Mol Med Rep. 2018 Mar 29. doi: 10.3892/mmr.2018.8823. [Epub ahead of print] Zearalenone regulates endometrial stromal…
Sex Reprod Healthc. 2016 Mar;7:65-9.
“A challenge” – healthcare professionals’ experiences when meeting women with symptoms that might indicate endometriosis.
The aim of the study was to identify and describe the experiences of healthcare professionals when meeting women with symptoms that might indicate endometriosis.
Semi-structured interviews were conducted with 10 gynecologists, six general practitioners and nine midwives working at one university hospital, one central hospital, one private gynecology clinic and five healthcare centers in south-east Sweden. The interviews were recorded and transcribed verbatim and analyzed using qualitative conventional content analysis.
Three clusters were identified: the corroborating encounter, the normal variation of menstruation cycles, and the suspicion of endometriosis. The healthcare professionals tried to make a corroborating encounter by acknowledging the woman, taking time to listen, and giving an explanation for the problems. Healthcare professionals had different ways to determine what was normal as regards menstrual pain, ovulation pain and dyspareunia. They also needed to have the competence to act and react when the symptoms indicated endometriosis.
Meeting women with symptoms that might indicate endometriosis is challenging and demands a certain level of competence from healthcare professionals. Sometimes the symptoms are camouflaged as “normal” menstruation pain, making it hard to satisfy the needs of this patient group.
J Minim Invasive Gynecol. 2016 May-Jun;23(4):643-6.
Recurrent Hemoperitoneum During Pregnancy in Large Deep EndometriosisInfiltrating the Parametrium.
We present the case of a young woman at 16 weeks’ gestation who presented to a peripheral hospital with severe recurrent hemoperitoneum related to severe deep endometriosis infiltrating the left parametrium. She underwent 2 surgical open procedures in emergency, followed by pregnancy loss. Deep endometriosis infiltrated the rectum, the vagina, and the left parametrium, leading to stenosis of the left ureter and advanced destruction of the left kidney. Ovarian reserve was low with an antimullerian hormone level at .6 ng/mL. To improve endometriosis-related symptoms and preserve fertility, a laparoscopic conservative rectal and ureteral management was proposed with an aim to relieve symptoms, avoid further destruction of the left kidney, preserve the right splanchnic nerves and inferior hypogastric plexus, and enhance spontaneous conception. We performed a combined vaginal-laparoscopic approach that consisted of vaginal infiltration resection, adhesiolysis, rectal shaving, ureterolysis, and restoration of the permeability of the fallopian tubes. Seven months after surgery the patient spontaneously conceived and is doing well.
Fertil Steril. 2016 May;105(5):1266-1273.
Estrogen receptor β regulates endometriotic cell survival through serum and glucocorticoid-regulated kinase activation.
To determine the expression and biological roles of serum and glucocorticoid-regulated kinase (SGK1) in tissues and cells from patients with endometriosis and from healthy control subjects.
University research setting.
Endometriotic tissues were obtained from women with ovarian endometriosis, and normal endometrial tissues were obtained from women undergoing hysterectomy for benign conditions.
MAIN OUTCOME MEASURE(S):
Expression levels of SGK1, the role of SGK1 in endometriosis pathology, and regulation of SGK1 by estrogen receptor (ER) β.
Transcript and protein levels of SGK1 were significantly higher in endometriotic tissues and cells compared with normal endometrium. SGK1 mRNA and protein levels were stimulated by E2, by the ERβ-selective agonist diarylpropionitrile, and by prostaglandin E2. SGK1 was transcriptionally regulated by ERβ based on small interfering RNA knockdown and chromatin immunoprecipitation of ERβ followed by quantitative polymerase chain reaction. SGK1 knockdown led to increased cleavage of poly(ADP-ribose) polymerase, and SGK1 activation was correlated with the phosphorylation of FOXO3a, a proapoptotic factor.
ERβ leads to SGK1 overexpression in endometriosis, which contributes to the survival of endometriotic lesions through inhibition of apoptosis.
Syst Biol Reprod Med. 2016;62(2):93-105.
Comparative systems genetics view of endometriosis and uterine leiomyoma: Two sides of the same coin?
Endometriosis (EM) and uterine leiomyoma (UL) are two most frequent benign tumors of monoclonal origin affecting about 30% of all women in their reproductive age. Modern molecular technologies have made a tremendous impact in understanding both disorders. Here is the first comparative analysis of molecular mechanisms underlying development of EM and UL as it looks from the platform of systems genetics. Similarities and differences of EM and UL at their incipient stages are enlightened with special emphasis on their gene networks, gene expression, and epigenetic regulation, of pathologic development. The analysis substantiates a new hypothesis postulating tumors as outgrowths of the stem cells with mesenchymal commitment lineage (mSC) which migrate from the endometrium/myometrium junctional zone of the uterus. Comparative analysis has revealed basic similarities of molecular pathogenesis of EM and UL suggesting molecular syntropy of both disorders. Peculiarities of the epigenetic landscape determining development of mSC may explain the existence of different clinical forms of EM and UL as well as their unique clinical manifestation. Some perspectives for practical and scientific application in EM and UL studies of this new hypothesis are outlined.
Cell Mol Biol (Noisy-le-grand). 2016 Jan 11;62(1):1-5.
Protective effect of Honokiol against endometriosis in Rats via attenuating Survivin and Bcl-2: A mechanistic study.
Nearly 10-15% of women in the reproductive age were affected by endometriosis and currently facing the unmet need of effective therapeutic interventions for its management. Concerning this, the present study was intended to investigate the effect of Honokiol (HK) for the treatment of endometrial hyperplasia. The rat endometrial model was established and subsequently administered with a numerous dose of HK. The histopathology of tissues was also investigated. Results showed that, HK effectively inhibit the proliferation of rat edometeriotic tissues in a dose dependent manner. In terminal deoxynucleotidyl transferase (TdT) -mediated dUTP biotin nick end labeling (TUNEL) method, HK was able to bring apoptosis in endometrotic cells. Moreover, it also inhibits the mRNA levels of Survivin gene and Bcl-2 (B-cell lymphoma 2) in qPCR and Western blot analysis together with increases the mRNA level of apoptosis promoting factor Bax. These results clearly suggest that, HK was proficient to provoke apoptosis of rat endometriotic cells.
Am J Obstet Gynecol. 2016 May;214(5):559-65.
Obesogens: an emerging threat to public health.
Endocrine disrupting chemicals (EDCs) are defined as exogenous chemicals, or mixtures of chemicals, that can interfere with any aspect of hormone action. The field of endocrine disruption is historically rooted in wildlife biology and reproductive endocrinology where EDCs are demonstrated contributors to infertility, premature puberty, endometriosis, and other disorders. Recently, EDCs have been implicated in metabolic syndrome and obesity. Adipose tissue is a true endocrine organ and, therefore, an organ that is highly susceptible to disturbance by EDCs. A subset of EDCs, called “obesogens,” promote adiposity by altering programming of fat cell development, increasing energy storage in fat tissue, and interfering with neuroendocrine control of appetite and satiety. Obesity adds more than $200 billion to US healthcare costs and the number of obese individuals continues to increase. Hence, there is an urgent, unmet need to understand the mechanisms underlying how exposures to certain EDCs may predispose our population to be obese. In this review, we discuss the history of obesogen discovery from its origins in reproductive biology to its latest role in the transgenerational inheritance of obesity in mice. We discuss the development of adipose tissue in an embryo, maintenance of adipocyte number in adults, how EDC disruption programs stem cells to preferentially make more adipocytes, the mechanisms by which chemicals can permanently alter the germline epigenome, and whether there are barriers to EDCs in the gametes.
Mol Hum Reprod. 2016 May;22(5):329-37
(Partial) Loss of BAF250a (ARID1A) in rectovaginal deep-infiltrating endometriosis, endometriomas and involved pelvic sentinel lymph nodes.
Loss of protein BAF250a (ARID1A) expression is present in women with rectovaginal deep-infiltrating endometriosis (DIE) and endometriosis affecting the pelvic sentinel lymph nodes (PSLN).
Partial loss of protein BAF250a was found in some of our patient samples, comprising all endometriosis entities, including rectovaginal DIE and endometriosis affecting the PSLN.
WHAT IS KNOWN ALREADY:
Loss of BAF250a (BRG-associated factor 250a)/ARIDIA (AT-rich interactive domain 1A) protein expression was identified among endometriosis-associated ovarian carcinomas and ovarian endometriosis, and this phenomenon was described as a possible early event in the transformation of endometriosis into cancer. DIE affecting the bowel/rectovaginal site is the most aggressive presentation of endometriosis and its ‘risk’ of malignant transformation has not been studied so far.
STUDY DESIGN, SAMPLES/MATERIALS, METHODS:
We evaluated the immunohistochemical expression of BAF250a protein in 70 samples from patients enrolled in this study who were surgically treated at a tertiary center, university Hospital. The samples submitted to investigation were from rectovaginal DIE (n= 25/30), endometriosisaffecting the PSLN (n= 5/7), ovarian endometriosis (n= 20/20) and endometrium from patients without endometriosis used as controls (n= 20/20).
MAIN RESULTS AND THE ROLE OF CHANCE:
Partial loss (i.e. in one tissue section some cells stained positive for BAF250a while other cells, usually an adjacent group, were negative) of BAF250a protein was identified in 36% (9/25) of rectovaginal DIE samples, 40% (2/5) of endometriosis lesions involving the PSLN, 30% (6/20) of endometriomas, and also in 25% (5/20) of endometrium from controls. We found no statistical correlation between occurrence of partial loss of BAF250a protein and the use or not of hormone medications (P = 0.106), cycle phase (P = 0.917) and stage of disease (P = 0.717).
LIMITATIONS, REASONS FOR CAUTION:
We only found partial loss of BAF250a protein expression, and in a small population of women, with relatively high frequency in all benign tissues assessed in the present analysis. Therefore, this finding alone should not be correlated directly with the risk of malignant transformation in these lesions.
WIDER IMPLICATIONS OF THE FINDINGS:
The occurrence of partial loss of BAF250a protein expression in women with rectovaginal DIE and endometriosis affecting the PSLN is described for the first time. The value of this finding as a predictor of malignant transformation in endometriosis must still be clarified and further studied in association with other molecular events, such as PTEN (phosphatase and tensin homolog) deletion and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) mutation. We might then be able to identify in the future which patients with endometriosis are at higher risk of cancer.
STUDY FUNDING AND COMPETING INTERESTS:
This study was supported by an internal Charité grant to the Endometriosis Research Center and the authors declare no conflicts of interest.
Diagn Pathol. 2016 Feb 2;11:17.
Clear cell carcinomas of the ovary: a mono-institutional study of 73 cases in China with an analysis of the prognostic significance of clinicopathological parameters and IMP3 expression.
Ovarian clear cell carcinoma (CCC) is an uncommon subtype of ovarian epithelial tumor. The prognostic significance of its clinicopathological parameters is discordant, with the exception of stage as the adverse prognostic factor. The present study aimed to evaluate the prognostic significance of its clinicopathological characteristics and the expression of IMP3 (Insulin-like growth factor-II mRNA-binding protein 3, IMP3 or IGF2BP3) in Chinese patients with primary pure CCC.
We collected clinicopathological data from 73 cases with a minimum of 5 years of follow-up and evaluated the expression of IMP3 by immunohistochemistry.
In total, 49.3 % of the patients were in stage I. Advanced stages were closely related to poor prognosis of disease-free survival (DFS) and overall survival (OS) (P < 0.005). Patients with CCC coexisting with endometriosis tended to be younger and to have unilateral involvement but did not exhibit differences in prognosis compared with patients with CCC without endometriosis. Other histological features such as growth pattern, mitosis, and necrosis did not have prognostic significance. IMP3 was positive in 63 % of patients (46 of 73 cases); Thus, positive expression of IMP3 is an adverse prognostic marker in terms of OS (P = 0.012), even in stage I patients (P = 0.038).
The present study demonstrates that IMP3 expression is a prognostic marker, with the exception of stage. IMP3 represents a biomarker of unfavorable prognosis even in stage I patients.
Panminerva Med. 2016 Jun;58(2):143-50.
Endometriosis and infertility.
Endometriosis remains a very enigmatic and perplexing disease. The exact mechanism by which endometriosiscauses infertility is still unclear. In the present paper, we will review possible mechanisms leading to subfertility or infertility in women with endometriosis and examine them according to location. Endometriosis in the pelvic cavity is a pathology associated with a general inflammatory response and should therefore be considered an inflammatory disease. Inflammatory changes affect the peritoneal fluid and hence the intratubal milieu, since the ampulla (where fertilization takes place) is exposed to peritoneal fluid through the fimbria. Any inflammatory change at this level may therefore impact fertilization and natural conception. The relationship between ovarian endometriomas and infertility may, of course, be explained by the presence of periovarian endometriosis. In the ovary, fibrosis observed in some cortical areas is induced by the inflammatory reaction caused by the presence of endometriomas. The association between fibrosis and a reduced ovarian reserve was demonstrated. Upregulated recruitment and the subsequent demise of early follicles may result in focal exhaustion of primordial follicles. Burn-out of early follicles by a local pelvic inflammatory environment caused by endometriomas may therefore be suggested. However, intraovarian inflammation, subsequent fibrosis and depletion of the ovarian reserve constitute another reason that should also be given due consideration. In addition, surgery should not be ruled out as a possible cause of ovarian reserve depletion. In conclusion, potential mechanisms leading to infertility are numerous, and while some of them remain hypothetical for now, others are supported by clear evidence. These possible mechanisms were reviewed in the present paper.
J Huazhong Univ Sci Technolog Med Sci. 2016 Feb;36(1):127-31.
Pituitary suppression before frozen embryo transfer is beneficial for patients suffering from idiopathic repeated implantation failure.
Long-term gonadotropin-releasing hormone agonist (GnRHa) administration before in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) in infertile women with endometriosis or adenomyosis significantly enhanced the chances of pregnancy in both fresh and frozen embryo transfer cycles. We hypothesized that long-term GnRHa treatment might also be beneficial for the idiopathic repeated implantation failure (RIF) patients. In the 21 patients receiving GnRHa and hormone replacement therapy (G-HRT) protocols for frozen embryo transfer, their data were compared with those of the 56 of frozen/fresh cycles they had previously undergone (previous protocols). Comparison showed that the finial results were significantly better with G-HRT protocols than with their previous protocols, with pregnancy rate, clinical pregnancy rate, implantation rate and on-going pregnancy rate being 70%, 60%, 40% and 38% respectively with G-HRT protocols, against 17%, 11%, 6.3% and 5% with previous protocols. The results showed that hormonally controlled endometrial preparation with prior GnRHa suppression could be used for patients who had experienced repeated failures of IVF treatment despite having morphologically optimal embryos, and the treatment may help increase the receptivity of the endometrium in these patients.
J Am Stat Assoc. 2015 Sep 1;110(511):923-934.
An Integrated Bayesian Nonparametric Approach for Stochastic and Variability Orders in ROC Curve Estimation: An Application to Endometriosis Diagnosis.
In estimating ROC curves of multiple tests, some a priori constraints may exist, either between the healthy and diseased populations within a test or between tests within a population. In this paper, we proposed an integrated modeling approach for ROC curves that jointly accounts for stochastic and variability orders. The stochastic order constrains the distributional centers of the diseased and healthy populations within a test, while the variability order constrains the distributional spreads of the tests within each of the populations. Under a Bayesian nonparametric framework, we used features of the Dirichlet process mixture to incorporate these order constraints in a natural way. We applied the proposed approach to data from the Physician Reliability Study that investigated the accuracy of diagnosing endometriosis using different clinical information. To address the issue of no gold standard in the real data, we used a sensitivity analysis approach that exploited diagnosis from a panel of experts. To demonstrate the performance of the methodology, we conducted simulation studies with varying sample sizes, distributional assumptions and order constraints. Supplementary materials for this article are available online.
Rev Assoc Med Bras (1992). 2015 Nov-Dec;61(6):507-18
Evaluation of endometriosis-associated pain and influence of conventional treatment: a systematic review.
Endometriosis is a chronic gynecological disease characterized by sustained painful symptoms that are responsible for a decline in the quality of life of sufferers. Conventional treatment includes surgical and pharmacological therapy aiming at reducing painful symptoms. This study aimed to evaluate pain levels in women with endometriosis, focusing on the influence of conventional treatment in controlling this variable. To do so, a literature search was conducted in the Medline/Pubmed databases, with 119 scientific articles found. After applying the inclusion and exclusion criteria, 27 were selected for reading and elaboration of this review. Thus, 9 studies evaluated the contribution of surgery, 17 the use of drugs to reduce pain levels in patients with endometriosis and one assessed surgical and medical treatment. The main results of these searches are presented and discussed in this revision. Surgery and the use of drugs provided reduced pain scores in patients with endometriosis but nevertheless exhibit disadvantages, such as risk of recurrence and side effects, respectively. Treatment of endometriosis is, therefore, a challenge for gynecologists and patients, as they must select the best therapeutic approach for this disease. However, improved quality of life in these patients has been obtained with the use of conventional treatment.
Rev Assoc Med Bras (1992). 2015 Nov-Dec;61(6):519-23
Nutritional aspects related to endometriosis.
This literature review analyzed the evidence on nutritional aspects related to the pathogenesis and progression of endometriosis. Diets deficient in nutrients result in changes in lipid metabolism, oxidative stress and promote epigenetic abnormalities, that may be involved in the genesis and progression of the disease. Foods rich in omega 3 with anti-inflammatory effects, supplementation with N-acetylcysteine, vitamin D and resveratrol, in addition to the increased consumption of fruits, vegetables (preferably organic) and whole grains exert a protective effect, reducing the risk of development and possible regression of disease. Dietary re-education seems to be a promising tool in the prevention and treatment of endometriosis.
Pediatr Endocrinol Rev. 2015 Dec;13(2):512-20.
Primary Dysmenorrhea in Adolescents: Prevalence, Impact and Recent Knowledge.
BACKGROUND AND OBJECTIVES:
Dysmenorrhea is commonly categorized into two types; primary and secondary. Primary dysmenorrhea (PD) is the focus of this review. PD is defined as painful menses with cramping sensation in the lower abdomen that is often accompanied by other symptoms, such as sweating, headache, nausea, vomiting, diarrhea, and tremulousness. All these symptoms occur just before or during the menses in women with normal pelvic anatomy. In adolescents the prevalence of PD varies between 16% and 93%, with severe pain perceived in 2% to 29% of the studied girls. Several studies suggest that severe menstrual pain is associated with absenteeism from school or work and limitation of other daily activities. One-third to one-half of females with PD are missing school or work at least once per cycle, and more frequently in 5% to 14% of them. The wide variation in the prevalence rates may be attributed to the use of selected groups of subjects. Many risk factors are associated with increased severity of dysmenorrhea including earlier age at menarche, long menstrual periods, heavy menstrual flow, smoking and positive family history. Young women using oral contraceptive pills (OCP) report less severe dysmenorrhea. The considerably high prevalence of dysmenorrhea among adolescents verified that this condition is a significant public health problem that requires great attention. SUMMARY OF MAIN RESULTS: Many methodological problems are encountered during quantifying and grading severity of pain related to dysmenorrhea. Quantifying and assessment tools depend on women’s self-reporting with potential bias. There is a scarcity of longitudinal studies on the natural history of dysmenorrhea as well as the possible effects of many modifiable risk factors. In addition, the duration of follow-up in the available studies is relatively short. Therefore, several aspects are still open for research. Medical treatment for dysmenorrhea includes anti-inflammatory drugs (NSAIDs), OCP or surgical intervention. The efficacy of conventional treatments using NSAIDs and OCP is high. However, failure rate may reach up to 20% to 25%, besides the occurrence of drug-associated adverse effects. Only 6% of adolescents receive medical advice to treat dysmenorrhea while 70% practice self-management. Unfortunately, some girls even abuse these medications (non-therapeutic high doses) for quick pain relief. The persistence of dysmenorrhea despite the use of OCP and/or NSAIDs drugs is a strong indicator of an organic pelvic disease. This condition mandates an appropriate referral to a gynecologist with proper laparoscopic diagnosis of endometriosis and/or other pelvic diseases.
Dysmenorrhea is an important health problem for adolescents, school and occupational as well as practitioners that adversely affects the daily activities and quality of life for adolescent women. The accurate prevalence of dysmenorrhea is difficult to establish due to the variety of diagnostic criteria and the subjective nature of the symptoms. In adolescents, moderate to severe dysmenorrhea that affects lifestyle and does not respond to medical treatment requires professional attention and proper diagnosis of possible underlying pelvic disease. Therefore, adolescent care providers should be more knowledgeable and actively involved in the care of dysmenorrhea.
Cell Tissue Res. 2016 Jul;365(1):187-96.
Exosomes derived from endometriotic stromal cells have enhanced angiogenic effects in vitro.
Our objective has been to establish a pro-angiogenic role for exosomes in endometriosis and to determine whether a differential expression profile of cellular and exosomal microRNAs (miRNAs) exists in endometriosis. We performed an in vitro study of human primary endometrial stromal cells (ESCs) and human umbilical vein endothelial cells (HUVECs). We isolated and characterized exosomes from ESCs from five endometriosis patients and five phase-matched controls. Exosomes were characterized by transmission electron microscopy and NanoSight technology. MiRNA was assessed by deep sequencing and reverse transcription with quantitative polymerase chain reaction. Exosome uptake studies were achieved by means of confocal microscopy. The pro-angiogenic experiments were executed by treating HUVECs with ESC-derived exosomes. We observed differential profiles of exosomal miRNA expression between exosomes derived from endometriosis lesion cells and diseased eutopic stromal cells compared with exosomes derived from control ESCs. We also demonstrated autocrine cellular uptake of exosomes and paracrine functional angiogenic effects of exosomes on HUVECs. The results of this study support the hypothesis that exosomes derived from ESCs play autocrine/paracrine roles in the development of endometriosis, potentially modulating angiogenesis. The broader clinical implications are that Sampson’s theory of retrograde menstruation possibly encompasses the finding that exosomes work as intercellular communication modulators in endometriosis.
Br J Radiol. 2016;89(1060):20150672.
Extragenital endometriosis: assessment with MR imaging. A pictorial review.
Endometriosis is a gynaecologic disease characterized by endometrial tissue outside the uterine cavity. Commonly it affects the pelvic organs. When endometrial nodules or plaques are localized in sites other than the uterus or ovaries, it is termed extragenital endometriosis. Adequate pre-operative assessment is essential for treatment planning. MRI is a non-invasive method with high spatial resolution that allows the multiplanar evaluation of genital and extragenital endometriosis. Herein, we present a pictorial review of a variety of extragenital endometriosis cases, all of which can be encountered in clinical practice.
Arch Gynecol Obstet. 2016 Sep;294(3):519-23.
Assessment of pelvic floor muscles in women with deep endometriosis.
To assess function and prevalence of spasms and trigger points of the pelvic floor muscles in women with deep endometriosis.
One hundred and four (104) patients were assessed. Group 1 (G1) was composed of 52 subjects diagnosed with deep endometriosis proven by magnetic resonance imaging (MRI); Group 2 (G2) was composed of 52 women with no signs of endometriosis. Subjects from both G1 and G2 were seen at the Division of Pelvic Pain and Endometriosis and at Center for Prevention of Sexually Transmitted Diseases, both at Federal University of São Paulo (UNIFESP), respectively. A full physical therapy evaluation was carried out, including medical history, presence of dyspareunia and physical examination, which included detailed evaluation of pelvic floor muscles and occurrence of muscle spasm, trigger point and muscle function.
The average age of the subjects in the study group was 36.4 and 30.9 years in the control group (p = 0.002). A greater prevalence of deep dyspareunia was found in the subjects in the endometriosis group when compared to the control group (p = 0.010). Women in G1 had higher prevalence of muscle spasms. In this group, 53.9 % had spasms-compared to only 17.3 % of women in G2 (p < 0.001). On the other hand, no significant difference between the groups (p = 0.153) was found while searching for the presence of trigger points.
Women with deep endometriosis have increased prevalence of pelvic floor muscle spasms when compared to the control group.
Gynecol Obstet Fertil. 2016 Feb;44(2):113-20.
Infertility and breast cancer: Is there a link? Updated review of the literature and meta-analysis.
The objective of this review was to assess the level of risk of breast cancer of patients consulting for infertility.
Studies of cohorts and case-control were extracted from the Pubmed database from January 2000 until May 2015 through the following keywords: “infertility”; “endometriosis”; “polycystic ovary syndrome”; “breast cancer”, “cancer risk”. Eleven publications were finally selected after exclusion of publications dealing with infertility after breast cancer. Our meta-analysis, involving 10 of these publications, was performed using Review Manager software, Cochrane Collaboration, 2014. The results were calculated by etiology of infertility, polycystic ovary syndrome (PCOS) and endometriosis, as well as globally.
The analysis of these published epidemiological studies confirms that infertility is not a breast cancer risk factor, but the results are contradictory. Three studies have shown a significantly increased risk of breast cancer in a population of infertile women, while 7 others have not found this risk. These contradictions are due to the heterogeneity of the studies, the included populations, the follow-up periods and confounding factors. Our meta-analysis of the selected studies has not identified a significant association between infertility and breast cancer risk (1.05; 95% CI [0.96-1.16]). A subgroup analysis on endometriosis and PCOS showed no significant association either, with an OR of 1.02 (95% CI [0.87-1.19]) and 1.19 (95% CI [0.93-1.51]), respectively.
Infertility is not an identified risk factor for breast cancer. A message reassuring about a possible risk of infertility-related breast cancer should be given to these patients. Infertility is therefore not an indication of increased breast surveillance.
Gynecol Obstet Fertil. 2016 Feb;44(2):106-12.
Is endometriosis a precancerous lesion? Perspectives and clinical implications.
Epidemiological studies have shown a relationship between endometriosis and clear cell/endometrioid ovarian cancers (named “Endometriosis Associated Ovarian Cancer” or EAOC). The recent discovery of signaling pathways (especially the SWI/SNF and PI3K/AKT/mTOR pathways) that linked endometriosis and EAOC could lead to the development of specific biomarkers as ARID1A to screen benign to premalignant endometriosis and to new targeted treatment. Moreover, the better understanding of the pathogenesis of the epithelial ovarian cancer arising from the Fallopian tube could allow new early prevention strategies that will be described in this review.
Gynecol Endocrinol. 2016;32(4):298-301.
Impact of laparoscopic cystectomy of endometriotic and non-endometriotic cysts on ovarian volume, antral follicle count (AFC) and ovarian doppler velocimetry.
To evaluate the effect on ovarian reserve and blood flow of unilateral laparoscopic stripping of endometriotic versus non-endometriotic cysts.
Prospective observational study.
Tertiary university gynecology unit.
During the study period, 71 subjects underwent the first laparoscopic surgery for removal of a monolateral benign ovarian cyst.
Trans-vaginal ultrasound scans of the pelvis about six months after surgery.
MAIN OUTCOME MEASURES:
Ovarian volume, Antral Follicle Count (AFC) and Resistance Index (RI) of ovarian artery of the operated and the contralateral ovary.
Among 71 cysts, 39.4% were endometriotic and 60.6% non-endometriotic benign cysts. All the procedures were performed by the same experienced surgeons with a standardized technique. No major complications were reported during surgery. The mean (±SD) age and BMI of women were 31.0 ± 6.8 years and 24.2 ± 3.3 kg/m(2), respectively. Mean diameter of the removed cysts was smaller for endometriotic than non-endometriotic cysts (4.35 ± 1.77 cm versus 6.33 ± 3.71 cm, p = 0.046). In comparison to non-operated, volume of the operated ovary was significantly lower and with a reduced AFC, with no difference between endometriotic and non-endometriotic cysts (-2.41 ± 2.35 versus -2.00 ± 2.23 cm(3), p = 0.496) (-3.45 ± 3.07 versus -2.43 ± 1.95, p = 0.11). Ovarian artery RI was higher in the operated ovary with no difference between endometriotic and non-endometriotic cysts (0.19 ± 0.14 versus 0.14 ± 0.10, p = 0.455). The difference in ovarian volume (r = 0.178), AFC (r = 0.094) and RI (r = 0.079) between operated and non-operated ovary was not dependent on the diameter of the removed cyst.
Ovarian surgery is associated with a decline of ovarian reserve, independently on the histological type and the diameter of the removed cyst.
J Minim Invasive Gynecol. 2016 May-Jun;23(4):573-7.
Elevated Serum CD95/FAS and HIF-1α Levels, but Not Tie-2 Levels, May Be Biomarkers in Patients With Severe Endometriosis: A Preliminary Report.
To evaluate serum values of cluster of differentiation 95 (CD95/FAS), hypoxia-inducible factor 1-alpha (HIF-1α), and tyrosine kinase receptor 2 (Tie-2) as possible biomarkers of disease presence and severity in women with endometriosis, and to characterize the changes in these values in women with stage I/II and stage III/IV endometriosis.
Prospective study (Canadian Task Force classification I).
Thirty women with endometriosis and 30 healthy women without endometriosis.
For the diagnosis of endometriosis and prediction of its severity, we measured the serum levels of CD95/FAS, which assess apoptotic conditions, and of HIF-1α and Tie-2, which assess angiogenesis. Endometriosis was diagnosed and staged through surgical laparoscopy and later confirmed histologically. During the surgery, the patients with endometriosis were divided into 2 groups based on disease stage. Eleven patients had stage I/II endometriosis, and 19 had stage III/IV endometriosis.
MEASUREMENTS AND MAIN RESULTS:
Endometriosis was associated with increased serum CD95/FAS and HIF-1α levels, but not Tie-2 levels. We also determined that stage III/IV endometriosis was associated with higher serum CD95/FAS and HIF-1α levels, but not Tie-2 levels, compared with stage I/II endometriosis.
Endometriosis, in accordance with its severity, increases serum CD95/FAS and HIF-1α levels, but not Tie-2 levels. These biomarkers may be useful for reproductive surgeons to improve the quality of counseling women about the presence and severity of endometriosis.
Am J Obstet Gynecol. 2016 Aug;215(2):195-200.
Surgical treatment of deep infiltrating rectal endometriosis: in favor of less aggressive surgery.
Deep infiltrating endometriosis of the rectum is a severe disease concerning young women of reproductive age. Because it is a benign condition, aggressive surgical treatment and subsequent complications are not always accepted by young patients. Two surgical approaches exist: the radical approach, employing colorectal resection; and the conservative approach, based on rectal shaving or full-thickness disc excision. At present, the majority of patients with rectal endometriosis worldwide are managed by the radical approach. Conversely, as high as 66% of patients with colorectal endometriosis can be managed by either rectal shaving or full-thickness disc excision. Most arguments that used to support the large use of the radical approach may now be disputed. The presumed higher risk of recurrence related to conservative surgery can be balanced by a supposed higher risk of postoperative bowel dysfunction related to the radical approach. Bowel occult microscopic endometriosis renders debatable the hypothesis that more aggressive surgery can definitively cure endometriosis. Although most surgeons consider that radical surgery is unavoidable in patients with rectal nodules responsible for digestive stenosis, conservative surgery can be successfully performed in a majority of cases. In multifocal bowel endometriosis, multiple conservative procedures may be proposed, provided that the nodules are separated by segments of healthy bowel of longer than 5 cm. Attempting conservation of a maximum length of rectum may reduce the risk of postoperative anterior rectal resection syndrome and subsequent debilitating bowel dysfunction and impaired quality of life. Promotion of less aggressive surgery with an aim to better spare organ function has become a general tendency in both oncologic and benign pathologies; thus the management of deep colorectal endometriosis should logically be concerned, too.
Hum Reprod. 2016 Apr;31(4):712-22.
The direct and indirect costs associated with endometriosis: a systematic literature review.
What is the economic burden of endometriosis?
The identified studies indicate that there is a significant economic burden associated with endometriosis, as observed by both direct and indirect costs.
WHAT IS KNOWN ALREADY:
Two previous systematic literature reviews suggested that there were considerable direct costs associated with endometriosis and there was a general lack of measurement of indirect costs.
STUDY DESIGN, SIZE, DURATION:
We performed a systematic literature review. MEDLINE and EMBASE databases from 2000 to 2013 were searched. The literature search was limited to human studies of patients with endometriosis. Papers in languages other than English were excluded.
PARTICIPANTS/MATERIALS, SETTING, METHODS:
Studies reporting direct or indirect costs among patients with endometriosis were considered for inclusion. Direct costs included inpatient, outpatient, surgery, drug and other healthcare service cost. Indirect costs were related to absenteeism and presenteeism (lost productivity at work).
MAIN RESULTS AND THE ROLE OF CHANCE:
After evaluating the 1396 articles in the search results, 12 primary studies that reported direct or indirect costs associated with endometriosis were identified and included in the data extraction. Three of the studies were conducted in the USA, one study each was conducted in Austria, Belgium, Brazil, Canada, Finland, Germany and Italy, and two studies included data from 10 countries. Significant variability was observed in the reviewed studies in methodology, including data source, cost components considered and study perspective. Estimates of total direct costs ranged from $1109 per patient per year in Canada to $12 118 per patient per year in the USA. Indirect costs of endometriosis ranged from $3314 per patient per year in Austria to $15 737 per patient per year in the USA.
LIMITATIONS, REASONS FOR CAUTION:
The studies identified in the systematic literature review varied greatly by study methodology as well as by country owing to different healthcare systems and costs of healthcare services, which contributed to large variations in the direct and indirect cost estimates.
WIDER IMPLICATIONS OF THE FINDINGS:
A majority of the studies we found were published after the periods covered in the prior systematic literature reviews, which provided substantial contributions to an understanding of the economic burden of endometriosis, especially in the area of indirect costs. The long-term burden of endometriosis following diagnosis is still under-studied, which is a concern given the chronic nature of the disease and the substantial recurrence of endometriosis symptoms.
STUDY FUNDING/COMPETING INTERESTS:
This study was funded by AbbVie, which also develops the oral GnRH antagonist elagolix (in collaboration with Neurocrine Biosciences) for the management of endometriosis and uterine fibroids. A.M.S. is an employee of AbbVie and currently owns AbbVie stocks. H.Y., E.X.D. and C.K. are employees of Analysis Group, Inc., which has received consultancy fees from AbbVie. C.W. is a Clinical Professor at the Department Obstetrics and Gynecology at Georgetown University in Washington, DC, USA and has served in a consulting role to AbbVie for this project.
J Reprod Immunol. 2016 Apr;114:6-9.
Increased IL-25 levels in the peritoneal fluid of patients with endometriosis.
Previous studies have indicated a higher prevalence of allergic disease among women with endometriosis. It is already well established that type 1 allergies develop in a Th2 cytokine environment. Recent studies have shown, however, that IL-25 induces a Th2 development of naive T lymphocytes and is central in the Th2 response. The aim of this case-control study was to investigate the presence of IL-25 in the peritoneal fluid of women suffering from endometriosis. PF was obtained both from women undergoing laparoscopic surgery due to endometriosis (25 cases) and from women wanting sterilisation (19 controls). IL-25 levels were then investigated by ELISA. Women with endometriosis showed significantly higher levels of IL-25 in their PF (p=0.019) compared to controls. IL-25 levels did not correlate with the stage of endometriosis. Both Th2-cells and mast cells express IL-25, which could favor the development of allergies by perpetuating a hypersensitivity reaction. Further, IL-25 may also hold a role as a diagnostic tool.
Postgrad Med. 2016;128(3):307-10.
Silent obstruction in a young woman with systemic lupus erythematosus: a case report and literature review on kidney injury from ureteral endometriosis.
Endometriosis is the most common pelvic gynaecologic disorder affecting pre-menopausal women. However ureteral endometriosis (UE) especially intrinsic urinary tract endometriosis is a rare finding that is notorious for causing silent renal insult. The pathogenesis of endometriosis still remains a mystery but studies have suggested an association between endometriosis and systemic lupus erythematosus (SLE) suggesting an immunological aspect to endometriosis. There is very little recognition in the renal literature of the significance of UE leading to progressive kidney injury and the association with autoimmune conditions in particular SLE.
We present a case of a 30-year old female with a background history of SLE with a silent progressive kidney injury due to an obstructive uropathy secondary to bilateral intrinsic UE and severe loss of her left kidney function that was treated with ureteric stenting. She subsequently underwent bilateral re-implantation of her ureters as a definitive treatment plan as she expressed a wish to conceive.
Progressive kidney injury as a result of UE has been reported in the past, however its true incidence is not known. The time of diagnosis is crucial as it reflects renal prognosis. This article outlines the clinical implications from the renal perspective of the disease considering the relevant health problem UE can impose to women. This paper discusses the emerging evidence of an association between SLE and endometriosis that remains poorly understood.
A high index of suspicion is required to diagnose UE as the disease occurs insidiously with non-specific symptoms leading to a silent obstructive uropathy. If missed it can ultimately lead to irreversible kidney dysfunction and mortality. We suggest that patients with endometriosis especially UE should be followed up regularly with renal function testing and imaging. Any health professionals dealing with patients suffering from SLE should consider appropriate investigations and referral if any symptom that suggests endometriosis is reported.
Histol Histopathol. 2016 Aug;31(8):933-42.
Aberrant levels of Wnt/β-catenin pathway components in a rat model of endometriosis.
Endometriosis is a benign gynecological disease affecting approximately 10-15% of women of reproductive age and 25-50% of all infertile women. It is characterized by the presence of glands and/or endometrial stroma outside the uterine cavity. Angiogenesis is a crucial process for the development and maintenance of endometriotic lesions. The Wnt/β-catenin pathway is a major promoter of angiogenesis in both physiological and pathological conditions. In the present study, we evaluated the expression of molecules related to the Wnt/β-catenin pathway in a rat model of peritoneal endometriosis. mRNA analyses showed significantly increased expression of Wnt4 and Wnt7b and decreased expression of Gsk3beta and E-cadherin in endometriotic lesions. However, there were no differences in β-catenin and Fzd2 mRNA expression. In addition, we observed a significant increase of nuclear β-catenin in endometriotic lesions, a hallmark of Wnt/ β-catenin pathway activation. Stromal β-catenin staining was found in 45.4% of endometrial tissues and 77.8% of endometriotic lesions. β-catenin nuclear localization was found in 18.2% of the endometrial tissues and 33.3% of endometriotic lesions. Finally, the expression of galectin-3, a regulator of this pathway, was increased in endometriosis. In summary, this pattern of Wnt/β-catenin components expression suggests an increased activity of this pathway in endometriosis.
Lancet Haematol. 2016 Feb;3(2):e72-9.
Anticoagulation with rivaroxaban for livedoid vasculopathy (RILIVA): a multicentre, single-arm, open-label, phase 2a, proof-of-concept trial.
Livedoid vasculopathy is a thrombotic skin disease characterised by recurrent occlusion of the cutaneous microcirculation in lower extremities, which results in skin infarctions with painful ulcerations and irreversible scar formation. Rivaroxaban is a direct factor Xa inhibitor that prevents thrombus formation. We investigated whether rivaroxaban is effective for the treatment of livedoid vasculopathy.
We did this single-arm, open-label, multicenter, phase 2a, proof-of concept trial at three university hospitals in Germany. Patients with livedoid vasculopathy and a minimum pain score of 40 on the visual analogue scale were eligible to participate. Patients received oral rivaroxaban tablets for 12 weeks at an initial dose of 10 mg twice per day, which was reduced to once per day if a reduction of pain by 50% on the visual analogue scale was achieved. Subcutaneous enoxaparin at 1 mg per kg bodyweight once or twice per day was allowed as a backup treatment in case of insufficient efficacy and increased pain. The primary endpoint was change in pain on the visual analogue scale from baseline to 12 weeks. Efficacy was assessed in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study drug. This trial is registered with the EU Clinical Trials Register, EudraCT number 2012-000108-13-DE, and is closed to new participants.
Between Dec 28, 2012, and April 24, 2014, 36 patients were screened, 28 patients were recruited for the study, and 25 patients received treatment. During treatment, five patients dropped out of the study because of withdrawal of consent (one patient), lack of compliance (one patient), violation of inclusion criteria (two patients), and a serious adverse event (one patient). Median pain on the visual analogue scale decreased from 65·0 (IQR 52·0-78·0) at baseline to 6·0 (1·0-14·0) after 12 weeks of treatment (p<0·0001). Six of the 20 patients required additional treatment with enoxaparin. Eight treatment-related adverse events were recorded in six (24%) of the 25 patients: five cases of menorrhagia including one classified as both menorrhagia and dysmenorrhoea, one case of dyspnoea, and one case of gingival bleeding. The only serious adverse reaction to rivaroxaban during the study was one case of menorrhagia in a patient with concomitant endometriosis, which resulted in study discontinuation.
Rivaroxaban seems to effectively reduce pain in livedoid vasculopathy. Therefore we suggest that rivaroxaban with enoxaparin as a backup treatment is a suitable treatment option for patients with livedoid vasculopathy.
Reprod Biomed Online. 2016 Apr;32(4):434-45.
microRNA miR-200b affects proliferation, invasiveness and stemness of endometriotic cells by targeting ZEB1, ZEB2 and KLF4.
Endometriosis is characterized by growth of endometrial tissue at ectopic locations. Down-regulation of microRNA miR-200b is observed in endometriosis and malignant disease, driving tumour cells towards an invasive state by enhancing epithelial-to-mesenchymal transition (EMT). miR-200b up-regulation may inhibit EMT and invasive growth in endometriosis. To study its functional impact on the immortalized endometriotic cell line 12Z, the stromal cell line ST-T1b, and primary endometriotic stroma cells, a transient transfection approach with microRNA precursors was employed. Expression of bioinformatically predicted targets of miR-200b was analysed by qPCR. The cellular phenotype was monitored by Matrigel invasion assays, digital-holographic video microscopy and flow cytometry. qPCR revealed significant down-regulation of ZEB1 (P < 0.05) and ZEB2 (P < 0.01) and an increase in E-cadherin (P < 0.01). miR-200b overexpression decreased invasiveness (P < 0.0001) and cell motility (P < 0.05). In contrast, cell proliferation (P < 0.0001) and the stemness-associated side population phenotype (P < 0.01) were enhanced following miR-200b transfection. These properties were possibly due to up-regulation of the pluripotency-associated transcription factor KLF4 (P < 0.05) and require attention when considering therapeutic strategies. In conclusion, up-regulation of miR-200b reverts EMT, emerging as a potential therapeutic approach to inhibit endometriotic cell motility and invasiveness.
Lupus. 2016 Aug;25(9):1045-9.
Endometriosis and systemic lupus erythematosus: a population-based case-control study.
To investigate the association between endometriosis and systemic lupus erythematosus (SLE) in prospectively collected population-based data.
We conducted a case-control study using Swedish registers, identifying female SLE cases from the National Patient Register and female controls sampled from the general population matched on birth year, sex and county during 1964-2011. We identified endometriosis diagnoses from the National Patient Register using ICD codes. We estimated odds ratios and 95% confidence intervals using conditional logistic regression models.
We identified 2834 cases of SLE and 14,164 controls. Seventy-eight cases were diagnosed with endometriosis prior to their SLE diagnosis and 288 controls were diagnosed prior to the index date. We observed a significant association between endometriosis and subsequent SLE with an odds ratio of 1.39 (95% confidence interval = 1.09-1.78). The association was similar when requiring a laparoscopy/laparotomy within six months of the endometriosis diagnosis (odds ratio = 1.33; 95% confidence interval = 0.84-2.12) while the association was stronger when restricted to endometriosis diagnosed at the same time as hysterectomy (odds ratio = 2.26; 95% confidence interval = 1.47-3.64).
Our findings suggest an association between endometriosis and SLE. Future prospective studies with extended follow-up will be necessary to clarify whether this association is influenced by the timing and severity of endometriosis diagnosis.
Semin Reprod Med. 2016 Mar;34(2):74-82.
Fixed or Rotating Night Shift Work Undertaken by Women: Implications for Fertility and Miscarriage.
This review summarizes the evidence concerning effects of night shift work on women’s reproductive health, specifically difficulty in conceiving and miscarriage. We distinguish between fixed night shift and rotating night shift, as the population subgroups exposed, the social and biological mechanisms, and the magnitude of effects are likely to differ; of note, women working fixed night shift are known to have high tolerance for this schedule. We identified two relevant systematic reviews with meta-analyses and five additional studies. Night shift work may give rise to menstrual cycle disturbances, but effect sizes are imprecise. Endometriosis may be elevated in night shift workers, but evidence is only preliminary. Adequate data are lacking to assess associations between night shift work and infertility or time to pregnancy. The weight of evidence begins to point to working at night, whether in fixed or rotating shifts, as a risk factor for miscarriage. There are many methodological problems with this literature, with substantial variation in the definitions of night shift and schedule types making comparisons between studies difficult and pooling across studies questionable. Nevertheless, there appears to be grounds for caution and counselling where women have concerns about night shift work and their reproductive health.
Niger J Clin Pract. 2016 Mar-Apr;19(2):233-6.
Video-assisted thoracic surgery in a Nigerian teaching hospital: Experience and challenges.
Video-assisted thoracic surgery (VATS) is well established. Its application in Nigeria has however been limited and not been reported. The aim of this study was to describe our institutional experience and challenges with VATS.
MATERIALS AND METHODS:
This was a retrospective cross-sectional study of all patients that underwent VATS in our institution between March 2008 and June 2013. Data were extracted from a prospectively maintained database.
Two hundred and sixty-one patients were assessed as potential VATS cases. VATS was initiated in 26 patients, but completed in 25 patients (9.6%) as there was one case of conversion of a planned VATS bullectomy due to the failure of one lung ventilation. There were 12 males and 13 females. Mean age was 40.7 ± 13.9 years. The indication was interstitial lung disease in 9 patients (36%), malignant pleural effusion in 6 patients (24%), spontaneous pneumothorax in 5 patients (20%), indeterminate pulmonary nodule in 2 patients (8%), pleural endometriosis in 2 patients (8%) and bronchogenic cyst in one patient (4%). Procedures performed were lung biopsy in 13 patients (52%), pleural biopsy and pleurodesis in 6 patients (24%), bullectomy and pleurodesis in 5 patients (20%) and excision of bronchogenic cyst in one patient (4%). Mean hospital stay was 4 ± 0.7 days. There were no complications and no mortalities.
VATS is being performed in our institution with successful outcomes. The use of VATS in Nigeria is encouraged. The relatively high cost of VATS is, however, a major limitation to more widespread use.
Appl Immunohistochem Mol Morphol. 2017 Jul;25(6):415-421.
Overexpression of SIRT1 is Associated With Poor Outcomes in Patients With Ovarian Carcinoma.
Sirtuin 1 (SIRT1), originally identified as a longevity gene, regulates DNA repair and metabolism by deacetylating target proteins such as p53. SIRT1 plays a key role in the pathophysiology of metabolic diseases and neurodegenerative disorders, and is considered to protect against age-related diseases including cancer. In contrast, SIRT1 may be oncogenic because its overexpression has been detected in many cancers. The aim of the present study was to clarify the expression and the role of SIRT1 in ovarian carcinoma (OvCa). The expression of SIRT1 was evaluated immunohistochemically in 16 cases of normal ovaries, 35 cases of endometriosiswith/without carcinoma, and 68 cases of OvCa (endometrioid, 16; clear cell, 20; mucinous, 16; serous, 16). Staining results were evaluated semiquantitatively by the Immunoreactive Scoring System, and the relationships with clinicopathologic features and outcomes of patients were analyzed. The expression of SIRT1 was higher in endometrioid, mucinous, and clear-cell carcinomas than in the inclusion cysts of normal ovaries, but not in serous carcinoma (P=0.038). The expression of SIRT1 on OvCa did not correlate with age, stage, location of metastasis, or capsular penetration. However, elevated SIRT1 expression was a significant predictor of shorter survival in univariate (P=0.038) and multivariate (P=0.037) survival analyses, regardless of the tumor stage. Results of the present study suggest a positive role for SIRT1 in the development of OvCa and its potential as a novel therapeutic target.
Oncotarget. 2016 Mar 29;7(13)
The prognostic value of pretreatment CA-125 levels and CA-125 normalization in ovarian clear cell carcinoma: a two-academic-institute study.
The present study investigated the clinical implications of pretreatment carbohydrate antigen 125 (CA-125) levels and CA-125 normalization in patients with ovarian clear cell carcinoma (CCC), and it provides useful information for the improvement of monitoring strategies for this lethal disease.
The medical records of patients with ovarian CCC who had undergone primary staging surgery or cytoreductive surgery followed by systemic chemotherapy were retrospectively reviewed. A range of clinico-pathological parameters were collected and examined.
A total of 375 women were included in the analysis. FIGO stage (p < 0.001) was identified as the only significant prognostic factor for relapse. Residual tumor and advanced stage (p = 0.001 and p < 0.001, respectively) were identified as independent adverse factors for survival. The potential risk factors associated with elevated pretreatment CA-125 levels included advanced-stage disease, positive residual tumors and negative endometriosis (p < 0.001, p = 0.001 and p <0.001, respectively). Pretreatment CA-125 levels were not associated with relapse-free survival (RFS) or overall survival (OS) (p = 0.060 and p = 0.176, respectively). CA-125 normalization after chemotherapy exhibited a positive linear correlation with advanced stage (r = 0.97, p = 0.001) and residual tumor (r = 0.81, p = 0.027) and a negative relationship with 5-year RFS (r = -0.97, p = 0.002) and 5-year OS (r = -0.97, p= 0.001). Patients with CA-125 levels that normalized before cycle 2 of chemotherapy had a similar prognosis as patients whose CA-125 levels normalized prior to chemotherapy (RFS: p = 0.327; OS: p = 0.654). By contrast, patients with CA-125 levels that normalized after cycle 2 of chemotherapy or never normalized were significantly more likely to experience disease progression.
Pretreatment CA-125 levels are not very useful for predicting clinical outcome. CA-125 levels following treatment are a valid indicator for treatment monitoring. CA-125 normalization after the completion of cycle 1 of chemotherapy represents a distinct inflection point for decreased RFS and OS.
Vet Pathol. 2016 Mar;53(2):399-416.
Age-Associated Pathology in Rhesus Macaques (Macaca mulatta).
The rhesus macaque (Macaca mulatta) is one of the most extensively used nonhuman primate models for human diseases. This article presents a literature review focusing on major organ systems and age-associated conditions in humans and primates, combined with information from the Wisconsin National Primate Research Center Electronic Health Record database to highlight and contrast age-associated lesions in geriatric rhesus macaques with younger cohorts. Rhesus macaques are excellent models for age-associated conditions, including diabetes, osteoarthritis, endometriosis, visual accommodation, hypertension, osteoporosis, and amyloidosis. Adenocarcinoma of the large intestine (ileocecocolic junction, cecum, and colon) is the most common spontaneous neoplasm in the rhesus macaque. A combination of cross-sectional and longitudinal studies is required to truly define mechanisms of maturation, aging, and the pathology of age-associated conditions in macaques and thus humans. The rhesus macaque is and will continue to be an appropriate and valuable model for investigation of the mechanisms and treatment of age-associated diseases.
Reprod Sci. 2016 Apr;23(4):455-63
Aberrant HOXA10 Methylation in Patients With Common Gynecologic Disorders: Implications for Reproductive Outcomes.
HomeoboxA10 (HOXA10) is a transcription factor that is crucial for the development and patterning of the uterus during embryogenesis. In the adult endometrium, HOXA10 expression is regulated by steroid hormones and embryonic signals. Expression of sufficient HOXA10 messenger RNA is essential to endometrial receptivity and embryo implantation. Aberrant methylation is believed to alter the expression of HOXA10. Methylation of this gene may be associated with decreased fertility, implantation defects, and/or reproductive wastage seen in certain disease states that affect the female reproductive tract. This study describes the differences in methylation patterns of HOXA10 gene in uterine myomas, endometriosis, uterine septum, Asherman syndrome, or uterine polyps of women undergoing hysteroscopic surgery. In the endometrium of uteri with polyps, submucosal myomas, and intramural myomas, there were CpG sites within the HOXA10 gene that were highly methylated compared to controls. The HOXA10 gene in women with endometriosis was hypomethylated compared to controls. DNA methylation may be a common molecular mechanism that results in reproductive dysfunction seen in gynecologic disease.
Obstet Gynecol Sci. 2016 Jan;59(1):32-8.
Effects of different add-back regimens on hypoestrogenic problems by postoperative gonadotropin-releasing hormone agonist treatment in endometriosis.
To compare the efficacy of different add-back regimens on hypoestrogenic symptoms during postoperative gonadotropin-releasing hormone (GnRH) agonist treatment in endometriosis patients.
This prospective cohort study included reproductive-aged women who underwent conservative laparoscopic surgery for ovarian endometriosis and received add-back therapy during a 6-month course of GnRH agonist therapy after surgery. Participants received one of four different add-back regimens: 1 mg of estradiol valerate, 2.5 mg of tibolone, or a combination of 1 mg of estradiol and 2 mg of drospirenone or 0.5 mg of norethisterone acetate. Changes in quality of life, hypoestrogenic symptoms, and bone mineral density were compared according to add-back regimens.
A total of 57 participants completed a 6-month course of GnRH agonist and add-back therapy. All components of quality of life did not differ across groups. However, within the same treatment group, social relationship factors decreased significantly with estradiol valerate and tibolone alone, and environmental factors decreased significantly with estradiol valerate alone. Menopausal Rating Scale score did not change significantly, but the incidence of hot flushes significantly decreased with a combination of estradiol and norethisterone acetate. Bone mineral densities at the lumbar spine declined significantly after treatment in all groups except with a combination of estradiol and norethisterone acetate.
This preliminary study suggests that an add-back regimen containing estradiol valerate and norethisterone acetate may have better efficacy in terms of quality of life, hypoestrogenism-associated symptoms, and bone mineral density.
Eur Radiol. 2016 Nov;26(11):3968-3977.
MR diagnosis of diaphragmatic endometriosis.
To evaluate magnetic resonance imaging (MRI) for diaphragmatic endometriosis diagnosis.
MATERIALS AND METHODS:
Over a 2-year period, all diaphragmatic MRI performed in the context of diaphragmatic endometriosis were reviewed. Axial and coronal fat-suppressed T1- and T2-weighted sequences were analyzed by two independent readers for the presence of nodules, plaque lesions, micronodule clustering, or focal liver herniation. MR abnormalities were correlated to surgical findings in women surgically treated. Interobserver agreement was assessed by κ statistics.
Twenty-three women with diaphragmatic endometriosis criteria comprised the population; 14 had surgical confirmation and nine had symptoms relief with hormonal treatment. MRI sensitivity was 83 % (19/23; 95 % confidence interval [CI]: 68, 98) for reader 1 and 78 % (18/23; 95 % CI: 61, 95) for reader 2. Kappa value was 0.86 (95 % CI: 0.47, 1.00). Readers 1 and 2 detected 35 and 36 lesions, respectively, all right-sided and agreed for 32 lesions on the type, location, and signal. Lesions were mostly nodules (23/32, 72 %), predominantly posterior (28/32, 87.5 %) and hyperintense on T1 (20/32, 63 %). MRI was negative for both readers in 2 surgically treated patients with small nodules or isolated diaphragmatic holes.
MRI allows diaphragmatic endometriosis diagnosis with 78 to 83 % sensitivity and excellent interobserver agreement.
- MRI allows the diagnosis of diaphragmatic endometriosiswith up to 83 % sensitivity. • Diaphragmatic endometriosislesions are better depicted on fat-suppressed T1-weighted sequences. • Diaphragmatic lesions, mostly hyperintense nodules, are right-sided and predominantly posterior. • MRI can help in timely diagnosis of diaphragmatic endometriosis.
Oncol Lett. 2016 Jan;11(1):23-30
Endometriosis and breast cancer: A survey of the epidemiological studies.
Endometriosis is a chronic gynecological disease with a wide spectrum of clinical manifestations that affects approximately 10% of women of reproductive age. Recent reviews have demonstrated the connection between endometriosis and breast cancer, which represents the most frequently diagnosed female cancer and the most common cause of cancer-related mortality among women worldwide. The aim of this study was to conduct a survey of available published epidemiological studies indicating the association between endometriosis and breast cancer, and simultaneously to categorize the results based on the strength of the association, with the intention of the critical evaluation of the existing data. We performed a rigorous search of the PubMed/Medline database, using the key words ‘endometriosis’ and ‘breast cancer’ for all studies published in the English language until September 2015. We found 4 retrospective cohort studies, 4 case-control studies and 3 case-cohort studies that demonstrated a notable risk for developing breast cancer among women with endometriosis. By contrast, we also found 5 case-control studies, 1 prospective cohort study, 1 case-cohort study and 1 cross-sectional study that demonstrated a negative association between endometriosis and breast cancer. In conclusion, as regards the clarification of a ‘robust’ or ‘weak’ association between endometriosis and breast cancer, no definite conclusions could be drawn, due to the limited number of studies and the limitations of each of these studies. New well-designed, prospective cohort or randomized control trials with long-term follow-up are warranted in order to provide evidence-based clinical recommendations for proper counseling, screening and treatment strategies for patients with endometriosis, and hence to improve public health.
Gynecol Obstet Invest. 2016;81(6):512-517.
Prospective Evaluation of a Panel of Plasma Cytokines and Chemokines as Potential Markers of Pelvic Endometriosis in Symptomatic Women.
Endometriosis is a chronic inflammatory disease for which no accurate peripheral diagnostic marker is available. Many cytokines and chemokines have been found altered in the plasma and peritoneal fluid of women with endometriosis compared to healthy controls, but little is known about their diagnostic utility to confirm or discard endometriosis among symptomatic women.
The study aims to assess the diagnostic value of a panel of plasma cytokines and chemokines to detect endometriosis in women undergoing laparoscopy for gynecological complains.
We performed a prospective cohort study evaluating simultaneously plasma concentrations of interleukin (IL)-2, IL-4, IL-6, IL-10, MCP-1/CCL2, IP-10/CXCL10 and eotaxin/CCL11 in 75 symptomatic women (chronic pelvic pain, infertility or ovarian cyst) submitted to laparoscopy. Assays were performed by Cytometric Bead Array System. Endometriosis was confirmed by histopathological examination of surgical specimens.
Plasma IL-2, IL-4, IL-6, IL-10, MCP-1/CCL2, IP-10/CXCL10 and eotaxin/CCL11 concentrations were not able to distinguish the women who eventually were diagnosed with endometriosis.
Although previously shown to be altered in women with endometriosis compared to healthy women, the tested cytokines and chemokines were not useful to predict the presence of endometriosis among symptomatic women. This finding suggests that inflammatory markers modified by endometriosis may also be altered by other conditions associated with similar symptoms, which limits their use in clinical practice.
PLoS One. 2016 Feb 12;11(2):e0148165.
Pathophysiology of Endometriosis: Role of High Mobility Group Box-1 and Toll-Like Receptor 4 Developing Inflammation in Endometrium.
Oxidative stress has been proposed as a potential factor associated with the establishment and progression of endometriosis. Although a few studies have shown possible mechanisms which may play roles in development, progression of endometriosis, few are known in regards of initiation of the disease, especially in the relationship with endometrium. The aim of our study was to investigate whether normal endometrium may be changed by Damage-associated molecular patterns (DAMPs), which may contribute developing pathologic endometrium to induce endometriosis. Endometrial tissues were obtained from 10 patients with fibroids undergoing hysterectomy at a university hospital. High mobility group box-1 (HMGB-1), which is a representative DAMP, has been chosen that may induce alteration in endometrium. In preceding immunohistochemistry experiments using paraffin-block sections from endometriosis (N = 33) and control (N = 27) group, retrospectively, HMGB-1 expression was shown in both epithelial and stromal cell. HMGB-1 expression was significantly increased in secretory phase of endometriosis group, comparing to the controls. To examine the alteration of endometrial stromal cell (HESC) by oxidative stress in terms of HMGB-1, cell proliferation and expression of its receptor, TLR4 was measured according to recombinant HMGB-1 use. Cell proliferation was assessed by CCK-8 assay; real-time PCR and western blotting were used to quantify Toll like receptor 4 (TLR4) mRNA and protein expression respectively. A TLR4 antagonist (LPS-RS) and an inhibitor of the NF-κB pathway (TPCA-1, an IKK-2 inhibitor) were used to confirm the relationships between HMGB-1, TLR4, and the NF-κB pathway. Passive release of HMGB-1 was significantly proportional to the increase in cell death (P<0.05). HESCs showed significant proliferation following treatment with rHMGB-1 (P<0.05), and increased TLR4 expression was observed following rHMGB-1 treatment (P<0.05) in a concentration-dependent manner. Treatment with a TLR4 antagonist and an NF-κB inhibitor resulted in suppression of rHMGB-1-induced HESC proliferation (P<0.05). Levels of IL-6 were significantly decreased following treatment with an NF-κB inhibitor (P<0.05). Our results support the development of altered, pathological endometrium resulted from oxidative stress in normal endometrium. These findings may provide important insights into the changes in endometrium linking the development and progression of endometriosis.
Int J Gynaecol Obstet. 2016 May;133(2):199-201
Social isolation in women with endometriosis and chronic pelvic pain.
To evaluate the perceptions of women with endometriosis and chronic pelvic pain regarding their social ties.
A qualitative study was undertaken of women with chronic pelvic pain and endometriosis. Focus groups discussions among four to six participants were performed until saturation at the Clinics Hospital of Ribeirão Preto Medical School, Ribeirão Preto, southwest Brazil, between February 2013 and January 2014. Transcripts were analyzed according to the grounded theory approach and the emerging categories were coded using the WebQDA platform.
Six focus group discussions took place, with a total of 29 patients. Social isolation was the main emerging theme. Social isolation was associated with a lack of understanding about endometriosis symptoms and with resignation in face of recurrent pain episodes. Avoiding partner intimacy and isolation from family and friends were components of social isolation.
Women with endometriosis develop progressive social isolation after the onset of chronic pelvic pain. This finding is important for the multidisciplinary management of the disease.
Cancer Imaging. 2016 Feb 12;16:3.
Differentiation of epithelial ovarian cancer subtypes by use of imaging and clinical data: a detailed analysis.
Primary epithelial ovarian carcinoma is sub-classified into serous, mucinous, endometrioid and clear cell subtypes. Neoadjuvant chemotherapy has become an alternative treatment option past several years, as serous carcinoma, the most common subtype, is known as chemotherapy-sensitive tumor. On the other hand, mucinous and clear cell carcinoma are known as chemotherapy-resistive. Therefore, it may be meaningful to estimate subtype of ovarian carcinoma using imaging modality. The purpose of this study is to study whether CT or MRI can determine the subtypes of epithelial ovarian cancers.
The imaging and clinical findings obtained from 125 consecutive patients with primary ovarian carcinoma were retrospectively analyzed. Forty-four of the patients had serous carcinoma; 13, mucinous carcinoma; 53, clear cell carcinoma; and 15, endometrioid carcinoma. We studied the bilateralism, morphological type, tumor diameter, solid portion ratio, relative signal intensity on T2WI and DWI, contrast ratio, and endometriosis on MRI and the calcification, peritoneal dissemination and lymph node metastasis, clinical staging, and thromboembolism on CT. We also studied the tumor markers and serum calcium concentrations. Each parameter was statistically analyzed by univariate and multivariate analyses.
Serous carcinoma showed a significantly higher incidence of bilateral disease, smaller tumor size, higher signal intensity on DWI, and less frequent hypercalcemia. The CA19-9 level was significantly higher in mucinous carcinoma, in which most of the tumors appeared as multilocular cystic masses. Clear cell carcinoma appeared as unilateral disease with a larger solid portion and hypercalcemia in younger patients. Endometrioid carcinoma only showed a lower incidence of intraperitoneal dissemination.
CT and MRI combined with clinical data especially tumor markers and presence of paraneoplastic syndrome could partly predict epithelial ovarian cancer subtypes.
Contraception. 2016 Sep;94(3):202-15.
The safety of subcutaneously administered depot medroxyprogesterone acetate (104mg/0.65mL): A systematic review.
Depot medroxyprogesterone acetate (DMPA), a progestogen-only contraceptive injectable, has traditionally been formulated as a crystalline suspension delivered intramuscularly (IM) at a dose of 150mg/1.0mL. A new, lower dose formulation of DMPA (104mg/0.65mL) has been developed for subcutaneous administration (SC). Given its increasing global availability and public health relevance, DMPA-SC was prioritized for inclusion as a new method referenced in the World Health Organization (WHO) Medical Eligibility Criteria for Contraceptive Use (MEC), 5th Edition.
This systematic review evaluated the published peer-reviewed literature regarding the safety of DMPA-SC among women with various characteristics or medical conditions. Results of this review informed the decision-making of a WHO Guideline Development Group in order to include recommendations on contraceptive eligibility within the revised MEC.
We searched PubMed and Cochrane Library databases to identify all relevant evidence published in peer-reviewed journals regarding the safety of DMPA-SC when used by women of reproductive age, particularly those with select characteristics or conditions specified in the MEC, from inception through June 2015. The quality of each individual study was assessed using the system for grading evidence developed by the United States Preventive Services Task Force.
Fourteen studies met criteria for inclusion. Ten reported results relevant to DMPA users of varying age or with obesity, endometriosis or HIV; four compared the safety of DMPA-SC and DMPA-IM when used by general populations of healthy women. A randomized trial evaluating changes in bone mineral density among adult DMPA-SC and DMPA-IM users demonstrated no differences at 2years of follow-up. Limited evidence reported no consistent differences in weight change or bleeding patterns according to age; however, adolescents (<18years) were not included in any studies. Similar contraceptive efficacy, weight change, bleeding patterns and occurrence of other adverse effects among obese and nonobese DMPA-SC users were observed. Women with endometriosisusing DMPA-SC over 6months had minimal decreases in bone mineral density, weight gain, few serious adverse events and experienced improved pain symptoms. Women living with HIV tolerated injection of DMPA-SC with rare complications. DMPA-SC and DMPA-IM also show therapeutic equivalence and similar effects on weight gain, changes in bleeding patterns and reports of other adverse effects when these different delivery systems were used by general populations of women.
Evidence for use of DMPA-SC by women with select conditions and characteristics including age, obesity, endometriosis or HIV demonstrates that this method can generally be used safely in these contexts. Further, DMPA-SC and DMPA-IM appear to be therapeutically equivalent with similar safety profiles when used by healthy women.
Hum Reprod. 2016 Apr;31(4):723-33.
Elevated phosphatase of regenerating liver 3 (PRL-3) promotes cytoskeleton reorganization, cell migration and invasion in endometrial stromal cells from endometrioma.
Is phosphatase of regenerating liver-3 (PRL-3) associated with increased motility of endometriotic cells from endometrioma?
Elevated PRL-3 promotes cytoskeleton reorganization, cell migration and invasion of endometrial stromal cells (ESCs) from endometrioma.
WHAT IS KNOWN ALREADY:
Overexpression of PRL-3 is associated with cancer cell migration, invasion and metastatic phenotype.
STUDY DESIGN, SIZE, DURATION:
Primary human ESCs were isolated from eutopic endometrium of women without endometriosis (EuCo, n = 10), with histologically proven endometrioma (EuEM, n = 19) and from the cyst wall of ovarian endometriosis (OvEM, n = 26).
PARTICIPANTS/MATERIALS, SETTING, METHODS:
The expression of PRL-3 in ESCs derived from EuCo, EuEM and OvEM at different phases of menstrual cycle were compared. The protein and mRNA levels of PRL-3 were examined by western blot and RT-qPCR, respectively. ESCs from OvEM were transfected with/without short hairpin RNA (shRNA) or small interfering RNA (siRNA). Additionally, a plasmid-mediated delivery system was used to achieve PRL-3 overexpression in ESCs from EuEM. The cellular distribution of F-actin and α-tubulin were examined by immunocytochemistry. Cell motility was evaluated by a transwell migration/invasion assay.
MAIN RESULTS AND THE ROLE OF CHANCE:
The protein and mRNA levels of PRL-3 are significantly elevated in ESCs from OvEM compared with EuCo and EuEM. The expression of PRL-3 was not altered between proliferative phase and secretory phase in ESCs from all groups. Knockdown of PRL-3 significantly modified the distribution of F-actin and α-tubulin cytoskeleton, inhibited cell migration and invasion. Endogenous inhibition of PRL-3 attenuated the expression of Ras homolog gene family members A and C (RhoA, RhoC), Rho-associated coiled-coil-containing protein kinase 1 (ROCK1) and matrix metalloproteinase (MMP) 9, but not MMP2 in ESCs from OvEM. Additionally, overexpression of PRL-3 in ESCs from EuEM up-regulates cell migration and invasion, and increases the expression of RhoA, RhoC, ROCK1 and MMP9.
LIMITATIONS, REASONS FOR CAUTION:
Lack of in vivo animal studies is the major limitation of our report. Our results should be further confirmed in a larger cohort of patients and extended to include eutopic and ectopic endometrium from patients with peritoneal endometriosis at different stages of the disease.
WIDER IMPLICATIONS OF THE FINDINGS:
Our study describes that elevated expression of PRL-3 contributes to the cell motility of ESCs from endometrioma. The results emphasize the importance of metastatic-related factor PRL-3 in the pathogenesis of endometrioma.
STUDY FUNDING/COMPETING INTEREST:
This work was supported by National Natural Science Foundation of China (No. 81170546) and Zhejiang Medicine Science and Technology Projects (No. Y13H040003). The authors declare no conflict of interest.
J Gynecol Obstet Biol Reprod (Paris). 2016 Mar;45(3):214-25
Pictures balance for optimal surgical management of pelvic endometriosis. Imaging and surgery of endometriosis.
Endometriosis is a frequent benign pathology that is found in 10-15% of women and in 20% of infertile women. It has an impact on fertility, but also in everyday life. If medical treatment fails, surgical treatment can be offered to the patient. To provide adequate treatment and give clearer information to patients, it seems essential to achieve an optimal preoperative imaging assessment. Thus, the aim of this work is to define the information expected by the surgeon and the indications of each imaging test for each compartment of the pelvis, allowing an ideal surgical management of pelvic endometriosis. We will not discuss imaging techniques’ principles and we will not develop the indications and surgical techniques.