Behav Neurol. 2017;2017:9194261.
Effects of Extremely Low-Frequency Electromagnetic Fields on Neurogenesis and Cognitive Behavior in an Experimental Model of Hippocampal Injury.
Exposure to extremely low-frequency electromagnetic fields may induce constant modulation in neuronal plasticity. In recent years, tremendous efforts have been made to design a suitable strategy for enhancing adult neurogenesis, which seems to be deterred due to brain senescence and several neurodegenerative diseases. In this study, we evaluated the effects of ELF-EMF on neurogenesis and memory, following treatment with trimethyltin chloride (TMT) as a neurotoxicant. The mice in all groups (n = 56) were injected with BrdU during the experiment for seven consecutive days to label newborn cells. Spatial memory was assessed by the Morris water maze (MWM) test. By the end of the experiment, neurogenesis and neuronal differentiation were assessed in the hippocampus, using immunohistochemistry and Western blot analysis. Based on the findings, exposure to ELF-EMF enhanced spatial learning and memory in the MWM test. ELF-EMF exposure significantly enhanced the number of BrdU+ and NeuN+ cells in the dentate gyrus of adult mice (P < 0.001 and P < 0.05, resp.). Western blot analysis revealed significant upregulation of NeuroD2 in ELF-EMF-exposed mice compared to the TMT-treated group (P < 0.05). These findings suggest that ELF-EMF might have clinical implications for the improvement of neurodegenerative processes and could help develop a novel therapeutic approach in regenerative medicine.
Reprod Med Biol. 2016 Dec 26;16(1):40-44.
Analyzing the risk factors for a diminished oocyte retrieval rate under controlled ovarian stimulation.
To investigate which risk factors contribute to a lower oocyte retrieval ratio in women who are receiving controlled ovarian hyperstimulation.
The authors retrospectively analyzed 329 in vitro fertilization (IVF) cycles under controlled ovarian hyperstimulation by using a gonadotropin-releasing hormone antagonist or agonist at Osaka Medical College, Japan. The patients were classified into five groups: advanced age, male infertility, severe endometriosis, tubal infertility, and unexplained infertility. The primary outcomes were the patients’ age, oocyte retrieval ratio, serum basal follicle-stimulating hormone, total dose of gonadotropin, and the clinical outcome. A secondary outcome was the stepwise multivariate logistic regression analysis to assess the factors associated with the failure of oocyte retrieval.
The oocyte retrieval ratio declined significantly with the patient’s age. The ratio of endometriosisin unsuccessful cases was significantly higher than that in successful cycles. Advanced age and endometriosis were the factors that were significantly associated with a lowered oocyte retrieval rate.
Advanced age and endometriosis are high-risk factors that contribute to oocyte retrieval failure in infertile patients who are receiving IVF treatment.
Reprod Med Biol. 2017 Mar 26;16(2):170-178. doi: 10.1002/rmb2.12028. eCollection 2017 Apr.
Overexpression of microRNA-542-3p attenuates the differentiating capacity of endometriotic stromal cells.
Endometriosis is defined as the presence of endometrial glandular and stromal cells outside of the uterine cavity. A previous study reported that microRNA (miR)-542-3p plays a critical role in eutopic endometrial decidualization. This study aims to clarify the potential role of miR-542-3p and the target gene, IGFBP-1 (insulin-like growth factor-binding protein 1), in the impairment of the decidualizing capacity of human ectopic endometrial stromal cells (HEcESCs).
In vitro analysis of primary undifferentiated and decidualizing human eutopic endometrial stromal cells (HEuESCs) and HEcESCs was conducted. The primary HEuESCs or HEcESCs were expanded in culture and decidualized with 8-bromo-cyclic adenosine monophosphate (8-bromo-cAMP) and medroxyprogesterone acetate (MPA).
The morphological and biological differentiating capacities of the HEcESCs were markedly impaired. In contrast to the HEuESCs, the HEcESCs that were treated with the decidual stimulus retained the mesenchymal phenotype and capacity for migration. The down-regulation of miR-542-3p in the HEcESCs treatment with 8-bromo-cAMP and MPA was much weaker than that of the HEuESCs. High expression of miR-542-3p led to a significant decrease in the expression of IGFBP1 in the HEcESCs.
Impairment of the differentiating capacity by the overexpression of miR-542-3p could influence the capacity for migration and invasion of endometriotic cells in an ectopic environment.
Reprod Med Biol. 2017 Jul 23;16(4):314-319.
Epigenetic regulation of the pathological process in endometriosis.
Endometriosis is one of the most common gynecological diseases that greatly compromises the quality of life in affected individuals. A growing body of evidence shows that the remodeling of retrograde endometrial tissues to the ectopic endometriotic lesions involves multiple epigenetic alterations, such as DNA methylation, histone modification, and microRNA expression.
This article retrospectively reviewed the studies that were related to the epigenetic regulatory factors that contribute to the development and maintenance of endometriosis. A literature search was performed in order to collect scientific articles that were written in English by using the key words of “endometriosis,” “epigenetics,” “DNA methylation,” “histone modification,” and “microRNA.”
Epigenetic modifications, including DNA methylation, histone modification, and microRNA expression, are involved in the pathogenesis of endometriosis. These epigenetic players are regulated or tuned by microenvironmental cues, such as locally produced estradiol, proinflammatory cytokines, and hypoxic stress, and reciprocally regulate the process or response to those stimuli.
Understanding the molecular mechanisms that underlie these epigenetic regulatory processes would shed light on the etiology and/or progression of endometriosis and facilitate the development of novel therapeutic strategies.
J Med Case Rep. 2017 Dec 21;11(1):354.
Endometriosis-associated hydrocele of the canal of Nuck with immunohistochemical confirmation: a case report.
The canal of Nuck is an embryological vestige of the processus vaginalis, and presents a potential site for endometriosis seeding. Hydroceles in this region are a rare cause of inguinal swelling in females. In addition, endometriosis localized to the canal of Nuck is exceedingly rare.
A 44-year-old Japanese woman presented with a painful mass overlying her right pubis. She underwent surgery to completely excise the mass. During surgery, division of the external oblique aponeurosis revealed a cyst that occupied the inguinal canal and it adhered to the transverse fascia, inguinal ligament, and pubic bone. The cyst was dissected from the round ligament, and the defect in the internal inguinal ring was repaired and reinforced with mesh. On macroscopic examination, the cyst had a heterogeneous fibrous aspect with dark brown inclusions. Microscopic examination revealed that the cyst was tortuous, lined by mesothelial-like cells, and accompanied by partial subcapsular hemorrhage. Endometrium-like tissue was observed in the cystic wall. Immunohistochemical staining for podoplanin confirmed the mesothelial origin of the cyst-lining cells. The epithelial cells and stromal cells were positive for estrogen receptors.
In this case of an endometriosis-associated hydrocele of the canal of Nuck, the mesothelial origin of the cyst-lining cells and endometriosis were confirmed by positive immunohistochemical staining for podoplanin and estrogen receptors, respectively. We determined that hydrocele resection and reinforcement of the anterior inguinal canal wall (if necessary) are appropriate treatments for this condition.
Sci Rep. 2017 Dec 20;7(1):17903.
Interleukin-33 modulates inflammation in endometriosis.
Endometriosis is a debilitating condition that is categorized by the abnormal growth of endometrial tissue outside the uterus. Although the pathogenesis of this disease remains unknown, it is well established that endometriosis patients exhibit immune dysfunction. Interleukin (IL)-33 is a danger signal that is a critical regulator of chronic inflammation. Although plasma and peritoneal fluid levels of IL-33 have been associated with deep infiltrating endometriosis, its contribution to the disease pathophysiology is unknown. We investigated the role of IL-33 in the pathology of endometriosis using patient samples, cell lines and a syngeneic mouse model. We found that endometriotic lesions produce significantly higher levels of IL-33 compared to the endometrium of healthy, fertile controls. In vitro stimulation of endometrial epithelial, endothelial and endometriotic epithelial cells with IL-33 led to the production of pro-inflammatory and angiogenic cytokines. In a syngeneic mouse model of endometriosis, IL-33 injections caused systemic inflammation, which manifested as an increase in plasma pro-inflammatory cytokines compared to control mice. Furthermore, endometriotic lesions from IL-33 treated mice were highly vascularized and exhibited increased proliferation. Collectively, we provide convincing evidence that IL-33 perpetuates inflammation, angiogenesis and lesion proliferation, which are critical events in the lesion survival and progression of endometriosis.
J Endocr Soc. 2017 Mar 15;1(4):359-369.
The Use of Resveratrol as an Adjuvant Treatment of Pain in Endometriosis: A Randomized Clinical Trial.
Resveratrol has been used for the treatment of endometriosis.
To compare resveratrol (40 mg/d) with monophasic contraceptive pill (COC) to COC with placebo for the reduction of pain scores.
A randomized clinical trial.
Women (ages 20 to 50) with laparoscopic diagnosis of endometriosis were eligible for the study. Exclusion criteria: pregnancy, allergy to resveratrol, or contraindications to COC, use of agonists of gonadotropin release hormone or danazol in the last month, or had used depot medroxyprogesterone acetate or Mirena®.
Subjects were randomized using a computer-generated randomization list to receive COC for 42 days to be taken with identical capsules containing 40 mg of resveratrol or placebo in coded bottles (1:1 ratio). Allocation was concealed in coded, sequenced, opaque-sealed envelopes.
Median pain scores measured with a visual analog scale on day 42.
Between 18 June and 6 November 2015, 44 subjects were enrolled. Mean [95% confidence interval (CI)] pain scores on day 0 were 5.4 (4.2 to 6.6) in the placebo group and 5.7 (4.8 to 6.6) in resveratrol groups. After treatment, pain values were [3.9 (2.2 to 5); n = 22] and [3.2 (2.1 to 4.3); n = 22] in the placebo and resveratrol groups, respectively (P = 0.7; Mann-Whitney U test). Median (95% CI) difference between groups was 0.75 (-1.6 to 2.3).
Resveratrol is not superior to placebo for treatment of pain in endometriosis.
Gynecol Endocrinol. 2017;33(sup1):18-21.
Dienogest treatment after ovarian endometrioma removal in infertile women prior to IVF.
Severe forms of genital endometriosis are known to be associated with infertility and its subsequent treatment failure. Both gonadotropin-releasing hormone analogs (a-GnRH) and dienogest have been suggested as additional hormone therapy for patients with endometriomas. However, the result of hormonal suppression before an in vitro fertilization (IVF) cycle remains undetermined.
MATERIALS AND METHODS:
A prospective cohort study of 144 infertile women planning IVF after laparoscopic surgery of ovarian endometriomas was conducted at our department in 2012-2015. Patients were divided into three groups: group I (N = 38) with dienogest course, group II (N = 70) with a-GnRH group III (N = 70) without any hormonal therapy within 6 months preceding IVF.
The study groups did not differ by removed endometriomas size and ovarian reserve indicators. The gonadotropin dose per Cycle was higher, while the number of retrieved oocytes was lower in group III patients (p < .001). In women with dienogest pretreatment, clinical pregnancy rate was 2.5 times (44.7% versus 16.7%, p = .012) and delivery rate – three times higher (36.8% versus 11.1%, p = .013) as compared with those from group III.
The present study confirms the necessity of pre-cycle medical interventions in women with ovarian forms of endometriosis undergoing IVF. We suggest dienogest to be possibly more efficient treatment option for this kind of patients.
Mol Reprod Dev. 2017 Nov 20.
The DNA methylation status of genes encoding Matrix metalloproteinases and tissue inhibitors of Matrix metalloproteinases in endometriosis.
Endometriosis is a benign disease, with malignant properties. A necessary step in the progression of endometriosis is tissue remodeling, which is coordinated by the activities of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs). This study evaluated the regulation of abnormal MMP and TIMP gene expression during endometriosis. Among the two genes families, promoter regions of MMP2, MMP3, MMP7, TIMP3, and TIMP4 were significantly altered in proliferative-phase endometriotic lesions compared to menstrual cycle-matched eutopic tissue from endometriosis-free women. In addition, a negative correlation was found between the DNA methylation status of the promoter region and transcript abundance of MMP2. Our findings suggest that changes in DNA methylation at the promoter region of MMP2 could underlie the changes in its expression in the ectopic endometria from patients with endometriosis.
Ultrasound Obstet Gynecol. 2017 Dec 20.
Influence of adenomyosis on pregnancy and perinatal outcomes in women with endometriosis.
Several studies investigated the correlation between endometriosis and adverse pregnancy and perinatal outcomes. However, the role of adenomyosis as a risk factor for adverse perinatal outcomes in women with endometriosis has yet to be established. The aim of this study was to explore if fetal and maternal outcomes, in particular the incidence of small for gestational age (SGA) infants, are different in pregnant women with endometriosis (E) and the concomitant presence of diffuse (EDA) and focal ademonyosis (EFA).
This is a retrospective analysis of a database collected prospectively during a three-year period. We included 206 pregnant women with endometriosis; 148 (71.8%) with E, 38 (18.4%) with EFA and 20 (9.7%) with EDA. Adenomyosis was diagnosed by ultrasonography, it was classified in focal or diffuse. The study included patients who conceived spontaneously or by assisted reproductive techniques.
The three groups were similar in demographic characteristics (age, body mass index, mode of conception). Patients with diffuse adenomyosis compared with those with only endometriosis had significantly lower PAPP-A MoM (0.61 vs 0.88 MoM, p<0.001), higher mean uterine artery pulsatility index (UtA PI) in the 1st (2.23 vs 1.67, p<0.001) and 2nd (1.30 vs 0.94, p<0.001) trimester of pregnancy, and higher incidence of SGA (40% vs 10.8%, p<0.001; respectively). No statistically significant difference was found in patients with focal adenomyosis compared to those with only endometriosis. Logistic regression analysis demonstrated that diffuse adenomyosis (OR=3.744 CI 95%1.158-12.099; p=0.027) was the only independent risk factors for SGA.
The presence of diffuse adenomyosis in pregnant women with endometriosis is is strongly associated with SGA infants. Women with diffuse adenomyosis should be treated as being at high risk of placental dysfunction, therefore, these pregnancies might need a closer monitoring.
Genome Med. 2017 Dec 22;9(1):116..
The potential of circulating tumor DNA methylation analysis for the early detection and management of ovarian cancer.
Widschwendter M1, Zikan M2, Wahl B3, Lempiäinen H4, Paprotka T3, Evans I5, Jones A5, Ghazali S5, Reisel D5, Eichner J4, Rujan T4, Yang Z6, Teschendorff AE5,6, Ryan A5, Cibula D2, Menon U5, Wittenberger T4.
Despite a myriad of attempts in the last three decades to diagnose ovarian cancer (OC) earlier, this clinical aim still remains a significant challenge. Aberrant methylation patterns of linked CpGs analyzed in DNA fragments shed by cancers into the bloodstream (i.e. cell-free DNA) can provide highly specific signals indicating cancer presence.
We analyzed 699 cancerous and non-cancerous tissues using a methylation array or reduced representation bisulfite sequencing to discover the most specific OC methylation patterns. A three-DNA-methylation-serum-marker panel was developed using targeted ultra-high coverage bisulfite sequencing in 151 women and validated in 250 women with various conditions, particularly in those associated with high CA125 levels (endometriosis and other benign pelvic masses), serial samples from 25 patients undergoing neoadjuvant chemotherapy, and a nested case control study of 172 UKCTOCS control arm participants which included serum samples up to two years before OC diagnosis.
The cell-free DNA amount and average fragment size in the serum samples was up to ten times higher than average published values (based on samples that were immediately processed) due to leakage of DNA from white blood cells owing to delayed time to serum separation. Despite this, the marker panel discriminated high grade serous OC patients from healthy women or patients with a benign pelvic mass with specificity/sensitivity of 90.7% (95% confidence interval [CI] = 84.3-94.8%) and 41.4% (95% CI = 24.1-60.9%), respectively. Levels of all three markers plummeted after exposure to chemotherapy and correctly identified 78% and 86% responders and non-responders (Fisher’s exact test, p = 0.04), respectively, which was superior to a CA125 cut-off of 35 IU/mL (20% and 75%). 57.9% (95% CI 34.0-78.9%) of women who developed OC within two years of sample collection were identified with a specificity of 88.1% (95% CI = 77.3-94.3%). Sensitivity and specificity improved further when specifically analyzing CA125 negative samples only (63.6% and 87.5%, respectively).
Our data suggest that DNA methylation patterns in cell-free DNA have the potential to detect a proportion of OCs up to two years in advance of diagnosis and may potentially guide personalized treatment. The prospective use of novel collection vials, which stabilize blood cells and reduce background DNA contamination in serum/plasma samples, will facilitate clinical implementation of liquid biopsy analyses.
J Obstet Gynaecol Res. 2017 Dec 21.
Usefulness of hemostatic sealants for minimizing ovarian damage during laparoscopic cystectomy for endometriosis.
We aimed to evaluate the impact of topical hemostatic sealants and bipolar coagulation during laparoscopic ovarian endometriotic cyst resection on ovarian reserve by comparing the rates of decrease in anti-Müllerian hormone (AMH).
A randomized prospective data collection was made on women aged 19-45 years who planned to have laparoscopic ovarian cystectomy at one of two institutions (n = 80), Kangbuk Samsung Hospital, Seoul, Korea or National Health Insurance Service Ilsan Hospital, Goyang, Korea, from January 2014 to April 2016. Patients were randomly divided into two groups treated with either a topical hemostatic sealant or bipolar coagulation for hemostasis. The hemostatic group was randomized to the FloSeal or TachoSil subgroups. Preoperative and 3-month postoperative AMH levels were checked and the rates of decrease of AMH were compared. All patients enrolled were treated with dienogest (Visanne) for 6-12 months. None were lost to follow-up at postoperative 3 months, but about one-third of the patients had been lost to follow-up by 6-12 months.
AMH was significantly decreased in both groups 3 months postoperatively; however, the rate of decrease in the bipolar coagulation group was greater than that in the hemostatic sealant group, 41.9% (interquartile range [IQR], 22.29-65.24) versus 18.1% (IQR, 10.94-29.90), P = 0.007. Between the two hemostatic subgroups, there was no significant difference in AMH decrease rate, 14.95% (IQR, 11.34-21.21) versus 18.1% (IQR 9.76-40.70), P = 0.204.
Hemostatic sealants may be an alternative to bipolar coagulation for preservation of ovarian reserve after laparoscopic ovarian cystectomy for endometriosis.
Eur Rev Med Pharmacol Sci. 2017 Dec;21(24):5527-5533.
Overexpression of TAFI promotes epithelial mesenchymal transition in endometriosis.
Endometriosis is a disease that occurs in women. Thrombin-activated fibrinolytic inhibitor (TAFI) is mainly secreted by stem cells and acts as a regulatory role in the body. Epithelial leaf transition plays a leading role in cell growth and invasion. Our study focuses on the mechanism of TAFI in patients with endometriosis.
PATIENTS AND METHODS:
The expression of TAFI was determined by immunohistochemistry. Reverse transcriptase-polymerase chain reaction (RT-PCR) served to detect the expression of TAFI and the effect of TAFI on overall survival (OS) and progression-free survival (PFS) levels. The changes of primary cytology in patients with endometriosis were observed under a microscope. The cell source was further determined by immunofluorescence labeling of vimentin and cytokeratin, and the expression of TAFI was detected by Western-blot. 3-4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and cell invasion assay were utilized to detect the viability and aggressiveness of cells after epithelial mesenchymal transition (EMT).
TAFI was overexpressed in endometriosis tissues and no expression of TAFI was found in normal tissues, which is consistent with RT-PCR results. TAFI overexpressed endometriosis patients had low levels of overall OS and PFS. There were statistically significant differences. Cell morphology shows that endometriosis primary cells are mainly composed of epithelial cells and fibroblasts. Immunofluorescence assay showed that vimentin and cytokeratin were expressed in cells, and the expression of TAFI was detected by Western-blot. Compared with normal tissues, TAFI was considerably higher in patients with endometriosis. The results of Western-blot and RT-PCR showed that the expression of TAFI was significantly increased in patients with endometriosis and the cell proliferation and cell invasion were significantly accelerated.
Our results show that TAFI is highly expressed in endometriosis and causes EMT, which accelerated the cell proliferation and cell invasion. Snail is an inhibitor of E-cadherin, which may participate in metastasis and invasion of endometriosis by mediating EMT. So, we suspect that Snail controls the occurrence of the EMT and then affects the cell metastasis and invasion, which requires further verification.
Nat Genet. 2018 Jan;50(1):26-41.
Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.
Turcot V1, Lu Y2,3,4, Highland HM5,6, Schurmann C3,4, Justice AE5, Fine RS7,8,9, Bradfield JP10,11, Esko T7,9,12, Giri A13, Graff M5, Guo X14, Hendricks AE15,16, Karaderi T17,18, Lempradl A19, Locke AE20,21, Mahajan A17, Marouli E22, Sivapalaratnam S23,24,25, Young KL5, Alfred T3, Feitosa MF26, Masca NGD27,28, Manning AK7,24,29,30, Medina-Gomez C31,32, Mudgal P33, Ng MCY33,34, Reiner AP35,36, Vedantam S7,8,9, Willems SM37, Winkler TW38, Abecasis G20, Aben KK39,40, Alam DS41, Alharthi SE22,42, Allison M43, Amouyel P44,45,46, Asselbergs FW47,48,49, Auer PL50, Balkau B51, Bang LE52, Barroso I15,53,54, Bastarache L55, Benn M56,57, Bergmann S58,59, Bielak LF60, Blüher M61,62, Boehnke M20, Boeing H63, Boerwinkle E64,65, Böger CA66, Bork-Jensen J67, Bots ML68, Bottinger EP3, Bowden DW33,34,69, Brandslund I70,71, Breen G72,73, Brilliant MH74, Broer L32, Brumat M75, Burt AA76, Butterworth AS77,78, Campbell PT79, Cappellani S80, Carey DJ81, Catamo E80, Caulfield MJ22,82, Chambers JC83,84,85, Chasman DI7,86,87,88, Chen YI14, Chowdhury R77, Christensen C89, Chu AY90,91, Cocca M92, Collins FS93, Cook JP94, Corley J95,96, Corominas Galbany J97,98, Cox AJ33,34,99, Crosslin DS100, Cuellar-Partida G101,102, D’Eustacchio A80, Danesh J15,77,78,103, Davies G94,95, Bakker PIW68,104, Groot MCH105,106, Mutsert R107, Deary IJ94,95, Dedoussis G108, Demerath EW109, Heijer M110, Hollander AI98, Ruijter HM111, Dennis JG112, Denny JC55, Angelantonio E77,78, Drenos F113,114, Du M36,115, Dubé MP1,116, Dunning AM117, Easton DF112,117, Edwards TL13, Ellinghaus D118, Ellinor PT7,24,30, Elliott P119, Evangelou E84,120, Farmaki AE108,121, Farooqi IS53,54, Faul JD122, Fauser S123, Feng S20, Ferrannini E124,125, Ferrieres J126, Florez JC7,24,29,30, Ford I127, Fornage M128, Franco OH31, Franke A118, Franks PW129,130,131, Friedrich N132, Frikke-Schmidt R57,133, Galesloot TE40, Gan W17, Gandin I134, Gasparini P75,80, Gibson J135, Giedraitis V136, Gjesing AP67, Gordon-Larsen P137,138, Gorski M38,66, Grabe HJ139,140, Grant SFA10,141,142, Grarup N67, Griffiths HL143, Grove ML64, Gudnason V144,145, Gustafsson S146, Haessler J36, Hakonarson H10,141, Hammerschlag AR147, Hansen T67, Harris KM137,148, Harris TB149, Hattersley AT150, Have CT67, Hayward C151, He L152,153, Heard-Costa NL90,154, Heath AC155, Heid IM38,156, Helgeland Ø157,158, Hernesniemi J159,160,161, Hewitt AW162,163,164, Holmen OL165, Hovingh GK23, Howson JMM77, Hu Y166, Huang PL24, Huffman JE151, Ikram MA31,167,168, Ingelsson E146,169, Jackson AU20, Jansson JH170,171, Jarvik GP76,172, Jensen GB173, Jia Y14, Johansson S158,174, Jørgensen ME175,176, Jørgensen T57,177,178, Jukema JW179,180, Kahali B181,182,183,184, Kahn RS185, Kähönen M186,187, Kamstrup PR56, Kanoni S22, Kaprio J153,188,189, Karaleftheri M190, Kardia SLR60, Karpe F191,192, Kathiresan S7,24,88, Kee F193, Kiemeney LA40, Kim E14, Kitajima H17, Komulainen P194,195,196, Kooner JS83,85,197,198, Kooperberg C36, Korhonen T153,189,199, Kovacs P61, Kuivaniemi H81,200,201, Kutalik Z59,202, Kuulasmaa K189, Kuusisto J203, Laakso M203, Lakka TA194,195,196, Lamparter D58,59, Lange EM204, Lange LA204, Langenberg C37, Larson EB76,205,206, Lee NR207,208, Lehtimäki T160,161, Lewis CE209, Li H166, Li J169, Li-Gao R107, Lin H210, Lin KH211, Lin LA128, Lin X166, Lind L212, Lindström J189, Linneberg A178,213,214, Liu CT215, Liu DJ216, Liu Y217, Lo KS1, Lophatananon A218, Lotery AJ143, Loukola A153,188, Luan J37, Lubitz SA7,24,30, Lyytikäinen LP160,161, Männistö S189, Marenne G15, Mazul AL5, McCarthy MI17,191,192, McKean-Cowdin R219, Medland SE102, Meidtner K220,221, Milani L12, Mistry V53,54, Mitchell P222, Mohlke KL204, Moilanen L223, Moitry M224,225, Montgomery GW102,226, Mook-Kanamori DO107,227, Moore C78,228, Mori TA229, Morris AD230, Morris AP17,94, Müller-Nurasyid M156,231,232, Munroe PB22,82, Nalls MA233,234, Narisu N93, Nelson CP27,28, Neville M191,192, Nielsen SF56,57, Nikus K159, Njølstad PR157,158, Nordestgaard BG56,57, Nyholt DR102,235, O’Connel JR236, O’Donoghue ML237, Olde Loohuis LM238, Ophoff RA185,238, Owen KR191,192, Packard CJ127, Padmanabhan S127, Palmer CNA239, Palmer ND69, Pasterkamp G111,240, Patel AP7,24,88, Pattie A96, Pedersen O67, Peissig PL74, Peloso GM215, Pennell CE241, Perola M12,188,189,242, Perry JA236, Perry JRB37, Pers TH67,243, Person TN74, Peters A221,232,244, Petersen ERB245, Peyser PA60, Pirie A117, Polasek O230,246, Polderman TJ147, Puolijoki H247, Raitakari OT248,249, Rasheed A250, Rauramaa R194,195, Reilly DF91, Renström F129,251, Rheinberger M66, Ridker PM87,88,237, Rioux JD1,116, Rivas MA7,252, Roberts DJ78,253,254, Robertson NR17,191, Robino A80, Rolandsson O170,255, Rudan I230, Ruth KS256, Saleheen D250,257, Salomaa V189, Samani NJ27,28, Sapkota Y102, Sattar N127, Schoen RE258, Schreiner PJ109, Schulze MB220,221, Scott RA37, Segura-Lepe MP84, Shah SH259, Sheu WH260,261,262, Sim X20,263, Slater AJ264,265, Small KS266, Smith AV144,145, Southam L15,17, Spector TD266, Speliotes 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AR256, Wu Y204, Yaghootkar H256, Yao J14, Yao P166, Yerges-Armstrong LM236,300, Young R77,127, Zeggini E15, Zhan X301, Zhang W83,84, Zhao JH37, Zhao W60,257, Zhou W181,182, Zondervan KT17,302; CHD Exome+ Consortium; EPIC-CVD Consortium; ExomeBP Consortium; Global Lipids Genetic Consortium; GoT2D Genes Consortium; EPIC InterAct Consortium; INTERVAL Study; ReproGen Consortium; T2D-Genes Consortium; MAGIC Investigators; Understanding Society Scientific Group, Rotter JI14, Pospisilik JA19, Rivadeneira F31,32, Borecki IB26, Deloukas P22,42, Frayling TM256, Lettre G1,116, North KE303, Lindgren CM17,304, Hirschhorn JN305,306,307,308, Loos RJF309,310,311.
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
Arch Gynecol Obstet. 2017 Dec 22.
Should we consider integrated approach for endometriosis-associated infertility as gold standard management? Rationale and results from a large cohort analysis.
To evaluate reproductive and maternal-fetal outcomes after integrated approach for endometriosis-associated infertility (EAI).
We retrospectively analyzed reproductive and maternal-fetal outcomes of 277 women affected by EAI, subdividing patients in two groups: in the first one (surgery group), we included all women who underwent laparoscopic surgery for EAI; in the second one (integrated group), we included women who failed to conceive spontaneously after surgery within 6-12 months and underwent in vitro fertilization and embryo transfer (IVF). We evaluated delivery rate (DR), maternal and neonatal outcomes of the first pregnancies, and, finally, the type (spontaneous or IVF) of subsequent pregnancies.
We did not find significant difference regarding DR between surgery and integrated groups. We found significantly lower birth weight (p < 0.001) and gestational age at delivery (p < 0.001) in integrated group respect to surgery group; conversely, we found higher rate of preterm birth (p < 0.001), small for gestational age (p = 0.003), and admission to the neonatal intensive care unit (p < 0.001) respect to surgery group. Finally, 92 women became pregnant for the second time: 8% were spontaneous and 20% were IVF pregnancies.
We suggest the integrated approach as gold standard treatment for carefully selected patients (young, good ovarian reserve, partner with normal semen parameters) affected by EAI. As consequence, IVF should be reserved as the secondary treatment for women who fail to conceive spontaneously after surgery within 6-12 months, since it is able to increase DR significantly.
Exp Mol Pathol. 2017 Dec 21;104(1):38-44.
Detection of Aristaless-related homeobox protein in ovarian sex cord-stromal tumors.
To examine the potential of ARX as a novel biomarker of ovarian endometriosis and other ovarian pathologies.
The mRNA level of ARX in ovarian endometriosis and normal endometrium samples was determined by real-time PCR, while the protein level was determined by Western blotting and immunohistochemical staining. Immunohistochemical analysis was performed on nearly 200 tissue samples of different ovarian pathologies. GraphPad Prism was used for statistical analysis.
The expression of ARX was significantly increased in ovarian endometriosis samples as compared to normal endometrium. Also Western blotting data showed higher ARX levels in the ovarian endometriosis samples versus normal endometrium. Immunohistochemical analysis revealed that the protein is localized in the ovarian stroma and does not originate from endometriosis. Further immunohistochemical analysis performed on several different non-neoplastic and neoplastic ovarian tissue samples revealed that in the non-neoplastic ovary ARX protein is present only in the stromal cells and their derivates (luteinized stromal cells, theca and Leydig cells) and not in granulosa cells, oocites, surface epithelium or rete ovarii, while all stromal and sex cord tumors showed strong nuclear staining for ARX. All other primary or metastatic epithelial tumors of the ovary were ARX negative.
ARX is not associated with endometriosis and cannot be used as a biomarker for ovarian endometriosis. ARX is present in ovarian stroma and cells derived from ovarian stroma as well as in all types of sex cord-stromal tumors of the ovary and could thus be used as a marker for sex cord-stromal differentiation in ovarian tumors.
Zhonghua Yi Xue Za Zhi. 2017 Dec 5;97(45):3543-3547.
The effect of follicular fluid from patients with endometriosis, follicle stimulating hormone and bone morphogenetic protein 15 on the proliferation and progesterone secretion of granular cells.
Objective: The study was designed to evaluate the effect of follicular fluid from patients with endometriosis, follicle stimulating hormone (FSH), bone morphogenetic protein 15 (BMP-15) on the proliferation and progesterone secretion of human luteinized granular cells in vitro. Methods: Cumulus granulosa cells were collected from the patients who underwent in vitro fertilization and embryo transfer (IVF-ET) ovulation due to tubal or male factor infertility on the day of the retrieval. The cells in the control group were cultured with complete medium of DMEM/F-12, an extra of FSH at a dose of 12 μg/L was added in the FSH group, an extra of BMP-15 at a dose of 6 μg/L was added to the BMP-15 group, an extra of 5% of the follicular fluid from the patients with tubal or male factor infertility was added to the tubal group, an extra of 5% of the follicular fluid from the patients with endometriosis infertility was added to the endometriosis group, an extra of 5% of the follicular fluid from the patients with endometriosis infertility plus FSH at a dose of 12 μg/L were added to the endometriosis plus FSH group, and an extra of 5% of the follicular fluid from the patients with endometriosis infertility plus BMP-15 at a dose of 6 μg/L were added to the endometriosis plus BMP-15 group. Hemacytometer counting method was used to observe the growth of cells after 48 hours, and chemiluminescence method was utilized to measure the level of progesterone in culture supernatant. Results: The cell proliferation was enhanced in the FSH group, while the proliferation was inhibited in the endometriosis group and the endometriosis plus BMP-15 group, compared to the control group, both of which, were statistically significant. Compared to the control group, the progesterone levels from the culture supernatant of granular cells were significantly elevated in the FSH group, tubal group and endometriosisgroup. The secretion of progesterone in the endometriosis group was lower than that in the tubal group. After addition of FSH into the endometriosis group (the endometriosis plus FSH group), the secretion level of progesterone was significantly increased, compared to the control group and the endometriosis group. After adding BMP-15 into the endometriosis group (the endometriosis plus BMP-15 group), the secretion level of progesterone was increased, compared to the control group. Conclusions: FSH, but not BMP-15, was able to enhance the proliferation and progesterone secretion of granular cells. The proliferation of granular cells and secretion of progesterone were inhibited by the follicular fluid from patients with endometriosis, which was reversed by FSH. However, BMP-15 had no effect on the outcome of follicular fluid from patients with endometriosis.
Curr Obstet Gynecol Rep. 2017 Mar;6(1):34-41.
Endometriosis: Epidemiology, Diagnosis and Clinical Management.
PURPOSE OF REVIEW:
Endometriosis is a disease of adolescents and reproductive-aged women characterized by the presence of endometrial tissue outside the uterine cavity and commonly associated with chronic pelvic pain and infertility. Here we review the epidemiology of endometriosis as well as potential biomarkers for detection and with the goal of highlighting risk factors that could be used in combination with biomarkers to identify and treat women with endometriosis earlier..
Early age at menarche, shorter menstrual length, and taller height are associated with a higher risk of endometriosis while parity, higher body mass index (BMI) and smoking are associated with decreased risk. Endometriosis often presents as infertility or continued pelvic pain despite treatment with analgesics and cyclic oral contraceptive pills.
Despite a range of symptoms, diagnosis of endometriosis is often delayed due to lack of non-invasive, definitive and consistent biomarkers for diagnosis of endometriosis. Hormone therapy and analgesics are used for treatment of symptomatic endometriosis. However, the efficacy of these treatments are limited as endometriosis often recurs. In this review, we describe potential diagnostic biomarkers and risk factors that may be used as early non-invasive in vitro tools for identification of endometriosis to minimize diagnostic delay and improve reproductive health of patients.
Rev Esp Enferm Dig. 2017 Dec 26;110.
Ileocecal endometriosis as an infrequent cause of intussusception.
We present a case of ileocecal endometriosis as a cause of infrequent ileocolic intussusception in an adult patient. It is reviewed as published by the authors Sanchez Cifuentes, A et al. 2016, emphasizing the rarity of the location of endometriosis, and its association as a cause of intussusception.
J Turk Ger Gynecol Assoc. 2017 Dec 15;18(4):200-209.
Diagnostic and treatment guidelines for gastrointestinal and genitourinary endometriosis.
Endometriosis is commonly misdiagnosed, even among many experienced gynecologists. Gastrointestinal and genitourinary endometriosis is particularly difficult to diagnose, and is commonly mistaken for other pathologies, such as irritable bowel syndrome, interstitial cystitis, and even psychological disturbances. This leads to delays in diagnosis, mismanagement, and unnecessary testing. In this review, we will discuss the diagnosis and management of genitourinary and gastrointestinal endometriosis. Medical management may be tried first, but often fails in cases of urinary tract endometriosis. This is particularly important in cases of ureteral endometriosis because silent obstruction can lead to eventual kidney failure. Thus, we recommend complete surgical treatment in these cases. Bladder endometriosis may be managed more conservatively, and only if symptomatic, because these rarely lead to significant morbidity. In cases of bowel endometriosis, we recommend medical management first in all cases, and the least invasive surgical management only if medical treatment fails. This is due to the extensive nervous and vasculature supply to the lower rectum. Injury to these nerves and vessels can cause significant complications and postoperative morbidity.
G Chir. 2017 Sep-Oct;38(5):250-255.
Renal endometriosis mimicking complicated cysts of kidney: report of two cases.
Endometriosis is a common gynecologic disorder characterized by ectopic endometrial tissue growth outside the uterine cavity. Although usually occurring in pelvic organs, endometrial lesions may involve urinary tract. Renal endometriosis is extremely rare and it has only occasionally been reported in the past. We report two cases of patients with renal cystic lesions, incidentally found at imaging techniques during oncologic follow-up for gastric sarcoma and melanoma, initially misinterpreted as complicated haemorrhagic cysts and then histologically characterized as renal localizations of extragenital endometriosis.
Hum Reprod. 2018 Feb 1;33(2):212-219.
Safety of ovarian tissue transplantation in patients with borderline ovarian tumors.
Is transplantation of cryopreserved ovarian tissue from patients with borderline ovarian tumors (BOTs) a safe procedure?
BOT cells were found in frozen-thawed and xenografted ovarian tissue in 1 of 11 BOT patients.
WHAT IS KNOWN ALREADY:
The risk of reintroducing malignant cells upon ovarian tissue transplantation has been subject of debate for many years. Reimplantation of cryopreserved ovarian tissue from leukemia patients is unsafe, while results from studies of cryopreserved ovarian tissue from other forms of cancer, such as Hodgkin’s lymphoma, are reassuring.
STUDY DESIGN, SIZE, DURATION:
Prospective experimental study conducted in an academic research unit using ovarian tissue from 11 patients undergoing cryopreservation for BOTs.
PARTICIPANTS/MATERIALS, SETTING, METHODS:
Histology, immunohistochemistry (IHC) for mucin 1 (MUC1) and cytokeratin 7 (CK7) and molecular analysis by reverse transcription quantitative polymerase chain reaction (RT-qPCR) for CK7 and MUC1 were performed on frozen-thawed ovarian tissue from 11 patients. Long-term (5 months) xenografting of ovarian tissue in immunodeficient mice was performed. The xenografts were analyzed by histology, IHC and RT-qPCR, furthermore IHC for CD10, a marker of endometriosis, was performed on a selected sample.
MAIN RESULTS AND THE ROLE OF CHANCE:
Analysis by histology, IHC and RT-qPCR indicated 10 of the ovarian tissue samples were negative. Analysis of the xenograft samples indicated nine were negative for malignant cells but in two xenografts glandular lesions were detected by histology. In these two xenografts, CK7 and MUC1 markers were demonstrated by IHC and CK7 expression also by RT-qPCR. A BOT was confirmed in the xenograft in which the original ovarian tissue was positive, while in the other case IHC demonstrated expression of endometriosis marker CD10.
LIMITATIONS, REASONS FOR CAUTION:
Cryopreserved ovarian fragments cannot be tested before transplantation, therefore the preimplantation analysis cannot guarantee that all cryopreserved fragments will be free of BOT cells.
WIDER IMPLICATIONS OF THE FINDINGS:
BOT cells can be found in cryopreserved ovarian tissue from BOT patients, therefore preimplantation analysis is an absolute prerequisite. Endometriosis can also be detected in cryopreserved ovarian tissue and caution should also be exercised in this scenario.
Crit Rev Eukaryot Gene Expr. 2017;27(4):341-345.
N-myc Downstream-Regulated Gene 1 and Endometriosis: A Minireview.
NDRG1 (N-myc downstream-regulated gene 1) was previously considered to be a differentiation-related gene. However, many other functions of NDRG1 have since been identified, including proliferation, migration, invasion, and vascularization of tumor cells. Currently regarded as a tumor suppressor in most studies, NDRG1 is abundant in prostate, brain, kidney, placental, and intestinal tissues. It is expressed in normal endometrium, with higher expression occurring in the secretory phase. NDRG1 was first identified as an inhibitor of signaling pathways associated with the pathology of endometriosis. The NDRG1 protein regulation of endometriosis is assumed to be associated with several important pathways. This review summarizes the relationship between NDRG1 and endometriosis, focusing on the potential function of NDRG1 in endometriosis through signaling pathways and discusses the additional research that is required for future studies.
Gynecol Surg. 2017;14(1):27.
Recommendations for the surgical treatment of endometriosis-part 1: ovarian endometrioma.
What does this document on the surgical treatment of endometriosis jointly prepared by the European Society for Gynaecological Endoscopy (ESGE), ESHRE, and the World EndometriosisSociety (WES) provide?
This document provides recommendations covering technical aspects of different methods of surgery for endometriomas in women of reproductive age.
WHAT IS ALREADY KNOWN:
Endometriomas (ovarian endometriotic cysts) are a commonly diagnosed form of endometriosis, owing to the relative ease and accuracy of ultrasound diagnosis. They frequently present a clinical dilemma as to whether and how to treat them when found during imaging or incidentally during surgery. Previously published guidelines have provided recommendations based on the best available evidence, but without technical details on the management of endometriosis.
STUDY DESIGN SIZE AND DURATION:
A working group of ESGE, ESHRE and WES collaborated on writing recommendations on the practical aspects of endometrioma surgery.
PARTICIPANTS/MATERIALS SETTING AND METHODS:
This document focused on endometrioma surgery. Further documents in this series will provide recommendations for surgery of deep and peritoneal endometriosis.
MAIN RESULTS AND THE ROLE OF CHANCE:
The document presents general recommendations for surgery of endometrioma and specific recommendations for cystectomy, ablation by laser or by plasma energy, electrocoagulation and a combination of these techniques applied together or with an interval between them.
LIMITATIONS AND REASONS FOR CAUTION:
Owing to the limited evidence available, recommendations are mostly based on clinical expertise.
WIDER IMPLICATIONS OF THE FINDINGS:
These recommendations complement previous guidelines on the management of endometriosis.
STUDY FUNDING/COMPETING INTERESTS:
The meetings of the working group were funded by ESGE, ESHRE and WES. CB declares to be a member of the independent data monitoring committee for a clinical study by ObsEva and receiving research grants from Bayer, Roche Diagnostics, MDNA Life Sciences and Volition. ES received honoraria for provision of training to healthcare professionals from Ethicon, Olympus and Gedeon Richter. The other authors declare that they have no conflict of interest.
Exp Ther Med. 2017 Dec;14(6):5743-5750.
Effect of Hua Yu Xiao Zheng decoction on the expression levels of vascular endothelial growth factor and angiopoietin-2 in rats with endometriosis.
The aims of the present study were to investigate the effects of a traditional Chinese medicine, Hua Yu Xiao Zheng (HYXZ) decoction, on surgically induced endometriosis in a rat model and to determine the possible underlying regulatory mechanisms. A total of 108 female Sprague-Dawley rats were divided into the control group (n=12) and endometriosis group (EM group; n=96), in which endometriosis was surgically induced in model rats by autotransplantation of endometrial tissues and 72 rats survived. After 3 weeks, the EM model rats were randomly divided into four subgroups (n=18), including the untreated model group, and three groups administered 7, 14 or 21 g/kg HYXZ decoction. Following 28 days of treatment, the associated proteins and genes of ectopic endometrial tissues were analyzed using immunohistochemistry, western blotting and quantitative polymerase chain reaction to investigate the underlying mechanisms. Compared with the model group, the size of the endometriotic implants decreased significantly in the HYXZ-treated groups. Furthermore, the expression levels of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) were significantly decreased in HYXZ-treated groups compared with the model group. These results indicate that HYXZ affected the inhibition of angiogenesis and decreased the endometriotic implant volumes and histopathological scores. The effectiveness of HYXZ may be partially attributed to the decrease of VEGF and Ang-2 expression levels in the ectopic endometrium.
Mol Clin Oncol. 2017 Dec;7(6):1027-1031.
Role of endometriosis as a prognostic factor for post-progression survival in ovarian clear cell carcinoma.
The clinical significance of coexistence of endometriosis (EM) in ovarian clear cell carcinoma (CCC) has not yet been determined. The aim of the present study was to analyze the correlation of endometriosis with clinicopathological factors in CCC. The cases with CCC that received primary debulking surgery at the present hospital between 1990 and 2013 were identified. Retrospective analysis was conducted to evaluate the association between complications with EM and clinicopathological features in CCC. Of the 105 cases enrolled in the study, 45 cases were complicated with EM, and 60 cases did not have EM (non-EM). The patients with EM were diagnosed at a younger age (P=0.03), and at earlier stages (P<0.01) compared with non-EM cases. Although there was no significant difference of progression-free survival (P=0.36), complications with EM were identified as an independent prognostic factor for overall survival (OS; P<0.01) by multivariate analysis. A total of 48 patients (45.7%) developed recurrence: 18 patients in EM-group and 30 patients in non-EM group. There were no significant differences of clinicopathological factors in the treatment at recurrence between both groups. Recurrent cases in EM had significantly worse post-progression survival (PPS) compared with recurrent non-EM group (P<0.01). Multivariate analysis for PPS demonstrated that complications with EM (P<0.01) were identified as a worse prognostic factor. In CCC, the complication with EM was identified as a significant worse prognostic factor for PPS in recurrent cases. Additionally, EM was significantly associated with OS in all cases with CCC. Novel treatment strategies are therefore necessary for recurrent CCC, particularly for cases exhibiting EM.
Bosn J Basic Med Sci. 2017 Dec 29.
The clinical characteristics and surgical approach of abdominal wall endometriosis: A case series of 14 women.
Abdominal wall endometriosis (AWE) is a rare form of endometriosis that usually develops in the scar after cesarean section (CS). Recently, the occurrence of AWE has been increasing together with the increase of CS incidence. AWE can be clinically misdiagnosed as hernia, lipoma, or hematoma. Here we retrospectively analyzed the clinical aspects of AWE and surgical approach in 14 patients from a tertiary hospital, who were treated by surgery, between 2012 and 2017. The mean age was 32.71 ± 8.61 years (range: 19-45). Palpable mass and cyclic pain at the scar site were the most common complaints. Twelve patients had previously undergone CS, and two patients had undergone a surgery of ovarian endometrioma. The preoperative diagnosis was determined with ultrasonography (US), magnetic resonance imaging (MRI), or computed tomography (CT). Preoperatively, AWE was diagnosed in 12/14 patients (85.7%), while two patients (14.3%) were diagnosed with inguinal hernia. The treatment was surgical excision in all patients; in addition, mesh repair surgery was performed in one patient with recurrent AWE. Postoperatively, endometriosis was confirmed by histology in all patients.The average size of endometriomas was 24.71 ± 6.67 mm (range: 11-35). No woman had concurrent pelvic endometriosis. In the follow-up period (mean: 9 months) the recurrence of endometriosis was not observed. AWE should be considered in all women of reproductive age presenting with cyclic pain and swelling in their abdominal incision sites.
Int J Mol Med. 2018 Mar;41(3):1349-1356.
Analysis of the oncogene BRAF mutation and the correlation of the expression of wild-type BRAF and CREB1 in endometriosis.
B-Raf proto-oncogene, serine/threonine kinase (BRAF) has previously been identified as a candidate target gene in endometriosis. Wild-type and mutated BRAF serve important roles in different diseases. The aim of the present study was to explore BRAF mutation, the mRNA and protein expression of wild-type BRAF (wtBRAF) in endometriosis, and the association between the expression levels of wtBRAF and the predicted transcription factor cAMP responsive element binding protein 1 (CREB1). In the present study, BRAF mutation was detected using Sanger sequencing among 30 ectopic and matched eutopic endometrium samples of patients with endometriosis as well as 25 normal endometrium samples, and no BRAF mutation was detected in exons 11 or 15. A region of ~2,000 bp upstream of the BRAF gene was then screened using NCBI and UCSC databases, and CREB1 was identified as a potential transcription factor of BRAF by analysis with the JASPAR and the TRANSFAC databases. Quantitative polymerase chain reaction was used to analysis the mRNA expression levels of wtBRAF and CREB1, and the corresponding protein expression levels were evaluated using immunohistochemistry and western blot analysis. The results revealed that the mRNA and protein expression levels of wtBRAF and CREB1 were significantly upregulated in the eutopic endometrial tissues of patients with endometriosis compared with normal endometrial tissues (P<0.05) and no significant difference in wtBRAF and CREB1 levels was detected between the ectopic and eutopic endometrium (P>0.05). In addition, correlation analysis revealed that the protein expression of CREB1 was positively correlated with the transcript level and protein expression of wtBRAF. It is reasonable to speculate that CREB1 may activate the transcription of wtBRAF through directly binding to its promoter, increasing BRAF expression and regulating the cell proliferation, migration and invasion of endometriosis.
Am J Obstet Gynecol. 2017 Dec 26. pii: S0002-9378(17)32717-5. doi: 10.1016/j.ajog.2017.12.218. [Epub ahead of print]
Nationwide Trends in the Utilization of and Payments for Hysterectomy in the United States Among Commercially Insured Women.
Laparotomy followed by inpatient hospitalization has traditionally been the most common surgical care for hysterectomy. The financial implications of the increased use of laparoscopy and outpatient hysterectomy are unknown.
To quantify the increasing use of laparoscopy and outpatient hysterectomy and to describe the financial implications among women with commercially based insurance in the United States.
Hysterectomies between 2010 and 2013 were identified in the Health Care Cost Institute, a national dataset with inpatient and outpatient private insurance claims for more than 25 million women. Surgical approach was categorized with procedure codes as abdominal, laparoscopic, laparoscopic assisted vaginal, or vaginal. Payments were adjusted to 2013 U.S. dollars to account for change due to inflation.
Between 2010 and 2013, there were 386,226 women who underwent hysterectomy. The rate of utilization decreased 12.4%, from 39.9 to 35.0 hysterectomies per 10,000 women. The largest absolute decreases were observed among women less than 55 years and among those with uterine fibroids, abnormal uterine bleeding, and endometriosis. The proportion of laparoscopic hysterectomies increased from 26.1% to 43.4%, with concomitant decreases in abdominal (38.6% to 28.3%), laparoscopic assisted vaginal (20.2 to 16.7%), and vaginal (15.1% to 11.5%) hysterectomies. There was also a shift from inpatient to outpatient surgery. In 2010, the inpatient and outpatient rates of hysterectomy were 26.6 and 13.3 per 10,000 women, respectively. By 2013, the rates were 15.4 and 19.6 per 10,000 women. In each year of analysis, the average reimbursement for outpatient procedures was 44-46% less than for similar inpatient procedures. Offsetting the lower utilization of hysterectomy and lower reimbursement for outpatient surgery were increases in average inpatient and outpatient hysterectomy reimbursement of 19.4% and 19.8%, respectively. Total payments for hysterectomy decreased 6.3%, from $823.4 million to $771.3 million.
Between 2010 and 2013, laparoscopy emerged as the most common surgical approach for hysterectomy, and outpatient hysterectomy became more common than inpatient among women with commercially based insurance. While average reimbursement per case increased, overall payments for hysterectomy are decreasing due to decreased utilization and dramatic differences in how hysterectomy is performed.
Biotechnol Lett. 2017 Dec 29.
Sublethal concentration of H2O2 enhances the protective effect of mesenchymal stem cells in rat model of spinal cord injury.
To investigate the effect of H2O2 on the migration and antioxidant defense of mesenchymal stem cells (MSCs) and the neurotrophic effects of H2O2-treated MSCs on spinal cord injury (SCI).
Sublethal concentrations of H2O2 decreased cell migration and expression of CXCR4 and CCR2 as well as Nrf2 expression in MSCs. In the second phase, transplantation of treated and untreated MSCs to SCI caused minor changes in locomotor dysfunction. There was a significantly difference between cell-treated and spinal cord injury groups in expression of BDNF (brain-derived neurotrophic factor). Transplantation of H2O2-treated cells caused an increase in BDNF expression compared to non-treated cells.
Transplantation of H2O2-treated stem cells may have protective effects against SCI through by increasing neurotrophic factors.
J Radiol Case Rep. 2017 Dec 31;11(12):16-26..
Cesarean-Section Scar Endometrioma: A Case Report and Review of the Literature.
Endometriomas can occur after any surgery where there is endometrial manipulation, and there are a number of reports of endometriomas developing in the abdominal wall at the site of the Pfannenstiel incision following Cesarean-section. Although this is ultimately a histopathologically-confirmed diagnosis, preoperative imaging including ultrasound, computed tomography, and magnetic resonance imaging may be helpful in the diagnosis and assessment. We report a pathology-confirmed case of Cesarean-section endometrioma with a classic, clinical presentation and imaging findings on computed tomography. A comprehensive literature review and discussion of the multi-modality imaging appearance of Cesarean-section endometrioma is also provided.
Int J Surg Case Rep. 2017 Dec 27;42:247-249.
A case of endometriosis causing acute large bowel obstruction.
Endometriosis is a gynaecological condition which produce symptoms such as pelvic pain, abnormal menstruation and infertility. Intestinal endometriosis can occur however endometriosiscausing acute large bowel obstruction is extremely rare.
PRESENTATION OF CASE:
We present a 37-year-old lady with acute large bowel obstruction caused by endometriosis. Despite initial endoscopic decompression being unsuccessful due to severe mucosal stenosis, she underwent emergency laparoscopic wedge resection and decompression successfully.
Diagnosing intestinal endometriosis is difficult. While different modalities of investigation help, definitive diagnosis is achieved via laparoscopy. Treatment of obstruction is decompression followed by surgical resection.
Diagnosing intestinal endometriosis with or without obstruction is challenging. Correct diagnosis is needed for definitive management.
Ci Ji Yi Xue Za Zhi. 2017 Oct-Dec;29(4):232-234.
Fine-needle aspiration cytology of a cesarean scar endometriosis.
Endometriosis is the presence of functioning endometrium outside the basement membrane of the uterine endometrium. It affects women of reproductive age and usually presents as a painful nodule over a period of 3 months to 10 years after surgery. Extrapelvic endometriosis is uncommon and more difficult to diagnose due to its variable presentation and is often confused with other surgical conditions. Fine-needle aspiration cytology (FNAC) is a rapid, cost-effective, and accurate diagnostic tool when making this diagnosis. Wide excision is the treatment of choice for scar endometriosis as well as for recurrent lesions. We present a case of scar endometriosis in a 30-year-old female who had undergone a cesarean section 2 years previously and was diagnosed by FNAC. A later histopathological examination confirmed the cytological diagnosis of scar endometriosis.
J Pain Res. 2017 Dec 19;11:5-9.
Comparison of ultrasound-guided posterior transversus abdominis plane block and lateral transversus abdominis plane block for postoperative pain management in patients undergoing cesarean section: a randomized double-blind clinical trial study.
Due to the importance of pain control after abdominal surgery, several methods such as transversus abdominis plane (TAP) block are used to reduce the pain after surgery. TAP blocks can be performed using various ultrasound-guided approaches. Two important approaches to do this are ultrasound-guided lateral and posterior approaches. This study aimed to compare the two approaches of ultrasound-guided lateral and posterior TAP blocks to control pain after cesarean section.
MATERIALS AND METHODS:
In this double-blind clinical trial study, 76 patients scheduled for elective cesarean section were selected and randomly divided into two groups of 38 and underwent spinal anesthesia. For pain management after the surgery, one group underwent lateral TAP block and the other group underwent posterior TAP block using 20cc of ropivacaine 0.2% on both sides. Pain intensity was evaluated based on Numerical Analog Scale (NAS) at rest and when coughing, 2, 4, 6, 12, 24 and 36 hours after surgery.
The pain at rest in the posterior group at all hours post surgery was lower than the lateral group, especially at 6, 12 and 24 hours after the surgery and the difference was statistically significant (p=0.03, p<0.004, p=0.001).
The results of this study show that ultrasound-guided posterior TAP block compared with the lateral TAP block was more effective in pain control after cesarean section.
J Endocrinol. 2018 Jan 3. pii: JOE-17-0544.
Physiological and pathological implications of retinoid action in the endometrium.
Retinol (vitamin A) and its derivatives, collectively known as retinoids, are required for maintaining vision, immunity, barrier function, reproduction, embryogenesis, and cell proliferation and differentiation. Despite the fact that most events in the endometrium are predominantly regulated by steroid hormones (estrogens and progesterone), accumulating evidence shows that retinoid signaling is also involved in the development and maintenance of the endometrium, stromal decidualization, and blastocyst implantation. Moreover, aberrant retinoid metabolism seems to be a critical factor in the development of endometriosis, a common gynecological disease which affects up to 10% of reproductive-age women and is characterized by the ectopic localization of endometrial-like tissue in the pelvic cavity. This review summarizes recent advances in research on the mechanisms and molecular actions of retinoids in normal endometrial development and physiological function. The potential roles of abnormal retinoid signaling in endometriosis are also discussed. The objectives are to identify limitations in current knowledge regarding the molecular actions of retinoids in endometrial biology and to stimulate new investigations toward the development potential therapeutics to ameliorate or prevent endometriosis symptoms.
Oncotarget. 2017 Nov 27;8(66):110176-110186.
Reduced alternative splicing of estrogen receptor alpha in the endometrium of women with endometriosis.
Endometriosis is a condition which involves the presence of uterine stroma and glands outside of the uterine cavity and represents one of the most prevalent disorders of the female reproductive tract. The key symptom of endometriosis is pain, including dysmenorrhea, deep dyspareunia, and chronic pelvic pain. As such, endometriosis has significant economic consequences within the healthcare system and can influence the daily quality of life in affected patients. However, the pathophysiology of this disease and the mechanisms in which this condition generates pain are very unclear. This study, involving 30 women with endometriosis and 28 controls without endometriosis, aimed to investigate relative levels of estrogen receptor alpha (ERα) splice variants in the endometrium of women with and without endometriosis and investigate potential links to the severity of pain. Wild type (wt)-ERα was dominantly expressed in human endometrium while the expression of ERα-del.4, ERα-del.7, and ERα-del.3,4 was significantly reduced in endometriosis patients compared with healthy patients (p < 0.05). Furthermore, the relative ratios of wtERα:ERα-del.4, and wtERα:ERα-del.3,4 were associated with the severity of pain in endometriosispatients (p < 0.05). Consequently, analyzing differences in the relative levels of four types of ERα splice variant in the endometrium of patients with endometriosis may help in the development of endometriosis-targeted treatment and the development of appropriate therapies.
Ir J Med Sci. 2018 Jan 3.
Risk reduction surgery (RRS) for tubo-ovarian cancer in an Irish gynaecological practice: an analysis of indications and outcomes.
High-grade serous carcinoma (HGSC) is the most common tubo-ovarian cancer. The fallopian tube harbours the precursor lesion: serous tubal intraepithelial carcinoma (STIC). Bilateral salpingo-oophorectomy is an effective risk-reducing surgical (RRS) strategy for breast cancer susceptibility gene mutation carriers (BRCAm). The value of RRS in those without defined genetic risk is unknown but these women represent a substantial cohort in prophylactic surgical practice.
This is a retrospective review of RRS at an Irish university teaching hospital.
One hundred and thirty women underwent RRS; group 1 = 46 BRCAm; group 2 = 19 BRCAm negative/65 genetic status unknown. Group 1 had one occult HGSC. Group 2 had no STIC or cancers and were older and more likely to have hysterectomy and benign pathology. Other pathologies included serous tubal intraepithelial lesions (STIL) (2), p53 signatures (2), endometriosis (6), fibroids/adenomyosis (4) and atypical endometrial hyperplasia (1).
More than 60% of women undergoing RRS were BRCAm negative or untested. Counselling of high-risk women without defined germline mutations remains a challenge for gynaecologists because the likelihood of removing STIC lesions or occult invasive cancer is low. Removal of coincidental pathology may give added value to RRS in these women.
Hum Reprod. 2018 Feb 1;33(2):280-291.
Endometrial stromal cell attachment and matrix homeostasis in abdominal wall endometriomas.
How does progesterone alter matrix remodeling in abdominal wall endometriomas compared with normal endometrium?
Progesterone may prevent attachment of endometrial cells to the abdominal wall, but does not ameliorate abnormal stromal cell responses of abdominal wall endometriomas.
WHAT IS KNOWN ALREADY:
Menstruation is a tightly orchestrated physiologic event in which steroid hormones and inflammatory cells cooperatively initiate shedding of the endometrium. Abdominal wall endometriomas represent a unique form of endometriosis in which endometrial cells inoculate fascia or dermis at the time of obstetrical or gynecologic surgery. Invasion of endometrium into ectopic sites requires matrix metalloproteinases (MMPs) for tissue remodeling but endometrium is not shed externally.
STUDY DESIGN SIZE, DURATION:
Observational study in 14 cases and 19 controls.
PARTICIPANTS /MATERIALS, SETTING, METHODS:
Tissues and stromal cells isolated from 14 abdominal wall endometriomas were compared with 19 normal cycling endometrium using immunohistochemistry, quantitative PCR, gelatin zymography and cell attachment assays. P values < 0.05 were considered significant and experiments were repeated in at least three different cell preps to provide scientific rigor to the conclusions.
MAIN RESULTS AND THE ROLE OF CHANCE:
The results indicate that MMP2 and MMP9 are not increased by TGFβ1 in endometrioma stromal cells. Although progesterone prevents attachment of endometrioma cells to matrix components of the abdominal wall, it does not ameliorate these abnormal stromal cell responses to TGFβ1.
LARGE SCALE DATA:
LIMITATIONS REASONS FOR CAUTION:
Endometriomas were collected from women identified pre-operatively. Not all endometriomas were collected. Stromal cells from normal endometrium were from different patients, not women undergoing endometrioma resection.
WIDER IMPLICATIONS OF THE FINDINGS:
This work provides insight into the mechanisms by which progesterone may prevent abdominal wall endometriomas but, once established, are refractory to progesterone treatment.
STUDY FUNDING/COMPETING INTEREST(S):
Tissue acquisition was supported by NIH P01HD087150. Authors have no competing interests.
Health Qual Life Outcomes. 2018 Jan 4;16(1):3.
Development and content validation of a patient-reported endometriosispain daily diary.
Endometriosis is a common gynecological disorder that causes inflammation and pelvic pain. Endometriosis-related pain is best captured with patient-reported outcome (PRO) measures, however, assessment of endometriosis-related pain in clinical trials has been difficult in the absence of a reliable and valid PRO instrument. We describe the development of the Endometriosis Pain Daily Diary (EPDD), an electronic PRO developed as a survey instrument to assess endometriosis-related pain and its impact on patients’ lives.
The EPDD was initially developed on the basis of an existing Endometriosis Pain and Bleeding Diary, a targeted review of relevant literature, clinical expert interviews, and open-ended (concept elicitation) patient interviews in the United States (US) and Japan which captured patients’ experience with endometriosis. Cognitive interviews of patients with endometriosis were conducted to evaluate patient comprehension of the EPDD items. A conceptual model of endometriosis was developed, and meetings with US and European regulatory authorities provided feedback for validating the EPDD in the context of clinical trials. Translatability assessments of the EPDD were conducted to confirm its appropriate interpretation and ease of completion across 17 languages.
The iterative development progressed through three versions of the instrument. The EPDDv1 included 18 items relating to dysmenorrhea/pelvic pain, dyspareunia and sexual activity, bleeding, hot flashes, daily activities, and use of rescue medication. The EPDDv2 was a larger 43-item survey tested in cognitive interviews and subsequently revised to yield the current 11-item EPDDv3, consisting of five core items relating to dysmenorrhea, non-menstrual pelvic pain, and dyspareunia, and six extension items relating to sexual activity, daily activities, and use of rescue medication.
The EPDD is a PRO for the evaluation of endometriosis-related pain and its associated impacts on patients’ lives. The EPDD represents an important step in providing a PRO that is relevant to patients with endometriosis-related pain in the context of a clinical study setting (ie, fit-for-purpose), designed to evaluate pain associated with endometriosis, including regulatory agency support for its further exploration in clinical trials.
Reprod Sci. 2018 Jan 1:1933719
Is Shifting to a Progestin Worthwhile When Estrogen-Progestins Are Inefficacious for Endometriosis-Associated Pain?
The purpose of this study was to assess the proportion of patients satisfied with their treatment after a change from a low-dose oral contraceptive (OC) to norethisterone acetate (NETA) because of inefficacy of OC on pain symptoms. To this end, prospective, self-controlled study was conducted on 153 women using OC as a treatment for endometriosis and with persistence of one or more moderate or severe pain symptoms. At baseline and during 12 months after a shift from OC to oral NETA, 2.5 mg/d, pelvic pain was measured by means of a 0- to 10-point numerical rating scale and a multidimensional categorical rating scale. Variations in health-related quality of life, psychological status, and sexual function were also evaluated with validated scales. At the end of the study period, participants indicated the degree of satisfaction with their treatment according to a 5-degree scale from very satisfied to very dissatisfied. A total of 28 women dropped out of the study, the main reason was intolerable side effects (n = 15). At 12-month assessment, 70% of participants were very satisfied or satisfied with NETA treatment (intention-to-treat analysis). Statistically significant improvements were observed in health-related quality of life, psychological status, and sexual function. At per-protocol analysis, almost half of the patients (58/125) reported suboptimal drug tolerability. However, complaints were not severe enough to cause dissatisfaction, drug discontinuation, or request for surgery. These encouraging results could be used to counsel women with symptomatic endometriosis not responding to OC and to inform their decisions on modifications of disease managemen
Reprod Sci. 2018 Jan 1:1933719117749760.
Association Between Endometriosis and Preterm Birth in Women With Spontaneous Conception or Using Assisted Reproductive Technology: A Systematic Review and Meta-Analysis of Cohort Studies.
To perform a systematic review and meta-analysis to estimate the effect of endometriosis on preterm birth (PB) risk.
Searches were conducted in PubMed-MEDLINE, Embase, Scopus, Web of Science, Cochrane Library, Google Scholar, and SciELO for studies published in all languages from inception through April 2017. We included cohort studies evaluating pregnant women with and without endometriosis and conception either by spontaneous conception (SC) or with assisted reproductive technology (ART). Primary outcome was PB (<37 weeks), and secondary outcomes were intrauterine growth restriction (IUGR), low birthweight, small for gestational age (SGA), and birthweight. Pooled odds ratios (ORs) and its 95% confidence interval (CI) were calculated as effects, and random-effects models were used for meta-analyses. Risk of bias was assessed with the Newcastle-Ottawa Scale, and heterogeneity of effects among studies was described with the I2 statistic.
We identified 9 cohort studies including a total of 1 496 715 pregnancies (13 798 with endometriosis diagnosis). In women with endometriosis, the PB risk was significantly increased in both SC (OR: 1.59; 95% CI: 1.32-1.90) and ART (OR: 1.43; 95% CI: 1.14-1.79). The SGA risk was increased in women with endometriosis (OR: 1.16; 95% CI: 1.05-1.28), while the IUGR and low birthweight risks and birthweight were not affected by endometriosis.
Endometriosis is associated with increased PB risk in both SC and women who obtained pregnancy using ART. Prospective studies evaluating relevant outcomes are needed to confirm these results.
Ginekol Pol. 2017;88(11):585-590.
Is M235T polymorphism of the angiotensinogen gene involved in the development of endometriosis?
The aim of the study was to analyze the M235T polymorphism of the angiotensinogen (AGT) gene in women with endometriosis and to identify correlations between identified genotypes and the disease progression, its stage and clinical course as well as to evaluate the prognostic value of the investigated polymorphism in patients with endometriosis treated for infertility.
MATERIAL AND METHODS:
The study group consisted of 241 women with minimal to severe stage of endometriosis, the control group (without endometriosis) – 127. The molecular analysis was performed by PCR-RFLP technique.
The analysis of the frequency of genotypes and alleles of M235T polymorphism showed no significant differences between the study and the control groups and between the severity grades of the disease (p > 0.05). No such differences were reported in the case of different localizations of the disease lesions, either. Evaluation of the correlations related to pain accompanying endometriosis did not demonstrate association with any genotypes of the analyzed AGT gene poly-morphism. Comparison of the results obtained in the group in which infertility treatment was successful (n = 54) and in those who failed to conceive (n = 73) did not show the correlation between the investigated polymorphism and the effect of infertility treatment.
M235T polymorphism of the AGT gene seems unrelated to the development or the clinical course of en-dometriosis. No prognostic value has been found of the investigated polymorphism in predicting the effects of infertility treatment in women with endometriosis.
PLoS One. 2018 Jan 5;13(1):e0190573.
Positive associations between upregulated levels of stress-induced phosphoprotein 1 and matrix metalloproteinase-9 in endometriosis/adenomyosis.
Stress-induced phosphoprotein-1 (STIP1), an adaptor protein that coordinates the functions of HSP70 and HSP90 in protein folding, has been implicated in the development of human gynecologic malignancies. This case-control study investigates STIP1 serum levels and tissue expression in relation to endometriosis/adenomyosis in Taiwanese population. Female patients with surgically confirmed endometriosis/adenomyosis were compared with women free of endometriosis/adenomyosis. Serum STIP1 levels were measured using an enzyme-linked immunosorbent assay and surgical tissues were analyzed by immunohistochemistry. Both epithelial and stromal cells in surgical tissues of endometriosis and adenomyosis expressed STIP1 and MMP-9. Notably, MMP-9 expression was significantly decreased when STIP1 expression was knocked-down. In vitro experiments revealed that STIP1 was capable of binding to the MMP-9 promoter and enhanced its transcriptional expression. The preoperative serum STIP1 levels of patients with endometriosis/adenomyosis were significantly higher than those of the controls. In brief, our data suggest an association between STIP1 levels and endometriosis/adenomyosis.
Free Radic Biol Med. 2018 Jan 2;116:123-128.
Evaluation of the p53 and Thioredoxin reductase in sperm from asthenozoospermic males in comparison to normozoospermic males.
Thioredoxin (Trx) system has a defensive role against the harmful effect of oxidative stress in sperm. p53 is an important regulator of apoptosis and normal process of spermatogenesis. Regulation of p53 by redox state of the cell and Thioredoxin system has been reported. The aim of this study was to evaluate the ROS level, Thioredoxin reductase (TrxR) activity and p53 protein levels in sperm of asthenozoospermic and normozoospermic males. Semen samples from 80 donors were divided into asthenozoospermic (n = 40) and normozoospermic (n = 40) groups using the WHO criteria. DNA fragmentation (TUNEL assay) of spermatozoa was identified·H2O2 and O2•- were determined by flow cytometry. p53 protein levels and TrxR activity were measured in sperm cell lysate by appropriate kit. Total antioxidant capacity (TAC) and thiol groups in seminal plasma were measured spectrophotometery. MDA content in seminal plasma was determined fluorometrically.
The percentage of cells with H2O2, O2•- and DNA fragmentation was higher in asthenozoospermic compared to normozoospermic groups (p < 0.05). The p53 protein level was significantly higher in asthenozoospermic group (P < 0.001). TrxR activity in normozoospermic was significantly higher than asthenozoospermic group (P < 0.001). Total thiol groups and TAC levels were significantly higher in normozoospermic samples (P < 0.05). A significantly high negative correlation was seen between p53 protein levels with TrxR activity (r = – 0.49, P < 0.001), total motility (r = – 0.65, P < 0.001). p53 and ROS levels were increased in asthenozoospermic males while the TrxR activity was decreased. These changes lead to an increase in apoptotic, immotile and immature spermatozoa in the ejaculatory semen.
Pflugers Arch. 2018 Jan 5.
Sensing the heat with TRPM3.
Heat sensation, the ability to detect warm and noxious temperatures, is an ancient and indispensable sensory process. Noxious temperatures can have detrimental effects on the physiology and integrity of cells, and therefore, the detection of environmental hot temperatures is absolutely crucial for survival. Temperature-sensitive ion channels, which conduct ions in a highly temperature-dependent manner, have been put forward as molecular thermometers expressed at the endings of sensory neurons. In particular, several temperature-sensitive members of the transient receptor potential (TRP) superfamily of ion channels have been identified, and a multitude of in vivo studies have shown that the capsaicin-sensitive TRPV1 channel plays a key role as a noxious heat sensor. However, Trpv1-deficient mice display a residual heat sensitivity suggesting the existence of additional heat sensor(s). In this chapter, we provide evidence for the role of the non-selective calcium-permeable TRPM3 ion channel as an additional heat sensor that acts independently of TRPV1, and give an update of the modulation of this channel by various molecular mechanisms. Finally, we compare antagonists of TRPM3 to specific blockers of TRPV1 as potential analgesic drugs to treat pathological pain.
J Reprod Immunol. 2017 Dec 27;125:80-88.
Embryotoxic cytokines-Potential roles in embryo loss and fetal programming.
Cytokines in the reproductive tract environment at conception mediate a dialogue between the embryo and maternal tissues to profoundly influence embryo development and implantation success. Through effects on gene expression and the cell stress response, cytokines elicit an epigenetic impact with consequences for placental development and fetal growth, which in turn affect metabolic phenotype and long-term health of offspring. There is substantial evidence demonstrating that pro-survival cytokines, such as GM-CSF, CSF1, LIF, HB-EGF and IGFII, support embryos to develop optimally. Less attention has been paid to cytokines that adversely impact embryo development, including the pro-inflammatory cytokines TNF, TRAIL and IFNG. These agents elicit cell stress, impair cell survival and retard blastocyst development, and at sufficiently high concentrations, can cause embryo demise. Experiments in mice suggest these so-called ‘embryotoxic’ cytokines can harm embryos through pro-apoptotic and adverse programming effects, as well as indirectly suppressing uterine receptivity through the maternal immune response. Embryotrophic factors may mitigate against and protect from these adverse effects. Thus, the balance between embryotrophic and embryotoxic cytokines can impart effects on embryo development and implantation, and has the potential to contribute to endometrial ‘biosensor’ function to mediate embryo selection. Embryotoxic cytokines can be elevated in plasma and reproductive tract tissues in inflammatory conditions including infection, diabetes, obesity, PCOS and endometriosis. Studies are therefore warranted to investigate whether excessive embryotoxic cytokines contribute to infertility and recurrent implantation failure in women, and compromised reproductive performance in livestock animals.