Fertil Steril. 2009 Mar 30. [Epub ahead of print]Interleukin-4 induces expression of eotaxin in endometriotic stromal cells.Ouyang Z, Osuga Y, Hirota Y, Hirata T, Yoshino O, Koga K, Yano T, Taketani Y.Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Japan.OBJECTIVE: To study the relationship between eotaxin and ...
World J Psychiatry. 2016 Sep 22;6(3):339-44.
Chronic pelvic pain, psychiatric disorders and early emotional traumas: Results of a cross sectional case-control study.
To compare the prevalence of psychiatric disorders and early emotional traumas between women with chronic pelvic pain (CPP) and healthy women.
One hundred women in reproductive age, 50 of them had CPP (according to the criteria set by the International Association for Study of Pain), and 50 were considered healthy after the gynecological evaluation. The eligibility criteria were defined as follows: chronic or persistent pain perceived in the pelvis-related structures (digestive, urinary, genital, myofascial or neurological systems). Only women in reproductive age with acyclic pain for 6 mo, or more, were included in the present study. Menopause was the exclusion criterion. The participants were grouped according to age, school level and socio-economic status and were individually assessed through DSM-IV Structured Clinical Interview (SCID-I) and Early Trauma Inventory Self-report – short form (ETISR-SF Brazilian version). Descriptive statistics, group comparison tests and multivariate logistics regression were used in the data analysis.
The early emotional traumas are highly prevalent, but their prevalence did not differ between the two groups. The current Major Depressive Disorder was more prevalent in women with CPP. The CPP was associated with endometriosis in 48% of the women. There was no difference in the prevalence of disorders when endometriosis was taken into account (endometriosis vs other diseases: P > 0.29). The current Major Depressive Disorder and the Bipolar Disorder had greater occurrence likelihood in the group of women with CPP (ODDS = 5.25 and 9.0).
The data reinforce the link between mood disorders and CPP. The preview evidences about the association between CPP and early traumas tended not to be significant after a stronger methodological control was implemented.
Hum Reprod. 2016 Nov;31(11):2520-2526
Intrauterine administration of hCG immediately after oocyte retrieval and the outcome of ICSI: a randomized controlled trial.
Does the intrauterine administration of hCG immediately after oocyte retrieval in antagonist cycles with ICSI and fresh embryo transfer (ET) influence the implantation rate or chemical and clinical pregnancy rates?
The intrauterine administration of hCG after oocyte retrieval increases the implantation rate and chemical and clinical pregnancy rates.
WHAT IS KNOWN ALREADY:
Over half of IVF/ICSI cycles fail due to implantation failure. Intrauterine administration of hCG, a few minutes before ET, increased the implantation and pregnancy rates in most but not in all studies. The effect of intrauterine administration of hCG, after oocyte retrieval, has not yet been studied.
STUDY DESIGN, SIZE, DURATION:
The study was a parallel, triple-blind randomized clinical trial (RCT) performed from September 2015 to February 2016, in a university hospital. We recruited women undergoing antagonist ovarian stimulation, ICSI and ET. For an effect size of 0.2, power of 80% at a significance level of 0.05, we needed 150 participants. Accounting for a 7% dropout rate, a total of 160 women was considered appropriate. A computer-generated randomization list with a block size of 4, with 1:1 allocation was used. The treatment allocation was placed in a sealed, opaque, envelope and picked up consecutively. Immediately after oocyte retrieval, patients in the intervention and control groups were treated with intrauterine injection of hCG and saline, respectively. Participants underwent ET on Day 3. A beta-hCG test was done at 2 weeks. If positive, three transvaginal-ultrasonographies (TVSs) were done at 3, 4 and 10 weeks after ET. The participants were called up thereafter and questioned about the continuity of their pregnancy.
PARTICIPANTS/MATERIALS, SETTING, METHOD:
Of 1990 women attending the infertility clinic of our university hospital, 508 were IVF/ICSI candidates during the study period, and 245 of the patients on an antagonist cycle met the criteria to be invited into our trial. Inclusion criteria were normal ovarian reserve, age ≤41, undergoing ICSI, and fresh ET and normal TSH and prolactin. Uncontrolled chronic disease, severe hydrosalpinx, severe endometriosis, morphologic embryo deficiencies, non-obstructive azospermia and high risk of severe ovarian hyperstimulation syndrome were criteria for exclusion. After taking an informed consent, a total of 158 participants were recruited, of which 80 were randomly allocated to receive intrauterine 500 IU hCG in up to 0.5 ml normal saline and 78 to receive intrauterine 0.5 ml normal saline immediately after oocyte retrieval, during general anaesthesia. ICSI was performed conventionally. The 4-8 cell embryos were transferred on the third day after oocyte retrieval. Implantation rate, chemical and clinical pregnancy rates were analysed and compared between the two groups.
MAIN RESULTS AND THE ROLE OF CHANCE:
Patients’ demographic and baseline characteristics were comparable. The clinical results showed statistically significant differences between the two groups regarding the biochemical pregnancy rate (59.2 versus 31.3%; P = 0.001; odds ratio (OR) = 1.88; 95% CI, 1.26-2.82; risk difference (RD) = 27.8; 95% CI, 11.2-42.3), implantation rate (37 versus 17%; P = 0.012; OR = 2.29; 95% CI, 1.02-5.14; RD = 20.2; 95% CI, 5.4-33.8), clinical pregnancy rate (50.7 versus 16.4%; P < 0.001; OR = 3.08; 95% CI, 1.71-5.55; RD = 34.3; 95% CI, 18.7-47.6) and ongoing pregnancy rate (40.1 versus 13.4%; P = 0.001; OR = 3.04; 95% CI, 1.55-5.93; RD = 27.4; 95% CI, 12.7-40.6). The abortion and ectopic pregnancy rates were not statistically different between the two groups.
LIMITATIONS, REASONS FOR CAUTION:
The insertion of an intrauterine insemination catheter and the injection of a small amount of saline into the uterine cavity (without hCG) may also have some impact on implantation. This effect could be studied by comparing this intervention with another study group without any intrauterine injection.There are no specific side effects mentioned in the literature for the intrauterine administration of hCG, neither were any observed in our study, but it is best to be cautious about probable side effects, because this type of intervention is relatively new and experimental, and deserves more studies before being entered into routine clinical practice.
WIDER IMPLICATIONS OF THE FINDINGS:
Intrauterine administration of hCG immediately after oocyte pick up increases its effectiveness; however, further investigations are required before this procedure can be recommended for clinical practice.
STUDY FUNDING/COMPETING INTERESTS:
This study was supported by the Women’s Health Research Center, Tabriz University of Medical Sciences, Iran. No external funds were used. The authors have no conflicts of interest to declare.
Nature. 2016 Oct 13;538(7624):248-252.
Genome-wide associations for birth weight and correlations with adult disease.
Horikoshi M#1,2, Beaumont RN#3, Day FR#4, Warrington NM#5,6, Kooijman MN#7,8,9, Fernandez-Tajes J#1, Feenstra B10, van Zuydam NR1,2, Gaulton KJ1,11, Grarup N12, Bradfield JP13, Strachan DP14, Li-Gao R15, Ahluwalia TS12,16,17, Kreiner E16, Rueedi R18,19, Lyytikäinen LP20,21, Cousminer DL22,23,24, Wu Y25, Thiering E26,27, Wang CA6, Have CT12, Hottenga JJ28, Vilor-Tejedor N29,30,31, Joshi PK32, Boh ETH33, Ntalla I34,35, Pitkänen N36, Mahajan A1, van Leeuwen EM8, Joro R37, Lagou V1,38,39, Nodzenski M40, Diver LA41, Zondervan KT1,42, Bustamante M29,30,31,43, Marques-Vidal P44, Mercader JM45, Bennett AJ2, Rahmioglu N1, Nyholt DR46, Ma RCW47,48,49, Tam CHT47, Tam WH50; CHARGE Consortium Hematology Working Group, Ganesh SK51, van Rooij FJ8, Jones SE3, Loh PR52,53, Ruth KS3, Tuke MA3, Tyrrell J3,54, Wood AR3, Yaghootkar H3, Scholtens DM40, Paternoster L55,56, Prokopenko I1,57, Kovacs P58, Atalay M37, Willems SM8, Panoutsopoulou K59, Wang X33, Carstensen L10, Geller F10, Schraut KE32, Murcia M31,60, van Beijsterveldt CE28, Willemsen G28, Appel EVR12, Fonvig CE12,61, Trier C12,61, Tiesler CM26,27, Standl M26, Kutalik Z19,62, Bonas-Guarch S45, Hougaard DM63,64, Sánchez F45,65, Torrents D45,66, Waage J16, Hollegaard MV63,64, de Haan HG15, Rosendaal FR15, Medina-Gomez C7,8,67, Ring SM55,56, Hemani G55,56, McMahon G56, Robertson NR1,2, Groves CJ2, Langenberg C4, Luan J4, Scott RA4, Zhao JH4, Mentch FD13, MacKenzie SM41, Reynolds RM68, Lowe WL Jr69, Tönjes A70, Stumvoll M58,70, Lindi V37, Lakka TA37,71,72, van Duijn CM8, Kiess W73, Körner A58,73, Sørensen TI55,56,74,75, Niinikoski H76,77, Pahkala K36,78, Raitakari OT36,79, Zeggini E59, Dedoussis GV35, Teo YY33,80,81, Saw SM33,82, Melbye M10,83,84, Campbell H32, Wilson JF32,85, Vrijheid M29,30,31, de Geus EJ28,86, Boomsma DI28, Kadarmideen HN87, Holm JC12,61, Hansen T12, Sebert S88,89, Hattersley AT3, Beilin LJ90, Newnham JP6, Pennell CE6, Heinrich J26,91, Adair LS92, Borja JB93,94, Mohlke KL25, Eriksson JG95,96,97, Widén EE22, Kähönen M98,99, Viikari JS100,101, Lehtimäki T20,21, Vollenweider P44, Bønnelykke K16, Bisgaard H16, Mook-Kanamori DO15,102,103, Hofman A7,8, Rivadeneira F7,8,67, Uitterlinden AG7,8,67, Pisinger C104, Pedersen O12, Power C105, Hyppönen E105,106,107, Wareham NJ4, Hakonarson H13,23,108, Davies E41, Walker BR68, Jaddoe VW7,8,9, Jarvelin MR88,89,109,110, Grant SF13,23,108,111, Vaag AA83,112, Lawlor DA55,56, Frayling TM3, Davey Smith G55,56, Morris AP1,113,114, Ong KK4,115, Felix JF7,8,9, Timpson NJ55,56, Perry JR4, Evans DM5,55,56, McCarthy MI1,2,116, Freathy RM3,55.
Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10-13), T2D (Rg = -0.27, P = 1.1 × 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 × 10-9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.
Geburtshilfe Frauenheilkd. 2016 Sep;76(9):960-963.
Osteopathy for Endometriosis and Chronic Pelvic Pain – a Pilot Study.
Introduction: Pelvic pain is a common problem in gynaecological practice. It is often unclear whether definite causality exists between reported symptoms and objective clinical findings of the female genital tract, and medical or operative treatments do not always achieve long-term resolution of symptoms. Methods: This pilot study investigated 28 patients (age 20-65, median 36.5 years) from a gynaecology practice whose only clinical finding was painful pelvic floor muscle tightness. Following standardised gynaecological and physiotherapist examination, all patients received osteopathic treatment. Pain had been present for a median of 3 years (range 1 month to 20 years). 14 patients had previously confirmed endometriosis. Treatment success was evaluated on consultation with patients in person or in writing. Results: 22 of the 28 participants completed the treatment according to plan. Overall, 17 reported symptom improvement, while 10 of the 14 patients with endometriosis did. Conclusion: Osteopathy is well received by women with painful pelvic floor muscle tightness and appears to be an effective treatment option.
Schmerz. 2016 Oct;30(5):477-490.
Endometriosis : An often unrecognized pain disorder.
Endometriosis is a chronic disease of women during their reproductive age. The most typical symptoms are dysmenorrhoea, dyspareunia, dysuria, cyclical and acyclical pelvic pain, bleeding disorders and infertility. These symptoms lead to significant impairment of the quality of life and economic burden. The prevalence is estimated to be 2-20 % of all women in this age and due to this fact, it is one of the most frequently benign gynecological diseases. Not all women suffer from severe symptoms, but more than 50 % require ongoing treatment. Beside the severe physical impairment due to the pain, the high recurrence rate of 50-80 % also after surgical and/or hormonal treatment is problematic. The interval between onset of symptoms and diagnosis is approximately 6-8 years. These problems are a consequence of lack of knowledge about the pathogenesis of the disease and the pain mechanisms as well as the lack of awareness of physicians in this field.
J Pak Med Assoc. 2016 Oct;66(10):1327-1329.
Catamenial pneumothorax: A case report.
Catamenial pneumothorax (CP) is a rare and complex clinical condition caused by endometrial tissues, commonly found in reproductive women (age 15-49 years).Its diagnosis is often delayed or overlooked by clinicians, which may result in recurrent hospitalizations and other complications. A case of Catamenial pneumothorax is presented of a 38-year-old young married woman, admitted to hospital with signs and symptoms including chest pain and shortness of breath that started with her menstrual period. Right pneumothorax was observed in the Chest x-ray. Patient underwent Video-assisted thoracoscopic surgery (VATS). Patient was kept under observation, and was discharged when stable with no pain.Catamenial pneumothorax is still considered to be a mysterious disease and difficult to diagnose. Surgery is the best treatment.
Acta Obstet Gynecol Scand. 2017 Jun;96(6):668-687.
When love hurts. A systematic review on the effects of surgical and pharmacological treatments for endometriosis on female sexual functioning.
Endometriosis is associated with an increased risk of dyspareunia, therefore this chronic gynecologic disease should be considered as a major cause of sexual dysfunctions. The aims of this study were to review the literature on the effects of surgical and pharmacological treatments for endometriosis on female sexual functioning, and to provide suggestions for future treatment strategies.
MATERIAL AND METHODS:
We followed the PRISMA guidelines to conduct this systematic review, which involved an electronic database search of studies on the association between endometriosis and sexuality published between 2000 and 2016.
As a result of the screening process, 22 studies were included in this systematic review. The 22 studies included were divided into two categories: (a) surgical intervention studies (n = 17), examining postoperative sexual outcomes of surgery for endometriosis; (b) pharmacological intervention studies (n = 5), evaluating the effects of pharmacological endometriosis treatments on sexual functioning. The studies considered showed that overall surgical and pharmacological interventions for endometriosis can lead to medium-/long-term improvement, but not necessarily to a definitive resolution of female sexual dysfunctions due to endometriosis.
Sexual functioning is a multidimensional phenomenon and the ideal treatment for endometriosis-related sexual dysfunctions should be conducted by a multidisciplinary team that involves not only gynecologists, but also sexologists and psychologists/psychotherapists. Improving global sexual functioning, and not just reducing pain at intercourse, should be considered as a major clinical goal of endometriosis treatment.
Auton Neurosci. 2016 Dec;201:49-53
Reinnervation of rat endometrium in the anterior eye chamber model of experimental endometriosis: Old methods for new questions.
Endometriosis is a benign estrogen-dependent chronic gynecological disease characterized by the presence of endometrial-like tissue outside the uterine cavity. In both women and experimental endometriotic rats, endometriosis lesions endow autonomic and sensory nerves, which are thought to contribute to the disease-associated pain. Some evidence indicates that the reinnervation of lesions is regulated by factors produced by the endometrial tissue as well as by environmental factors from the peritoneum. In this study, we examined the reinnervation of the rat endometrial tissue in an ectopic environment different from the peritoneum employing the anterior eye chamber model of experimental endometriosis. At 3 and 6weeks following transplantation, endometrial grafts retained many histological features of the eutopic tissue. Both sympathetic and sensory nerves reinnervated endometrial grafts and distributed in the stroma-like tissue, around blood vessels and in close proximity to the glands and lining epithelium. Sympathetic innervation was more robust than sensory innervation. No significant topographical relationship between sympathetic nerves and macrophages was observed. These results suggest that the rat endometrium possesses intrinsic neuritogenic capacities and can be reinnervated by sympathetic and sensory nerves in ectopic sites different from the peritoneum.
Reprod Sci. 2017 Jun;24(6):829-835
Endometriosis-Derived Thromboxane A2 Induces Neurite Outgrowth.
Hyperinnervation in endometriosis is now well documented, but so far only a few neurotrophins have been identified. Since endometriotic stromal cells secrete thromboxane A2 (TXA2), we sought to determine whether TXA2, derived from endometriotic stromal cells, induces neurite outgrowth. Using primary sensory neurons derived from rat dorsal root ganglia (DRG) and ectopic endometrial stromal cells (EESCs) derived from human ovarian endometrioma tissues, we treated the primary neurons with different concentrations of U-46619, a stable TXA2 mimetic, and performed a neuronal growth assay. The primary neurons were also cocultured with a vehicle, nerve growth factor (NGF, serving as a positive control), the supernatant of EESC culture medium, or the supernatant of EESCs pretreated with ozagrel, a thromboxane synthase inhibitor, and a neuronal growth assay was performed. The total neurite length was evaluated through immunofluorescence microscopy. We found that U-46619 significantly increased the neurite outgrowth in DRG neurons in a concentration-dependent fashion ( P < .001). It also increased the number of neurite ends in a concentration-dependent fashion. Ozagrel treatment alone had no effect on the neurite growth ( P > .05), and the treatment with the supernatant of EESCs induced neurite outgrowth just as potently as that treated with NGF (positive control; P > .05). Remarkably, treatment with the EESC supernatant increased the neurite outgrowth by nearly 3-fold as compared with the control ( P < .01), but the pretreatment with ozagrel abolished the stimulatory effect of the EESC by 31.3% ( P < .05). These findings indicate that EESCs potently induce neurite outgrowth, and endometriosis-derived TXA2 is responsible, at least in part, for this neurotrophic effect.
Int J Surg Case Rep. 2016;28:65-67
Sigmoid endometriosis in a post-menopausal woman leading to acute large bowel obstruction: A case report.
Endometriosis is usually a disease involving women of reproductive age. Colonic endometriosis is a rare sequelae. It usually presents vaguely with nonspecific abdominal pain, dyspareunia, fecal tenesmus, rectal bleeding or painful defecation. There are very few case reports of sigmoid endometriosis in the literature, more so ones involving post-menopausal women. Our report highlights such a case, mimicking a malignant rectosigmoid stricture leading to a large bowel obstruction.
A 63year old lady was referred by her General Practitioner for further investigation of recent altered bowel habit. She underwent an incomplete colonoscopy due to stricturing in the sigmoid. She subsequently was admitted with abdominal pain, distension and vomiting, with imaging consistent with a large bowel obstruction secondary to a stricturing mass within the rectosigmoid which was suspicious for malignancy. An emergency laparotomy and Hartmann’s procedure was performed. She had an uncomplicated post-surgical recovery. Histology revealed no underlying malignancy, but confirmed colonic endometriosis.
This case report shows that colonic endometriosis, although rare, can be significantly infiltrative and lead to complications such as a large bowel obstruction. Diagnosing this condition can be challenging and usually requires histological confirmation.
Int J Surg Case Rep. 2016;28:78-80.
Primary umbilical endometriosis: A painful swelling in the umbilicus concomitantly with menstruation.
Primary umblikal endometriosis is a rare illness. In this report we aimed to discuss the management of this rare condition.
A 28-year-old nulliparous woman was present at our clinic who was suffering from painful swelling in the umbilicus during her menstruation for the last 3 months. Her examination showed a dark-color sensitive nodule of 20×15mm in size in the umbilicus. A lower abdominal tomography was performed to exclude the presence of a concomitant pelvic endometriosis, and it showed increased density consistent with subcutaneous inflammation in the umbilicus. Her medical history and physical examination suggested primary umbilical endometriosis. A total resection including umbilicus was performed.
Primary umbilical endometriosis is a rare benign disease and clinically difficult to differentiate from other diseases that cause umbilical nodule. Imaging modalities have no pathognomonic findings for diagnosis. Surgical exploration and excision are the definitive and safe treatment of primary umbilical endometriosis.
Total umbilical resection should be preferred to avoid local recurrent.
J Minim Invasive Gynecol. 2017 Jan 1;24(1):114-123.
Ultrastructural Investigation of Pelvic Peritoneum in Patients With Chronic Pelvic Pain and Subtle Endometriosis in Association With Chromoendoscopy.
To evaluate the pelvic peritoneum under chromoendoscopy by scanning electron microscopy (SEM) as well as light microscopy with hematoxylin and eosin staining and immunohistochemistry (IHC) assays in patients with chronic pelvic pain (CPP) associated with subtle endometriosis.
Case series study (Canadian Task Force classification II).
A referral academic community tertiary medical center.
Three women aged 29 to 37 years were referred to the obstetrics and gynecology clinic of the tertiary university hospital with CPP. They were suspicious for endometriosis, were not responding to medical treatments, and had undergone previous pelvic laparoscopy to determine the stage of endometriosis and preparation of peritoneal samples under the guidance of staining with methylene blue in 0.25% dilution.
Comparison of stained and unstained pelvic peritoneal samples after the instillation of 0.25% methylene blue into the pelvic cavity.
MEASUREMENTS AND MAIN RESULTS:
In 3 patients, laparoscopic examination showed minimal endometriosis. A total of 18 samples (9 stained and 9 unstained) from the 3 patients were prepared for SEM. Ten of the samples (55.6%) showed microstructural peritoneal destruction (7 of 9 stained [77.7%] and 3 of 9 [33.4%] unstained). Eighteen samples (9 stained and 9 unstained) from the 3 patients were also prepared for IHC. Six of these samples (33.3%) were S-100-positive, including 4 of 9 (44.4%) stained samples and 2 of 9 (22.2%) unstained samples.
In general, in the context of CPP and endometriosis, there is no established relationship between the severity of pain and stage of endometriosis. In the pathophysiology of CPP associated with endometriosis, ultrastructural changes can play a significant role. Under methylene blue staining, some destroyed areas were detected, but the stained areas do not necessarily correlate with increased microstructural peritoneal destruction.
Reprod Sci. 2017 Jun;24(6):836-843.
Silencing of SRA1 Regulates ER Expression and Attenuates the Growth of Stromal Cells in Ovarian Endometriosis.
Estradiol and its nuclear receptors, estrogen receptor (ER) α and ER-β, have important functions in endometriosis, and the transcriptional activity of these receptors is modulated by coactivators and corepressors. The steroid receptor RNA activator 1 (SRA1) produces SRA long noncoding RNA (lncRNA) and SRA protein (SRAP), which regulate ER expression at the RNA and protein levels in some hormone-dependent tumors via an alternative splicing event. However, only a few are reported on their expressions in endometriosis. Here, we observed that low expression levels of SRA lncRNA and ER-α but relatively high expression levels of SRAP and ER-β were detected in ovarian endometriotic tissues versus normal endometrial tissues. Steroid receptor RNA activator 1-small interfering RNA treatment significantly increased ER-α levels but reduced ER-β levels in endometriotic stromal cells (ESCs). Furthermore, the treatment can also attenuate the proliferation and promote early apoptosis in these cells. Our results indicate that the regulation of ER via SRA in ovarian endometriosis may play a significant role in the growth of ESCs.
PLoS One. 2016 Oct 3;11(10):e0163540.
Regulation of Matrix Metalloproteinase-2 Activity by COX-2-PGE2-pAKT Axis Promotes Angiogenesis in Endometriosis.
Endometriosis is characterized by the ectopic development of the endometrium which relies on angiogenesis. Although studies have identified the involvement of different matrix metalloproteinases (MMPs) in endometriosis, no study has yet investigated the role of MMP-2 in endometriosis-associated angiogenesis. The present study aims to understand the regulation of MMP-2 activity in endothelial cells and on angiogenesis during progression of ovarian endometriosis. Histological and biochemical data showed increased expressions of vascular endothelial growth factor (VEGF), VEGF receptor-2, cycloxygenase (COX)-2, von Willebrand factor along with angiogenesis during endometriosis progression. Women with endometriosis showed decreased MMP-2 activity in eutopic endometrium as compared to women without endometriosis. However, ectopic ovarian endometrioma showed significantly elevated MMP-2 activity with disease severity. In addition, increased MT1MMP and decreased tissue inhibitors of metalloproteinases (TIMP)-2 expressions were found in the late stages of endometriosis indicating more MMP-2 activation with disease progression. In vitro study using human endothelial cells showed that prostaglandin E2 (PGE2) significantly increased MMP-2 activity as well as tube formation. Inhibition of COX-2 and/or phosphorylated AKT suppressed MMP-2 activity and endothelial tube formation suggesting involvement of PGE2 in regulation of MMP-2 activity during angiogenesis. Moreover, specific inhibition of MMP-2 by chemical inhibitor significantly reduced cellular migration, invasion and tube formation. In ovo assay showed decreased angiogenic branching upon MMP-2 inhibition. Furthermore, a significant reduction of lesion numbers was observed upon inhibition of MMP-2 and COX-2 in mouse model of endometriosis. In conclusion, our study establishes the involvement of MMP-2 activity via COX-2-PGE2-pAKT axis in promoting angiogenesis during endometriosis progression.
Int J Fertil Steril. 2016 Oct-Dec;10(3):270-277.
Aromatase Inhibitors for Endometriosis-Associated Infertility; Do We Have Sufficient Evidence?
Orally active aromatase inhibitors (AIs) have gained attention for treatment of infertile women with endometriosis in whom aromatase p450 is aberrantly expressed. This review aimed to critically appraise and summarize the available evidence concerning the use of AIs for management of endometriosis-associated infertility. PubMed was searched to May 2015 with the following key words: endometriosis, infertility and aromatase. Priority was given for randomized controlled trials (RCTs) followed by other study designs. Main outcome measures were as follows: rates of clinical pregnancy, miscarriage and live birth as well as endocrine outcomes. Eighty-two abstracts were screened and six original articles were included. A RCT demonstrated that post-operative letrozole treatment did not improve spontaneous pregnancy rate. Another RCT reported no superiority of letrozole superovulation over clomiphene citrate (each combined with intrauterine insemination) in minimalmild endometriosis and previous laparoscopic treatment. Anastrozole significantly inhibited the growth of endometriotic cells and their estrogen production in culture. In assisted reproductive technology (ART) cycles, dual suppression (Agonist/anastrozole) was tested in a pilot study with a pregnancy rate of 45% however, high pregnancy loss (30%) occurred. A retrospective study showed that letrozole may improve endometrial receptivity in endometriotic patients undergoing in vitro fertilization (IVF). An opposite view from an in vitro study showed lower estradiol production and aromatase expression in cultured granulosa cells from endometriotic women undergoing IVF and marked reduction under letrozole. In conclusion, current evidence is limited. More trials are warranted to enhance our knowledge and provide a clear and unequivocal evidence to guide our clinical management of infertile women with endometriosis using AIs.
Mol Clin Oncol. 2016 Oct;5(4):395-401.
Effect of ARID1A/BAF250a expression on carcinogenesis and clinicopathological factors in pure-type clear cell adenocarcinoma of the ovary.
Frequent mutation of the ARID1A gene has been recently identified in ovarian clear-cell adenocarcinoma (CCA); however, the clinical significance of BAF250a expression encoded by the ARID1A gene remains to be determined. The aim of the present study was to assess whether BAF250a expression had an impact on the clinical features of CCA. A total of 97 cases of CCA treated at a single institution were enrolled in the present study. The tissue samples were evaluated by immunohistochemical staining. BAF250a-deficient expression was observed in 30% (29/97) of all CCA cases. Of this, 19% of non-atypical endometriosis, 26% of atypical endometriosis, 39% of endometriosis-related CCA, 5% of benign clear-cell adenofibroma (CCAF), 5% of borderline CCAF and 10% of CCAF-related CCA. BAF250a-deficient expression was significantly more frequent in endometriosis-related CCA compared with that in CCAF-related CCA (P=0.02). No significant difference was observed in the response rate of primary chemotherapy according to BAF250a expression status (P=0.48). Additionally, BAF250a expression status was not significantly correlated with progression-free and overall survival in patients with CCA. Although loss of BAF250a expression was associated with early tumorigenesis in endometriosis-related CCA, this alteration was not significantly correlated with chemosensitivity and prognoses of CCA. Further biomarker analyses, including BAF250a expression, are required to improve the prognoses of CCA.
Br J Cancer. 2016 Nov 22;115(11):1391-1399
Reproductive and hormonal factors in relation to survival and platinum resistance among ovarian cancer cases.
Ovarian cancer survival is poor, particularly for platinum-resistant cases. The previous literature on pre-diagnostic reproductive factors and ovarian cancer survival has been mixed. Therefore, we evaluated pre-diagnostic reproductive and hormonal factors with overall survival and, additionally, platinum-chemotherapy resistance.
We followed 1649 invasive epithelial ovarian cancer cases who were enrolled between 1992 and 2008 for overall mortality within the New England Case-Control Study and abstracted chemotherapy data on a subset (n=449). We assessed pre-diagnostic reproductive and hormonal factors during in-person interviews. We calculated hazard ratios (HRs) using Cox-proportional hazards models.
We observed 911 all-cause deaths among 1649 ovarian cancer cases. Self-reported endometriosis and longer duration of hormone therapy use were associated with improved survival (HR: 0.72; 95% confidence interval (CI): 0.54-0.94 and HR, ⩾5 years vs never: 0.70; 95% CI: 0.55-0.90, respectively). Older age at menopause and menarche were associated with worse survival (HR, ⩽50 vs >50 years: 1.23; 95% CI: 1.03-1.46 and HR, 13 vs <13 years: 1.24; 95% CI: 1.06-1.44, respectively). We observed no association between oral contraceptive use, parity and tubal ligation, and overall survival. No significant associations were observed for any of the reproductive and hormonal factors and platinum resistance.
These results suggest that pre-diagnostic exposures such as endometriosis and HT use may influence overall survival among ovarian cancer patients.
BJOG. 2017 Jan;124(2):306-312.
Spontaneous haemoperitoneum in pregnancy and endometriosis: a case series.
Lier M1, Malik RF1, van Waesberghe J2, Maas JW3, van Rumpt-van de Geest DA4, Coppus SF5, Berger JP6, van Rijn BB7,8, Janssen PF9, de Boer MA10, de Vries J10, Jansen FW11, Brosens IA12, Lambalk CB1, Mijatovic V1.
To report pregnancy outcomes of SHiP (spontaneous haemoperitoneum in pregnancy) and the association with endometriosis.
Retrospective case note review.
Dutch referral hospitals for endometriosis.
Eleven women presenting with 15 events of SHiP.
In collaboration with the Dutch Working Group on Endometriosis, unpublished cases of SHiP that occurred in the Netherlands between 2010 and 2015 were retrieved.
MAIN OUTCOME MEASURES:
Maternal and perinatal mortality and morbidity.
SHiP occurred predominantly in the second and third trimester of pregnancy. The earliest and major presenting symptom was an acute onset of abdominal pain, often combined with low haemoglobin levels or signs of fetal distress. Imaging was a diagnostic tool when free peritoneal fluid could be observed. For surgical treatment of the bleeding site, a midline laparotomy was mostly needed, the median estimated amount of blood loss was 2000 mL. No fetomaternal or perinatal mortality was reported, despite a high rate of preterm births (54.5%). In all women, endometriosis was diagnosed at a certain moment in time and therefore was probably involved in the pathogenesis of SHiP. Four women showed recurrence of SHiP. In one of these cases the second event of SHiP occurred in a subsequent pregnancy.
Pregnancy outcomes of SHiP are improving when compared with previous reports, with absent fetomaternal and perinatal mortality in this recent series. Growing knowledge and adequate multidisciplinary intervention may have contributed to these favourable results. Increasing awareness of this serious complication of pregnancy is advocated, especially in women diagnosed with endometriosis.
Growing awareness of SHiP is advocated, especially in women diagnosed with endometriosis.
Genet Mol Res. 2016 Aug 26;15(3).
Association of CYP1A1 (cytochrome P450) MspI polymorphism in women with endometriosis.
Endometriosis is a disease that affects 10 to 15% of the women of reproductive age. It is characterized by the presence of endometrial-like tissues outside of the uterus. Some definitions claim that the functional ectopic tissue is sensitive to the action of hormones. Severity of endometriosis is defined according to a system proposed by the American Society for Reproductive Medicine, which is based on laparoscopic findings. A large number of genetic polymorphisms has been reported for CYP1A1, the gene that is responsible for enzymes involved in stage I detoxification of xenobiotics; this gene is located at 15q22-24, and encodes an isoenzyme that catalyzes the oxidation of polycyclic aromatic hydrocarbons present in phenolic compounds and epoxides. The aim of this study was to analyze the frequency of the MspI polymorphism and its relation to endometriosis. We obtained peripheral blood samples from 52 women with endometriosis (confirmed by laparoscopy) as well as 42 women without endometriosis (control group). In the case group, the women were between 25 and 35 years of age; the age range was between 25 and 57 years old in the control group. Molecular analysis was performed by polymerase chain reaction. We found a significant association (P = 0.039) between the polymorphic allele m1 and endometriosis (32.70%). In conclusion, this study showed that the m1 polymorphism is associated with endometriosis, and that W1/m1 and m1/m1 polymorphisms are more frequently observed in patients with infertility and severe endometriosis.
J Obstet Gynaecol Res. 2016 Dec;42(12):1734-1743.
Differential micro ribonucleic acid expression profiling in ovarian endometrioma with leuprolide acetate treatment.
Micro ribonucleic acids (miRNAs) play an important pathological role in endometriosis. Leuprolide acetate, an analog of gonadotropin-releasing hormone, is widely used to treat endometriosis; however, the molecular mechanisms involved in endometriotic tissue regression remain unclear. We performed miRNA expression profiling of clinical ovarian endometrioma to obtain insight into the effects of leuprolide acetate treatment.
We obtained clinical samples from nine normal eutopic endometrium, eight ovarian endometriotic, and 12 leuprolide acetate-treated endometriotic tissues. We compared the miRNA expression profiles of the three groups by performing TaqMan Array MicroRNA Card and bioinformatic analysis.
Two miRNAs, miR-939 and miR-154, were upregulated in endometriotic tissue and downregulated in leuprolide acetate-treated endometriotic tissue. Five miRNAs (miR-146a, miR-142-3p, miR-136*, miR-125b-1* and miR-15b*) were unchanged in endometriotic tissue but were upregulated under leuprolide acetate treatment. Ingenuity pathway analysis using predicted target genes for the seven identified miRNAs suggested the involvement of a range of pathways, including axonal guidance, bone morphogenetic protein, phosphatase and tensin homolog and nitric oxide signaling; molecular mechanisms of cancer; and the adipogenesis and signal transducer and activator of transcription 3 (STAT3) pathways.
To our knowledge, this is the first report profiling the miRNAs of endometrioma under leuprolide acetate treatment. The expression of seven miRNAs was modulated, concomitant with the disease state. This result gives new insight into the effects of leuprolide acetate treatment. Further investigation using quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry will allow us to validate the results of this study and to explore new therapeutic targets and biomarkers of endometriosis.
Gynecol Obstet Invest. 2017;82(3):240-246.
Endometriotic Pain Is Associated with Adenomyosis but Not with the Compartments Affected by Deep Infiltrating Endometriosis.
The identification of presurgical clinical markers may be helpful to allow the staging of endometriosis severity. It has been suggested that pain characteristics orientate the gynecologist about the anatomical involvement of endometriosis. The study was performed to analyze the correlation between pain symptoms and the anatomical location of endometriosis.
One hundred fifty-five consecutive patients with a complete removal of deep infiltrating endometriosis (DIE) were included. Prior to surgery, data on patient and disease characteristics were obtained. The intensity of the pain symptoms was registered using a Visual Analogue Scale. The endometriotic lesions were categorized according to the Enzian morphological classification. Correlation and multivariate analysis were performed to assess the potential associations between pain characteristics (dysmenorrhea, pelvic pain, dyschezia, dyspareunia or dysuria) and the location of endometriosis or other disease-related characteristics (hematuria, rectal bleeding or adenomyosis).
Pelvic pain was significantly associated with the presence of adenomyosis. Dyschezia was correlated with rectal bleeding and dysuria with the presence of hematuria. No relationship was found between other kinds of pain and the morphological location of endometriosis or other disease-related characteristics.
Our data suggest that pelvic pain is correlated with the presence of adenomyosis in women with DIE. Further studies are required.
Mayo Clin Proc. 2016 Oct;91(10):1471-1486
Anorectal and Pelvic Pain.
Although pelvic pain is a symptom of several structural anorectal and pelvic disorders (eg, anal fissure, endometriosis, and pelvic inflammatory disease), this comprehensive review will focus on the 3 most common nonstructural, or functional, disorders associated with pelvic pain: functional anorectal pain (ie, levator ani syndrome, unspecified anorectal pain, and proctalgia fugax), interstitial cystitis/bladder pain syndrome, and chronic prostatitis/chronic pelvic pain syndrome. The first 2 conditions occur in both sexes, while the latter occurs only in men. They are defined by symptoms, supplemented with levator tenderness (levator ani syndrome) and bladder mucosal inflammation (interstitial cystitis). Although distinct, these conditions share several similarities, including associations with dysfunctional voiding or defecation, comorbid conditions (eg, fibromyalgia, depression), impaired quality of life, and increased health care utilization. Several factors, including pelvic floor muscle tension, peripheral inflammation, peripheral and central sensitization, and psychosocial factors, have been implicated in the pathogenesis. The management is tailored to symptoms, is partly supported by clinical trials, and includes multidisciplinary approaches such as lifestyle modifications and pharmacological, behavioral, and physical therapy. Opioids should be avoided, and surgical treatment has a limited role, primarily in refractory interstitial cystitis.
Int Arch Occup Environ Health. 2017 Jan;90(1):49-61
Environmental and occupational exposure to bisphenol A and endometriosis: urinary and peritoneal fluid concentration levels.
The study aimed to give a first data set of bisphenol A (BPA) levels in the peritoneal fluid of patients suffering from endometriosis and to investigate the relationship between BPA exposure and endometriosis.
A questionnaire investigating the occupational context, life environment, and habits was administered to 68 patients suffering from endometriosis and 60 endometriosis-free subjects (control group). Urine and peritoneal fluids samples were collected and analysed by GC/MSMS for BPA dosage.
Some of the investigated environmental/lifestyle risk factors (closeness to industries/activities at risk) were associated with an increase in endometriosis; smoking resulted as protective factor; others (use of food plastic boxes) did not seem to influence the onset of pathology. The association between the occupational exposure summarising all examined risk factors (working activity, personal protective equipment, seniority) and endometriosis was statistically significant (χ 2 = 5.252, p = 0.02). Contrasting results were obtained when specific activities were examined. Detectable urinary BPA levels were found in all analysed samples (patients: 1.17-12.68 pg/µl; mean ± SD, 5.31 ± 3.36 pg/µl; control group: 1.28-2.35 pg/µl; mean ± SD, 1.64 ± 0.49 pg/µl; median; 1.46 pg/µl), with a statistically significant difference between patients and controls, showing an association between BPA exposure and endometriosis. Only a few subjects from the control group supplied peritoneal fluid; hence, no comparison test with patients (range 0.39-1.46 pg/µl; mean ± SD, 0.67 ± 0.30 pg/µl; median, 0.58 pg/µl) was carried out.
Results highlight the potential association between BPA exposure and endometriosis, as well as the current lack of knowledge regarding occupational exposure to BPA and the need of epidemiological studies focused on single activities/occupations, such as housewives, cleaners, students.
Curr Oncol Rep. 2016 Nov;18(11):68.
Uterine Adenosarcoma: a Review.
Adenosarcomas are rare malignancies of the female genital tract, accounting for approximately 5 % of uterine sarcomas. Occasionally, adenosarcoma occurs in the ovaries or in extra-uterine tissue, which may be related to endometriosis. These tumors are characterized by benign epithelial elements and a malignant mesenchymal component. Pathologic diagnosis is dependent on the identification of the characteristic morphologic features. The most common immunohistochemical markers for adenosarcoma are CD10 and WT1, but these are not specific. The most frequent presenting symptom is abnormal uterine bleeding. The majority of patients present with stage I disease, with a 5-year overall survival of 60 to 80 %. Survival is influenced by the presence of myometrial invasion, sarcomatous overgrowth, lymphovascular invasion, necrosis, and the presence of heterologous elements including rhabdomyoblastic differentiation. Patients with sarcomatous overgrowth have significantly increased risk of recurrence 23 versus 77 % and decreased 5-year overall survival 50 to 60 %. Standard of care treatment is total hysterectomy with bilateral salpingo-oophorectomy without lymphadenectomy, as the incidence of lymph node metastasis is rare. Retrospective data does not support the use of adjuvant pelvic radiotherapy in uterine adenosarcomas as no survival benefit is seen. Insufficient data exists to recommend routinely neoadjuvant or adjuvant chemotherapy for uterine adenosarcomas. Limited evidence exists for the role of hormonal therapy in uterine adenosarcomas. The PIK3/AKT/PTEN pathway is mutated in ∼70 % of adenosarcomas, and this may represent a possible therapeutic target. This article reviews the current state of knowledge concerning uterine adenosarcoma and discusses the management of this rare tumor.
Ultrasound Obstet Gynecol. 2017 Oct;50(4):527-532.
PELVIC FLOOR MUSCLE DYSFUNCTION AT 3D/4D TRANSPERINEAL ULTRASOUND IN PATIENTS WITH DEEP INFILTRATING ENDOMETRIOSIS: A PILOT STUDY.
Pelvic floor muscle (PFM) dysfunction seems to play an important role in the pathophysiology of pain in women with with pelvic pain syndromes, including deep infiltrating endometriosis (DIE). The aim of the study was to evaluate static and dynamic morphometry of PFM in women affected by DIE, in comparison to asymptomatic control women, using three-dimensional (3D) and four-dimensional (4D) transperineal ultrasound.
A pilot, prospective study was conducted between March 2015 and November 2015, at our tertiary center. We enrolled 50 nulliparous patients with DIE (study group) and 35 nulliparous asymptomatic healthy women (control group). 3D/4D transperineal ultrasound examinations were performed in both groups. In particular, levator hiatal area (LHA), anteroposterior and left-right diameters were evaluated at rest, at maximum pelvic floor contraction and on maximal Valsalva manoeuvre. Persistent levator ani muscle (LAM) coactivation during Valsalva manoeuvre was also investigated.
Compared to control group, patients with DIE showed a smaller LHA at rest (p = 0.03) and during Valsalva manoeuvre (p < 0.01). Moreover, in the study group smaller changes in LHA narrowing during PFM contraction and in LHA enlargement during Valsalva manoeuvre were reported (p < 0.001 and p < 0.01, respectively). In comparison with controls women with DIE presented a higher frequency of LAM coactivation during Valsalva manoeuvre, although this did not reach statistical significance (p = 0.05).
3D and 4D transperineal ultrasound could represent an objective and non-invasive method to detect PFM dysfunction in women with DIE.
J Obstet Gynaecol Can. 2016 Oct;38(10):979-981.
Isolated Appendiceal Endometriosis.
Pain associated with appendiceal endometriosis can mimic other intra-abdominal pathology. The diagnosis is usually obvious during gross inspection of the appendix; however, the absence of classical macroscopic appearances may lead to missed cases in which the patient’s pain is misdiagnosed and inappropriately managed.
A 34-year-old woman presented with cyclical right iliac fossa pain and an elevated serum C-reactive protein of 13 mg/L (normal < 5 mg/L). Diagnostic laparoscopy showed an isolated appendiceal mass with no pelvic endometriosis, and an appendectomy was performed. Histopathology demonstrated appendiceal endometriosis without macroscopic involvement of other pelvic organs.
This case gives insight into the pathophysiology of endometriosis. We advocate routine appendectomy in women with unexplained recurrent abdominal pain because a diagnostic laparoscopy may miss isolated endometriosis of the appendix, and we now have evidence that this may have no external features suggesting the diagnosis. Additionally, endometriosis can involve the gastrointestinal tract without involvement of the reproductive organs. This is important information in the further progression of theories underlying the pathophysiology of endometriosis.
Ginekol Pol. 2016;87(9):609-616
Prevalence of cellular leiomyoma and partially cellular leiomyoma in postoperative samples – analysis of 384 cases.
The aim of the study was to evaluate the prevalence of cellular leiomyomas and partially cellular leiomyomas in postoperative samples.
MATERIAL AND METHODS:
A total of 2144 cases of uterine leiomyomas were diagnosed in postoperative samples at the Department of Obstetrics and Gynecology, RSzS, Radom, Poland, between 1998 and 2014. We analyzed 384 cases which were subdivided into 4 groups, taking into account the co-occurrence of leiomyomas and/or endometriosis. The following variables were investigated: age, weight, BMI, parity, type of surgical procedure, prevalence of atypical and borderline tumor forms, and concomitant malignancy of the reproductive system.
The prevalence of cellular leiomyomas and partially cellular leiomyomas was estimated at 17.9%. Nulliparous patients were significantly more numerous in the subgroups without endometriosis. Concomitant malignancy of the reproductive system was > 2 fold more commonin the subgroups with endometriosis as compared to the other subgroups.
The fact that cellular leiomyomas have a varying degree of cell atypia, together with clinical observations reported in the literature, support the view that cellular leiomyomas and partially cellular leiomyomas can progress to malignant leiomyosarcoma (LMS). Hysterectomy and the subsequent follow-up should be the mainstay of therapy for cellular leiomyoma. Conservative management (myomectomy) should be recommended only tothose patients who wish to preserve their fertility.
Reprod Biol Endocrinol. 2016 Oct 10;14(1):66.
Anti-platelet therapy holds promises in treating adenomyosis: experimental evidence.
Recently emerging evidence indicates that endometriotic lesions are wounds undergoing repeated tissue injury and repair (ReTIAR), and platelets induce epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT), leading ultimately to fibrosis. Due to the commonality of cyclic bleeding as in endometriosis, adenomyotic lesions are also wounds that undergo ReTIAR, and we have recently provided evidence corroborating platelet-induced EMT, FMT and fibrogenesis in adenomyosis. This study sought to evaluate the effect of antiplatelet therapy in a mouse model of adenomyosis.
Adenomyosis was induced in 57 female ICR mice with neonatal dosing of tamoxifen, while another 12 (group C) were dosed with solvent only, serving as a blank control. Starting from 4 weeks after birth, hotplate test was administrated to all mice every 4 weeks. At the 16th week, all mice with induced adenomyosis were randomly divided into 6 groups: untreated, low- and high-dose Ozagrel, low- and high-dose anti-mouse GPIbα polyclonal IgG antibody to deplete platelets, and isotype-matched inert IgG non-immune antibody. Group C received no treatment. After 3 weeks of treatment, they were hotplate tested again, their uterine horns and brains were harvested, and a blood sample was taken to measure the plasma corticosterone level by ELISA. The left uterine horn was used for immunohistochemistry analysis. The brainstem nucleus raphe magnus (NRM) sections were subjected to immunofluorescence staining for GAD65. The depth of myometrial infiltration and uterine contractility were evaluated.
We found that both Ozagrel treatment and platelet depletion dose-dependently suppressed myometrial infiltration, improved generalized hyperalgesia, reduced uterine contractility, and lowered plasma corticosterone levels, improved the expression of some proteins known to be involved in adenomyosis and slowed down the process of fibrogenesis. It also elevated the number of GAD65-expressing neurons in the brainstem NRM, possibly boosting the GABAergic inhibition of pain due to adenomyosis.
This study further provides evidence that platelets play important roles in the development of adenomyosis. Anti-platelet treatment is efficacious in suppression of myometrial infiltration, improving generalized hyperalgesia, reducing uterine hyperactivity and systemic corticosterone levels. Collectively, these results demonstrate that anti-platelet therapy seems to be promising for treating adenomyosis.
J Clin Endocrinol Metab. 2016 Dec;101(12):4752-4763.
Augmented Angiogenic Factors Expression via FP Signaling Pathways in Peritoneal Endometriosis.
Angiogenesis is required for ectopic endometrial tissue growth. Our previous studies showed that prostaglandin F2α (PGF2α) biosynthetic enzymes and receptor were markedly elevated in endometriotic lesions and that PGF2α is a potent angiogenic factor in endothelial cells.
We sought to determine whether or not the F-prostanoid receptor modulates angiogenesis in ectopic stromal cells.
Release of angiogenic factors by ectopic endometrial stromal cell primary cultures stimulated with PGF2αand exposed to agents that target PGF2α signaling was assessed.
The study was conducted in an immunology laboratory at the Centre Hospitalier Universitaire (Québec City) medical research center.
Women found to have peritoneal endometriosis during laparoscopy were included in this study.
MAIN OUTCOME MEASURE(S):
Prostaglandin E2, PGF2α, vascular endothelial cell growth factor, and CXC chemokine ligand 8 mRNA and protein; FP prostanoid receptor expression.
PGF2α markedly up-regulated prostaglandin E2, CXC chemokine ligand 8 and vascular endothelial cell growth factor secretion in endometriotic cells. This effect was suppressed in the presence of a specific F-prostanoid antagonist (AL8810) and its signaling pathway was dependent on F-prostanoid receptor variant. PGF2α can exert its proliferative and angiogenic activities either directly by stimulating endothelial cell proliferation, migration and angiogenesis through F-prostanoid receptor, or indirectly, by stimulating endometriotic stromal cells to produce potent angiogenic factors through either receptor variant.
These results show for the first time that PGF2α exerts an angiogenic effect on ectopic stromal cells, inducing the secretion of major angiogenic factors via different F-prostanoid signaling pathways. This study suggests a new interpretation of the mechanism underlying endometriosis development involving PGF2α in endometriosis-associated angio-inflammatory changes.
Reprod Sci. 2017 Apr;24(4):526-533.
Bone Marrow Stem Cell Chemotactic Activity Is Induced by Elevated CXCl12 in Endometriosis.
Endometriosis is an inflammatory gynecological disorder caused by the growth of endometrial tissue outside the uterus. Endometriosis produces chemokines, including CXCL12, that attract bone marrow cells to the lesions. In this study, we describe the expression, localization, and chemotactic activity of CXCL12 in endometriotic lesions. Biopsies were collected both from women with endometriosis undergoing laparoscopy and control endometrium from women without endometriosis. Expression of CXCl12 and CXCR4 messenger RNA was increased approximately 4- and 6-fold, respectively, in endometriosis compared to eutopic endometrium. Immunohistochemistry of lesions revealed that CXCR4 was expressed in the stroma and epithelium in both endometriosis and control eutopic endometrium. The level of CXCR4 protein expression was significantly higher in all cellular compartments of the endometriotic lesions compared to control endometrium. CXCL12 protein expression was also higher in endometriotic lesions and was greatest in the epithelial compartment. CXCL12 was increased more in the condition media of cultured endometriosis than in controls as measured by enzyme-linked immunosorbent assay. Transwell chamber migration was used to demonstrate 2-fold increased chemoattraction of mouse bone marrow stem cells toward CXCL12 in the endometriotic-conditioned medium compared with eutopic endometrium. Our results indicate that a preferential recruitment of stem cells to endometriosis can explain how endometriosis outcompetes eutopic endometrium in recruiting the limited supply of circulating stem cells. The CXCL12/CXCR4 signaling axis is a potential target for the treatment of endometriosis and its associated disorders.
Hum Reprod. 2016 Dec;31(12):2689-2703.
Uterine fibroids and cardiovascular risk.
Uimari O1,2,3,4,5, Auvinen J6,7, Jokelainen J6,7, Puukka K3,8, Ruokonen A3,8, Järvelin MR6,7, Piltonen T9,2,3, Keinänen-Kiukaanniemi S6,7, Zondervan K4,5, Järvelä I9,2,3, Ryynänen M9,2,3, Martikainen H9,2,3.
Are uterine fibroids associated with increased cardiovascular risk?
This study reports an association between increased serum lipids and metabolic syndrome with an increased risk of uterine fibroids.
WHAT IS KNOWN ALREADY:
Recent studies suggest similarities in biological disease mechanisms and risk factors for fibroids and atherosclerosis: obesity, hypertension and abnormal serum lipids. These findings are awaiting confirmation that a population-based follow-up study could offer with extensive health examination data collection linked with a national hospital discharge register.
STUDY DESIGN, SIZE, DURATION:
The Northern Finland Birth Cohort (NFBC1966) is a population-based long-term follow-up study including all children with estimated date of delivery in 1966 in the Northern Finland area. The data were collected from national registries, postal questionnaires and clinical health examinations. The study population for this study comprised all females included in the NFBC1966 that underwent an extensive clinical health examination at age 46 years (n = 3635).
PARTICIPANTS/MATERIALS, SETTING, METHODS:
All females included in the NFBC1966 who were alive and traceable (n = 5118) were invited for the 46-year follow-up study; 3268 (63.9%) responded, returned the postal questionnaire and attended the clinical examination. Uterine fibroid cases were identified through the national hospital discharge register that has data on disease diagnoses based on WHO ICD-codes. Uterine fibroid codes, ICD-9: 218 and ICD-10: D25 were used for case identification. Self-reported fibroid cases were identified through the postal questionnaire.
MAIN RESULTS AND THE ROLE OF CHANCE:
A total of 729 fibroid cases were identified, including 293 based on hospital discharge registries. With adjustment for BMI, parity, education and current use of exogenous hormones the risk of prevalent fibroids rose significantly for every 1 mmol/l increase in LDL (OR = 1.13, 95% CI: 1.02-1.26 for all cases) and triglycerides (OR = 1.27, 95% CI: 1.09-1.49 for all cases). Metabolic syndrome associated with hospital discharge-based fibroid diagnosis (OR = 1.48, 95% CI: 1.09-2.01). Additionally every 1 unit increase in waist-hip ratio associated with fibroids (OR = 1.32, 95% CI: 1.10-1.57).
LIMITATIONS, REASONS FOR CAUTION:
The case ascertainment may present some limitations. There was likely an under-identification of cases and misclassification of some cases as controls; this would have diluted the effects of reported associations. The data analysed were cross-sectional and therefore cause and effect for the associations observed cannot be distinguished.
WIDER IMPLICATIONS OF THE FINDINGS:
Increased serum lipids and metabolic syndrome are associated with increased risk of uterine fibroids. Along with central obesity these findings add to an increased risk for cardiovascular disease among women with fibroids. These observations may suggest that there are shared predisposing factors underlying both uterine fibroids and adverse metabolic and cardiac disease risk, or that metabolic factors have a role in biological mechanisms underlying fibroid development.
STUDY FUNDING/COMPETING INTERESTS:
This study was supported by the Academy of Finland, University Hospital Oulu, University of Oulu, Finland, Northern Finland Health Care Foundation, Duodecim Foundation, ERDF European Regional Development Fund-Well-being and health: Research in the Northern Finland Birth Cohort 1966. The authors declare no conflict of interest.
Acta Radiol Open. 2016 Sep 25;5(9):2058460116669385.
A rare case of pancreatic endometriosis in a postmenopausal woman and review of the literature.
Pancreatic endometriosis is very rare with only a few cases reported in the literature. The imaging features are non-specific and the definitive diagnosis is usually only established after surgery. We report on a 68-year-old woman with left upper quadrant pain who demonstrated a mass in the pancreatic tail on imaging. Laboratory results showed only mildly elevated liver enzymes, tumor markers were within the normal range. A left pancreatectomy was performed, frozen section suggesting a benign lesion, and final histopathology confirmed endometriotic cysts. A research of the literature found only eight reported cases of endometriotic cysts of the pancreas, with the majority affecting premenopausal women. Preoperative diagnosis is challenging and most patients undergo resection because of suspected neoplasm. Thorough diagnostic workup may help in avoiding extensive surgery and reduce postoperative complications.
Reprod Sci. 2017 Jun;24(6):911-918.
Oral Administration of Pentoxifylline Reduces Endometriosis-Like Lesions in a Nude Mouse Model.
Recent reports consider endometriosis to be an immunological disorder, thus suggesting potential efficacy of immunomodulators for its treatment. The aim of this study was to assess the effects of oral administration of pentoxifylline on endometriosis-like lesions in a heterologous mice model.
Human endometrial tissue obtained from women (n = 5) undergoing surgery for benign conditions was implanted in nude female mice (n = 30). The animals were distributed into 3 experimental groups receiving: saline 0.1 mL/d (control, group 1); pentoxifylline 100 mg/kg/d (group 2), and pentoxifylline 200 mg/kg/d (group 3). After 28 days, the number of implants and the total volume of surgically extracted tissue were recorded. Immunohistochemical analysis was performed to assess the area of endometriosis and vascularization of endometriosis-like lesions. Cytokine levels in peritoneal fluid samples were measured.
Macroscopic quantification showed a trend to dose-dependent reduction in the number of the endometriosis-like lesions after 28 days. The volume was significantly reduced in group 3 versus group 2 and controls (399.10 ± 120.68 mm3 vs 276.75 ± 94.30 mm3 and 145.33 ± 38.20 mm3, respectively; P = .04). Similarly, the mean area of endometriosis was significantly lower in group 3 (0.12 ± 0.08 mm2) versus group 2 (1.35 ± 0.43 mm2) and control (2.84 ± 0.60 mm2; P = .001). Vascularization and cytokine levels were also reduced posttreatment.
Our results suggest that the oral administration of pentoxifylline may be an alternative to current therapies for endometriosis. Nonetheless, further studies are required.
J Clin Psychol Med Settings. 2016 Dec;23(4):410-419.
Temperament, Beliefs About Pain Control, and Pain Intensity in Endometriosis Patients.
This correlational study investigated the relationships between temperament, beliefs about pain control, and pain intensity ratings in a group of 103 women diagnosed with endometriosis. Temperament traits were assessed using the Formal Characteristics of Behaviour-Temperament Inventory. Beliefs about pain control were measured using the Polish version of the Beliefs about Pain Control Questionnaire. The Numerical Rating Scale (NRS-11) was used to measure pain intensity. There was a high negative correlation between the temperament trait of endurance and pain intensity ratings. Moderate negative correlations with pain intensity were found for internal beliefs about pain control. Hierarchical multiple regression analysis indicated that the endurance trait and internal beliefs about pain control accounted for 33 % of the variance in pain intensity ratings in women with endometriosis.
Oncotarget. 2017 Jan 24;8(4):7138-7147.
Implications of immune dysfunction on endometriosis associated infertility.
Endometriosis is a complex, inflammatory disease that affects 6-10% of reproductive-aged women. Almost half of the women with endometriosis experience infertility. Despite the excessive prevalence, the pathogenesis of endometriosis and its associated infertility is unknown and a cure is not available. While many theories have been suggested to link endometriosis and infertility, a consensus among investigators has not emerged. In this extensive review of the literature as well as research from our laboratory, we provide potential insights into the role of immune dysfunction in endometriosis associated infertility. We discuss the implication of the peritoneal inflammatory microenvironment on various factors that contribute to infertility such as hormonal imbalance, oxidative stress and how these could further lead to poor oocyte, sperm and embryo quality, impaired receptivity of the endometrium and implantation failure.
Oncotarget. 2016 Nov 22;7(47):76713-76725.
Up-regulation of ribosome biogenesis by MIR196A2 genetic variation promotes endometriosis development and progression.
Aberrant miRNA expression has been reported in endometriosis and miRNA gene polymorphisms have been linked to cancer. Because certain ovarian cancers arise from endometriosis, we genotyped seven cancer-related miRNA single nucleotide polymorphisms (MiRSNPs) to investigate their possible roles in endometriosis. Genetic variants in MIR196A2 (rs11614913) and MIR100 (rs1834306) were found to be associated with endometriosisdevelopment and related clinical phenotypes, such as infertility and pain. Downstream analysis of the MIR196A2 risk allele revealed upregulation of rRNA editing and protein synthesis genes, suggesting hyper-activation of ribosome biogenesis as a driving force for endometriosis progression. Clinical studies confirmed higher levels of small nucleolar RNAs and ribosomal proteins in atypical endometriosis lesions, and this was more pronounced in the associated ovarian clear cell carcinomas. Treating ovarian clear cells with CX5461, an RNA polymerase I inhibitor, suppressed cell growth and mobility followed by cell cycle arrest at G2/M stage and apoptosis. Our study thus uncovered a novel tumorigenesis pathway triggered by the cancer-related MIR196A2 risk allele during endometriosis development and progression. We suggest that anti-RNA polymerase I therapy may be efficacious for treating endometriosis and associated malignancies.
Reprod Biomed Online. 2016 Dec;33(6):668-683.
Oxidative stress and alterations in DNA methylation: two sides of the same coin in reproduction.
The negative effect of oxidative stress on the human reproductive process is no longer a matter for debate. Oxidative stress affects female and male gametes and the developmental capacity of embryos. Its effect can continue through late stages of pregnancy. Metabolic disorders and psychiatric problems can also be caued by DNA methylation and epigenetic errors. Age has a negative effect on oxidative stress and DNA methylation, and recent observations suggest that older men are at risk of transmitting epigenetic disorders to their offspring. Environmental endocrine disruptors can also increase oxidative stress and methylation errors. Oxidative stress and DNA methylation feature a common denominator: the one carbon cycle. This important metabolic pathway stimulates glutathione synthesis and recycles homocysteine, a molecule that interferes with the process of methylation. Glutathione plays a pivotal role during oocyte activation, protecting against reactive oxygen species. Assisted reproductive techniques may exacerbate defects in methylation and epigenesis. Antioxidant supplements are proposed to reduce the risk of potentially harmful effects, but their use has failed to prevent problems and may sometimes be detrimental. New concepts reveal a significant correlation between oxidative stress, methylation processes and epigenesis, and have led to changes in media composition with positive preliminary clinical consequences.
Fertil Steril. 2017 Jan;107(1):160-166.
Endometriosis and pregnancy complications: a Danish cohort study.
To study the association between endometriosis and risk of pre-eclampsia, cesarean section, postpartum hemorrhage, preterm birth, and small for gestational age (SGA), in a large Danish birth cohort, while taking fertility treatment into account.
A total population of 82,793 singleton pregnancies from the Aarhus Birth Cohort (1989 through 2013); 1,213 women had a diagnosis of endometriosis, affecting 1,719 pregnancies.
MAIN OUTCOME MEASURE(S):
Pre-eclampsia, cesarean section, postpartum hemorrhage, preterm birth, and SGA.
Endometriosis was associated with an increased risk of preterm birth (adjusted odds ratio [AOR] 1.67, 95% confidence interval [CI] 1.37-2.05), with the risk being highest for very preterm birth (AOR 1.91, 95% CI 1.16-3.15). Compared with unaffected women, women with endometriosis also had an increased risk of pre-eclampsia (AOR 1.37, 95% CI 1.06-1.77) and cesarean section (AOR 1.83, 95% CI 1.60-2.09). Assisted reproductive technology did not explain these findings. No association was found between endometriosis and postpartum hemorrhage or SGA.
Women with endometriosis were at increased risk of pre-eclampsia, preterm birth, and cesarean section, irrespective of use of assisted reproductive technology.
J Pediatr Adolesc Gynecol. 2017 Apr;30(2):223-227.
The Efficacy of Postoperative Cyclic Oral Contraceptives after Gonadotropin-Releasing Hormone Agonist Therapy to Prevent Endometrioma Recurrence in Adolescents.
Young age is a possible risk factor of endometriosis recurrence after surgery. However, the efficacy of postoperative medical treatment has not been well addressed in adolescents. The purpose of this study was to evaluate whether postoperative medical treatment is as effective in adolescents as it is in adults in the prevention of endometrioma recurrence.
A retrospective cohort study.
Samsung Medical Center, Seoul, Korea.
This study included 176 reproductive-aged women who underwent conservative laparoscopic surgery for pathology-confirmed endometrioma. Women were classified into 2 groups according to age: adolescents (20 years of age and younger, n = 34; group I) and reproductive-aged women (aged 25-35 years, n = 142; group II).
The same surgeon performed all of the surgeries for uniformity. Postoperatively, patients were treated monthly with a gonadotropin-releasing hormone agonist depot for 3-6 months, followed by cyclic oral contraceptives.
MAIN OUTCOME MEASURES:
Endometrioma recurrence was determined using ultrasonography. The recurrence rate of endometrioma was compared between the 2 groups.
During the treatment period (median, 41.0 months; range, 6-159 months), recurrence was noted in 8 cases (4.5%). After adjusting for confounders (which were statistically different between the groups), the cumulative proportion of recurrent endometriomas after 60 months was comparable between the 2 groups (5.3% in group I and 8.5% in group II).
Long-term postoperative medical treatment with cyclic oral contraceptives after a gonadotropin-releasing hormone agonist can be as effective in adolescents as it is in adults in the prevention of endometrioma recurrence.
Med Sci Monit. 2016 Oct 16;22:3727-3736.
In Vitro and In Vivo Effects of Tumor Suppressor Gene PTEN on Endometriosis: An Experimental Study.
BACKGROUND Endometriosis can cause dysmenorrhea and infertility. Its pathogenesis has not yet been clarified and its treatment continues to pose enormous challenges. The protein tyrosine phosphatase (PTEN) gene is a tumor suppressor gene. The aim of this study was to investigate the role and significance of PTEN protein in the occurrence, development, and treatment of endometriosis through changes in apoptosis rate, cell cycle, and angiogenesis. MATERIAL AND METHODS PTEN was overexpressed and silenced in lentiviral vectors and inserted into primary endometrial cells. The changes in cell cycle and apoptosis in the different PTEN expression groups were evaluated using flow cytometry. Vessel growth mimicry was observed using 3-dimensional culture. A human-mouse chimeric endometriosis model was constructed using SCID mice. Hematoxylin and eosin staining and immunohistochemistry were used to detect pathological changes in ectopic endometrial tissues and the expression of VEGF protein in a human-mouse chimeric endometriosis mouse model. RESULTS PTEN overexpression significantly increased apoptosis and inhibited the cell cycle compared with the silenced and control groups. Furthermore, cells expressing low PTEN levels were better able to undergo vasculogenic mimicry, and exhibited significantly increased angiogenesis compared to cells overexpressing PTEN. We found that ectopic foci were more easily formed in the endometrial tissue of SCID mice with low PTEN expression, and the VEGF expression in this group was relatively high. CONCLUSIONS PTEN inhibits the occurrence and development of endometriosis by regulating angiogenesis and the apoptosis and cell cycle of endometrial cells; therefore, we propose that the PTEN gene can be used to treat endometriosis.
J Womens Health (Larchmt). 2016 Oct;25(10):1021-1029.
Women’s Reproductive History Before the Diagnosis of Incident Endometriosis.
Endometriosis is a gynecologic disease reported to be associated with infertility and, possibly, adverse pregnancy outcomes. While considerable research focuses on pregnancy outcomes following diagnosis and/or treatment, few data actually describe women’s reproductive history before diagnosis for a more complete understanding of endometriosis and reproduction.
MATERIALS AND METHODS:
The study sample comprised 473 women (aged 18-44 years) undergoing laparoscopies or laparotomies, irrespective of surgical indication at 14 clinical sites, during the period 2007-2009. Upon enrollment and before surgery, women were queried about pregnancy intentions and the time required to become pregnant for planned pregnancies. Endometriosis was defined as surgically visualized disease. Using discrete time survival analysis, we estimated fecundability odds ratios (FORs) and 95% confidence intervals (CIs) to assess time to pregnancy (TTP) after adjusting for potential confounders (age, body composition, cigarette smoking, site). Generalized estimating equations accounted for multiple pregnancy attempts per woman. FORs <1.0 denote a longer TTP or diminished fecundity.
Approximately 66% and 69% of women with and without endometriosis, respectively, reported having a planned pregnancy before surgery, respectively. After adjustment, an endometriosis diagnosis was associated with ≈29% reduction in fecundity or a longer TTP across all pregnancy-trying attempts (adjusted FOR = 0.71; 95% CI 0.46-1.10). While FORs were consistently <1.0, irrespective of endometriosis staging, CIs included 1.
Women with endometriosis had a longer TTP than unaffected women, irrespective of disease severity, although the findings did not achieve significance. Prior reproductive history may be informative for predicting fecundity and pregnancy outcomes following diagnosis/treatment.
Gynecol Oncol. 2016 Dec;143(3):526-531.
Prognostic value of endometriosis in patients with stage I ovarian clear cell carcinoma: Experiences at three academic institutions.
To investigate the prognostic value of endometriosis in patients with stage I ovarian clear cell carcinoma (OCCC).
The medical records of patients with stage I OCCC who had undergone complete staging surgery followed by systemic chemotherapy were retrospectively reviewed.
A total of 237 women were included in this study. Univariate analysis revealed that the patients with endometriosis-associated ovarian carcinoma (EAOC) had significantly improved recurrence-free survival (RFS) and overall survival (OS) than those without EAOC (5-year RFS: 91.4% vs. 73.0%, respectively, and 5-year OS: 97.5% vs. 89.9%). However, EAOC was not identified as a significant prognostic predictor in multivariate analysis. The potential risk factors determined to be associated with EAOC included the pretreatment CA-125 level, FIGO stage, lymphovascular space invasion (LVSI), and menopausal status (P<0.001, P=0.0031, P=0.020, and P=0.038, respectively).
Endometriosis was not independently associated with the prognosis of the OCCC patients, even when the tumor was confined to stage I. However, the intrinsic relationship between endometriosis and OCCC warrants further investigation.
Genomics. 2016 Oct;108(3-4):151-157.
A PubMed-wide study of endometriosis.
Endometriosis affects 5-10% of women in reproductive age, leading to dysmenorrhea, pelvic pain and infertility; however, our understanding on the pathogenesis of this disease remains incomplete. In the present study, we performed a systematic analysis of endometriosis-related genes using text mining. Taking text mining results as input, we subsequently generated a filtered gene set by computing the likelihood of finding more than expected occurrences for every gene across the disease-centered subset of the PubMed database. Characterization of this filtered gene set by gene ontology, pathway and network analysis provides clues to the multiple mechanisms hypothesized to be responsible for the establishment of ectopic endometrial tissues, including the migration, implantation, survival and proliferation of ectopic endometrial cells. Finally, using this gene set as “seed”, we scanned human genome to predict novel candidate genes based on gene annotations from multiple databases. Our study provides in-depth insights into the pathogenesis of endometriosis.
Case Rep Obstet Gynecol. 2016;2016:7401409.
Umbilical Nodule with Cyclical Bleeding: A Case Report and Literature Review of Atypical Endometriosis.
Endometriosis is defined as the presence of endometrial glands and stroma outside the uterus. It affects 3 to 10 percent of women of reproductive age. Umbilical endometriosis is rare, with an estimated incidence of 0.5-1.0% among all cases of endometriosis, and is usually secondary to prior laparoscopic surgery involving the umbilicus. In this report, we described a case of umbilical endometriosis treated with surgical resection and highlight the great importance of medical history compared to complementary diagnostic tests that can be sometimes inconclusive.