathepsins, a group of powerful extracellular matrix proteases, facilitate endometrial tissue invasion and endometriosis lesion establishment in the peritoneal wall and inhibiting this activity would decrease endometriosis lesion implantation. To test this, we used an immunocompetent endometriosis mouse model and found that endometriotic lesions exhibited a greater than 5-fold increase in active cathepsins compared to tissue from peritoneal wall or eutopic endometrium, with cathepsins L and K specifically implicated. Human endometriosis lesions also exhibited greater cathepsin activity than adjacent peritoneum tissue, supporting the mouse results. Finally, we tested the hypothesis that inhibiting cathepsin activity could block endometriosis lesion attachment and implantation in vivo. Intraperitoneal injection of the broad cysteine cathepsin inhibitor, E-64, significantly reduced the number of attached endometriosis lesions in our murine model compared to vehicle-treated controls demonstrating that cathepsin proteases contribute to endometriosis lesion establishment, and their inhibition may provide a novel, nonhormonal therapy for endometriosis.

Novel port placement and 5-mm instrumentation for robotic-assisted hysterectomy.

BACKGROUND AND OBJECTIVES: The value of robotic surgery for gynecologic procedures has been critically evaluated over the past few years. Its drawbacks have been noted as larger port size, location of port placement, limited instrumentation, and cost. In this study, we describe a novel technique for robotic-assisted laparoscopic hysterectomy (RALH) with 3 important improvements: (1) more aesthetic triangular laparoscopic port configuration, (2) use of 5-mm robotic cannulas and instruments, and (3) improved access around the robotic arms for the bedside assistant with the use of pediatric-length laparoscopic instruments. METHODS: We reviewed a series of 44 women who underwent a novel RALH technique and concomitant procedures for benign hysterectomy between January 2008 and September 2011. RESULTS: The novel RALH technique and concomitant procedures were completed in all of the cases without conversion to larger ports, laparotomy, or video-assisted laparoscopy. Mean age was 49.9 years (SD 8.8, range 33-70), mean body mass index was 26.1 (SD 5.1, range 18.9-40.3), mean uterine weight was 168.2 g (SD 212.7, range 60-1405), mean estimated blood loss was 69.7 mL (SD 146.9, range 20-1000), and median length of stay was <1 day (SD 0.6, range 0-2.5). There were no major and 3 minor peri- and postoperative complications, including 2 urinary tract infections and 1 case of intravenous site thrombophlebitis. Mean follow-up time was 40.0 months (SD 13.6, range 15-59). CONCLUSION: Use of the triangular gynecology laparoscopic port placement and 5-mm robotic instruments for RALH is safe and feasible and does not impede the surgeon's ability to perform the procedures or affect patient outcomes.

Office visceral slide test compared with two perioperative tests for predicting periumbilical adhesions.

OBJECTIVE: To determine whether the office visceral slide test is an effective screening test for predicting obliterating periumbilical adhesions compared with two ultrasound tests performed in the operating room. METHODS: Women undergoing benign laparoscopic gynecologic surgery between July 2012 and August 2013 were invited to participate. All participants had an office-based ultrasound test at their preoperative visit (the office visceral slide test), two operating room ultrasound tests (the preoperative examination with visceral slide and the periumbilical ultrasound-guided saline infusion test), and then their scheduled laparoscopic procedure. We measured the ability of the three screening tests to detect obliterating periumbilical adhesions. RESULTS: Eighty-two women completed the study; 12 women were excluded because they had no history of surgery and 70 women with a history of abdominal and pelvic surgery were analyzed in the study group. The study group (n=70) had a median of two (range, 1-6) previous abdominal surgeries. The median number of previous laparotomies was 0 (range, 0-5). The median number of previous laparoscopies was 1 (range, 0-6). At laparoscopy, 6 of 70 women (8.6%) had periumbilical adhesions diagnosed; 18 of 70 women (25.7%) had any adhesions located in the abdomen or pelvis. The office visceral slide test had a sensitivity of 83.3%, specificity of 100%, positive predictive value of 100%, negative predictive value of 98.5% and diagnostic accuracy of 98.6%. CONCLUSION: The office visceral slide test is a simple and reliable test for detecting obliterating periumbilical adhesions in the outpatient setting. LEVEL OF EVIDENCE: II.

Infiltration of tumor-associated macrophages is increased in the epithelial and stromal compartments of endometrial carcinomas.

Tumor-associated macrophages (TAMs) are derived from monocytes and recruited to the tumor microenvironment, where they play an important role in the progression of cancer. There is strong evidence for an inverse relationship between TAM density and clinical prognosis in solid tumors of the breast, prostate, ovary, and cervix. However, the role of TAMs in endometrial cancer is not well described. The objectives of this study were to determine whether macrophage distribution or density differed among normal endometrial tissue, hyperplasia, Type I, and II endometrial adenocarcinomas. In addition, we looked for a correlation among TAM density, known histopathologic prognostic indicators, and endometrial cancer progression. The pathologic specimens of women who underwent hysterectomy for benign disorders, endometrial hyperplasia, Type I, or Type II cancers were sectioned and stained with anti-CD68 antibody. The density of CD68 macrophages was quantified and stratified according to their epithelial or stromal location. Type I and II endometrial carcinomas had significantly higher macrophage density in both epithelial and stromal compartments than benign endometrium. In both benign and neoplastic specimens, the numbers of macrophages were significantly higher in the stroma compared with the epithelium. Although there were important trends in the density of TAMs with regard to several histopathologic prognostic indicators of endometrial cancer, none were statistically significant and the patients' cancer progression did not correlate significantly with the number of TAMs.

Analysis of follicular fluid retinoids in women undergoing in vitro fertilization: retinoic acid influences embryo quality and is reduced in women with endometriosis.

Retinol (ROL) and its biologically active metabolite, all-trans retinoic acid (ATRA), are essential for a number of reproductive processes. However, there is a paucity of information regarding their roles in ovarian folliculogenesis, oocyte maturation, and early embryogenesis. The objectives of this study were to quantify and compare peripheral plasma (PP) and follicular fluid (FF) retinoid levels, including ATRA in women undergoing in vitro fertilization (IVF) and to investigate the relationship between retinoid levels and embryo quality. Retinoid levels were evaluated in PP and FF from 79 women undergoing IVF at the time of oocyte retrieval and corresponding embryo quality assessed on a daily basis after retrieval for 3 days until uterine transfer. Analysis compared the retinoid levels with day 3 embryo grades and between endometriosis versus control patients. Results demonstrated distinctive levels of retinoid metabolites and isomers in FF versus PP. There was a significantly larger percentage of high-quality grade I embryos derived from the largest versus smallest follicles. An increase in follicle size also correlated with a >50% increase in FF ROL and ATRA concentrations. Independent of follicle size, FF yielding grade I versus nongrade I embryos showed higher mean levels of ATRA but not ROL. In a nested case-control analysis, control participants had 50% higher mean levels of ATRA in their FF and PP than women with endometriosis. These findings strongly support the proposition that ATRA plays a fundamental role in oocyte development and quality, and that reduced ATRA synthesis may contribute to decreased fecundity of participants with endometriosis.

A rare case of primary extranodal marginal zone B-cell lymphoma of the ovary, fallopian tube, and appendix in the setting of endometriosis.

Extranodal marginal zone B-cell lymphomas are uncommon. Most occur in the gastrointestinal tract. Marginal zone B-cell lymphomas of the female genital tract are rare, and few cases exist of marginal zone B-cell lymphomas of the uterus, cervix, and fallopian tubes. We report the first marginal zone B-cell lymphoma of the ovary, fallopian tube, and appendix arising in endometriosis.

Retinoic acid suppresses growth of lesions, inhibits peritoneal cytokine secretion, and promotes macrophage differentiation in an immunocompetent mouse model of endometriosis.

OBJECTIVE: To determine the effects of all-trans-retinoic acid (RA) on establishment and growth of endometrial lesions, peritoneal interleukin-6 (IL-6) and macrophage chemotactic factor-1 (MCP-1) concentrations, and CD38, CD11b, and F4/80 expression on peritoneal macrophages in an immunocompetent mouse model of endometriosis. DESIGN: Experimental transplantation study using mice. SETTING: Academic medical center. ANIMAL(S): C57BL/6 recipient mice and syngeneic green fluorescent protein transgenic (GFP+) mice. INTERVENTION(S): Recipient mice were inoculated with GFP+ minced uterine tissue to induce endometriosis and treated with RA (400 nmol/day) or vehicle for 17 days (3 days before to 14 days after tissue injection). MAIN OUTCOME MEASURE(S): Total number of GFP+ implants in recipient mice, number of implants showing visible blood vessels, total volume of established lesions per mouse, concentrations of IL-6 and MCP-1 in peritoneal fluid, and expression of CD11b, F4/80, and CD38 on peritoneal macrophages. RESULT(S): Retinoic acid treatment for 17 days reduced the number of implants versus controls and decreased the frequency of lesions with vessels. Peritoneal washings in RA-treated animals had lower concentrations of IL-6 and MCP-1 than controls 3 days after endometrial inoculation and lower levels of IL-6 on day 14 after inoculation. Concomitant with these effects on day 14, CD38, CD11b, and F4/80 were higher on macrophages from RA-treated mice versus controls. CONCLUSION(S): The development of endometriotic implants is inhibited by RA. This effect may be caused, at least in part, by reduced IL-6 and MCP-1 production and enhanced differentiation of peritoneal macrophages.

Gynecological history in chronic fatigue syndrome: a population-based case-control study.

BACKGROUND: Chronic fatigue syndrome (CFS) affects disproportionately more women than men, and the condition is more common at perimenopause. We examined gynecological history events as risk factors for CFS. METHODS: In a case-control study from a randomly selected population sample from Wichita, Kansas, 36 women with CFS and 48 nonfatigued controls, of similar age, race, and body mass index (BMI), answered a structured gynecological history questionnaire. RESULTS: CFS cases and controls had the same mean age (51 years) and age at menarche (12 years). Overall, a greater proportion of women with CFS than controls reported pelvic pain unrelated to menstruation (22.2% vs. 1.7%, p = 0.004), endometriosis (36.1% vs. 16.7, %, p = 0.046), and periods of amenorrhea (53.9 % vs. 46.2%, p = 0.06). Compared to controls, women in the CFS group had a higher mean number of pregnancies (2.8 vs 2.0, p = 0.05) and gynecological surgeries (1.8 vs. 1.1, p = 0.05). Similar proportions of the CFS (69.4%) and control (72.9%) groups were menopausal. Although menopausal women in the CFS and control groups had similar mean age (55.5 and 55.8, respectively), menopause occurred about 4.4 years earlier in the CFS group (41.7 years vs. 46.1 years, respectively, p = 0.11). Among menopausal women, 76% of the CFS group reported hysterectomy vs. 54.6% of controls (p = 0.09), and 56% of women with CFS reported oophorectomy vs. 34.3% of controls (p = 0.11). CONCLUSIONS: The higher prevalence of gynecological conditions and gynecological surgeries in women with CFS highlights the importance of evaluating gynecological health in these patients and the need for more research to clarify the chronologic and the pathophysiological relationships between these conditions and CFS.

Multiple anticancer activities of EF24, a novel curcumin analog, on human ovarian carcinoma cells.

Curcumin, a component of turmeric, has been reported to exhibit potential antitumor activities. This study assessed the effects of a novel synthetic curcumin analog, EF24, on proliferation, apoptosis, and vascular endothelial growth factor (VEGF) regulation in platinum-sensitive (IGROV1) and platinum-resistant (SK-OV-3) human ovarian cancer cells. EF24 time- and dose-dependently suppressed the growth of both cell lines and synergized with cisplatin to induce apoptosis. Although treatment with EF24 had no significant effect on VEGF messenger RNA (mRNA) expression,VEGF protein secretion into conditioned media was dose-dependently reduced with EF24 demonstrating ∼8-fold greater potency than curcumin (P < .05). EF24 significantly inhibited hydrogen peroxide (H(2)O(2))-induced VEGF expression, as did the phenolic antioxidant tert-butylhydroquinone (t-BHQ). EF24 upregulated cellular antioxidant responses as observed by the suppression of reactive oxygen species (ROS) generation and activation of antioxidant response element (ARE)-dependent gene transcription. Given its high potency, EF24 is an excellent lead candidate for further development as an adjuvant therapeutic agent in preclinical models of ovarian cancer.

Absence of microdeletions in the azoospermia-factor region of the Y-chromosome in Viennese men seeking assisted reproduction.

PURPOSE: The azoospermia-factor region of the Y-chromosome is essential for spermatogenesis in humans. In the literature, a wide range is given for the frequency of microdeletions in this region. The purpose of this study was to evaluate our own population of patients. METHODS: During a two-year period at Vienna Medical School, all male patients (n = 383) seeking assisted reproduction were screened for microdeletions. Thirty-three men had azoospermia and 154 severe oligozoospermia. Genomic DNA was prepared from peripheral lymphocytes and polymerase chain reaction analysis of the azoospermia-factor region was performed using the Promega kit. RESULTS: No case tested positive for azoospermia-factor microdeletions. In all cases amplification of 18 non-polymorphic sequence tagged sites was obtained. CONCLUSIONS: Y-chromosome microdeletions do not seem to be an important factor for male infertility in our patients. This suggests that screening should be restricted to men with azoospermia or severe oligozoospermia only.