Obstet Gynecol. 2018 Mar;131(3):557-571. doi: 10.1097/AOG.0000000000002469.

Clinical Management of Endometriosis.

Falcone T¹, Flyckt R.

 

Abstract

Endometriosis is a common and challenging condition of reproductive-aged women that carries a high individual and societal cost. The many molecular dissimilarities between endometriosis lesions and eutopic endometrium create difficulties in the development of new drug therapies and treatments. Surgery remains the gold standard for definitive diagnosis, but it must be weighed against the risks of surgical morbidity and potential decreases in ovarian reserve, especially in the case of endometriomas. Safe and effective surgical techniques are discussed within this article for various presentations of endometriosis. Medical therapy is suppressive rather than curative, and regimens that are long-term and affordable with minimal side effects are recommended. Recurrences are common and often rapid when medical therapy is discontinued. Endometriosis in the setting of infertility is reviewed and appropriate management is discussed, including when and whether surgery is warranted in this at-risk population. In patients with chronic pain, central sensitization and myofascial pain are integral components of a multidisciplinary approach. Endometriosis is associated with an increased risk of epithelial ovarian cancer; however, the risk is low and currently no preventive screening is recommended. Hormone therapy for symptomatic women with postsurgical menopause should not be delayed as a result of concerns for malignancy or recurrence of endometriosis.

 

 

 

Obstet Gynecol. 2018 Mar;131(3):572-574. doi: 10.1097/AOG.0000000000002472.

Appendiceal Endometriosis and Ectopic Pregnancy Occurring Simultaneously.

Chemerinski A¹, Lubin D, Holder S, Shah D.

Abstract

BACKGROUND:

In the setting of a known ectopic pregnancy, severe abdominal pain with clinical concern for rupture is an indication for emergency surgery. In rare cases, appendiceal pathology may occur simultaneously.

CASE:

A woman with a known ectopic pregnancy presented to the emergency department with a clinical picture consistent with its rupture. At the time of surgery, an appendectomy also was performed owing to concern for concurrent appendicitis; histopathologic examination revealed appendiceal endometriosis.

CONCLUSION:

During surgical management of ectopic pregnancy, it is important to undertake a thorough examination of the pelvis, because patients may present with multiple concurrent pathologies. In the setting of an emergency operation, when the diagnosis seems clear, this survey should not be forgotten.

 

 

 

Reprod Biol. 2018 Feb 5. pii: S1642-431X(17)30249-8. doi: 10.1016/j.repbio.2018.01.009. [Epub ahead of print]

Icon immunoconjugate treatment results in regression of red lesions in a non-human primate (Papio anubis) model of endometriosis.

Hufnagel D¹, Goetz LG¹, Hu Z², Nyachieo A³, D’Hooghe T⁴, Fazleabas A⁵, Duleba A⁶, Krikun G⁷, Taylor HS¹, Lockwood CJ⁸.

 

Abstract

Endometriosis is a common condition in reproductive-aged women characterized by ectopic endometrial lesions of varied appearance, including red, white, blue, black or powder burn coloration, which contribute to chronic pain and infertility. The immunoconjugate molecule (Icon) targets Tissue Factor, a transmembrane receptor for Factor VII/VIIa that is aberrantly expressed in the endothelium supporting ectopic endometrial tissue. Icon has been shown to cause regression of endometriosis in a murine model of disease but prior to this study had not been tested in non-human primates. This study evaluated Icon as a novel treatment for endometriosis in non-human primates (Papio anubis) using an adenoviral vector (AdIcon) delivery system. Female baboons (n = 15) underwent surgical induction of endometriosis. After laparoscopic confirmation of endometriosis lesions 6-weeks post-surgery, the treatment group (n = 7) received weekly intraperitoneal injections of viral particles carrying the sequence for Icon, resulting in expression of the protein, while the control group (n = 8) received no treatment. Icon preferentially reduced the number and volume of red vascularized lesions. Icon may present a novel treatment for endometriosis by degrading red vascularized lesions, likely by targeting tissue factor aberrantly expressed in the lesion vasculature.

 

 

 

Oncotarget. 2017 Dec 18;9(3):3704-3726. doi: 10.18632/oncotarget.23364. eCollection 2018 Jan 9.

Integrating the dysregulated inflammasome-based molecular functionome in the malignant transformation of endometriosis-associated ovarian carcinoma.

Chang CM^1,2, Wang ML^1,3, Lu KH⁴, Yang YP³, Juang CM^1,2, Wang PH^1,2,5, Hsu RJ^6,7, Yu MH⁸, Chang CC⁸.

 

Abstract

The coexistence of endometriosis (ES) with ovarian clear cell carcinoma (CCC) or endometrioid carcinoma (EC) suggested that malignant transformation of ES leads to endometriosis associated ovarian carcinoma (EAOC). However, there is still lack of an integrating data analysis of the accumulated experimental data to provide the evidence supporting the hypothesis of EAOC transformation. Herein we used a function-based analytic model with the publicly available microarray datasets to investigate the expression profiling between ES, CCC, and EC. We analyzed the functional regularity pattern of the three type of samples and hierarchically clustered the gene sets to identify key mechanisms regulating the malignant transformation of EAOC. We identified a list of 18 genes (NLRP3, AIM2, PYCARD, NAIP, Caspase-4, Caspase-7, Caspase-8, TLR1, TLR7, TOLLIP, NFKBIA, TNF, TNFAIP3, INFGR2, P2RX7, IL-1B, IL1RL1, IL-18) closely related to inflammasome complex, indicating an important role of inflammation/immunity in EAOC transformation. We next explore the association between these target genes and patient survival using Gene Expression Omnibus (GEO), and found significant correlation between the expression levels of the target genes and the progression-free survival. Interestingly, high expression levels of AIM2 and NLRP3, initiating proteins of inflammasomes, were significantly correlated with poor progression-free survival. Immunohistochemistry staining confirmed a correlation between high AIM2 and high Ki-67 in clinical EAOC samples, supporting its role in disease progression. Collectively, we established a bioinformatic platform of gene-set integrative molecular functionome to dissect the pathogenic pathways of EAOC, and demonstrated a key role of dysregulated inflammasome in modulating the malignant transformation of EAOC.

 

 

 

Biol Reprod. 2018 Feb 7. doi: 10.1093/biolre/ioy035. [Epub ahead of print]

Endometriosis alters brain electro-physiology, gene expression and increased pain sensitization, anxiety, and depression in female mice.

Li T¹, Mamillapalli R¹, Ding S², Chang H², Liu ZW¹, Gao XB¹, Taylor HS¹.

 

Abstract

Endometriosis is an estrogen-dependent inflammatory disorder among reproductive-aged women associated with pelvic pain, anxiety, and depression. Pain is characterized by central sensitization, however it is not clear if endometriosis leads to increased pain perception or if women with the disease are more sensitive to pain, increasing the detection of endometriosis. Endometriosiswas induced in mice and changes in behavior including pain perception, brain electrophysiology, and gene expression were characterized. Behavioral tests revealed that mice with endometriosis were more depressed, anxious and sensitive to pain compared to sham controls. Microarray analyses confirmed by qPCR identified differential gene expression in several regions of brain in mice with endometriosis. In these mice, genes such as Gpr88, Glra3 in insula, Chrnb4, Npas4 in the hippocampus, and Lcn2 in the amygdala were upregulated while Lct, Serpina3n (insula), and Nptx2 (amygdala) were downregulated. These genes are involved in anxiety, locomotion, and pain. Patch clamp recordings in the amygdala were altered in endometriosis mice demonstrating an effect of endometriosis on brain electrophysiology. Endometriosis induced pain sensitization, anxiety and depression by modulating brain gene expression and electrophysiology; the effect of endometriosis on the brain may underlie pain sensitization and mood disorders reported in women with the disease.

 

 

 

J Minim Invasive Gynecol. 2018 Feb 7. pii: S1553-4650(18)30103-1. doi: 10.1016/j.jmig.2018.01.028. [Epub ahead of print]

Transvaginal Natural Orifice Transluminal Endoscopic Surgery as a Rescue for Total Vaginal Hysterectomy.

Guan X¹, Bardawil E², Liu J³, Kho R⁴.

Abstract

BACKGROUND:

Transvaginal surgery is the most minimally invasive surgery for a gynecologic procedure but can be challenging for many to perform as evidenced by its declining rate. Vaginal removal of the adnexal structures can be difficult because of poor visualization. Factors such as abnormal pathology, incidental finding of early-stage endometriosis or adhesions from previous cesarean section or surgery, and obesity may further complicate the procedure. Transvaginal natural orifice transluminal endoscopic surgery (NOTES) may be performed during vaginal surgery using basic laparoscopic single-site skills as a “rescue” procedure for the complete removal of the adnexae. This allows the surgeon to complete the procedure vaginally without requiring conversion or addition of abdominal incisions. The combination of total vaginal hysterectomy (TVH) with NOTES as a “rescue” procedure may be a useful tool for gynecologic surgeons for removal of the adnexae and performance of other pelvic procedures.

STUDY OBJECTIVE:

To demonstrate various common pelvic procedures that can be performed by transvaginal NOTES after completion of TVH.

DESIGN:

Variety demonstrations of the transvaginal NOTES technique as a “rescure” for total vaginal hysterectomy with narrated video footage (Canadian Task Force classification III).

SETTING:

Academic tertiary care hospital.

PATIENTS:

Patients with various surgeries including prophylactic bilateral salpingectomy, salpingo-oophorectomy, adhesiolysis, and incidental finding of superficial endometriosis resection. This video is exempt from institutional review board review at our institution.

INTERVENTIONS:

Transvaginal NOTES adnexal surgery and other procedures using basic laparoscopic single-site surgical skills.

MEASUREMENTS AND MAIN RESULTS:

Salpingectomy, oophorectomy, lysis of adhesions, and resection of endometriosis can be performed using NOTES at the time of vaginal hysterectomy CONCLUSION: NOTES allows the surgeon to survey the pelvis for pathology and to complete other pelvic procedures transvaginally during TVH with no additional abdominal incisions. Transvaginal NOTES can be considered a “rescue” approach and can be a helpful tool for the pelvic surgeon.

Copyright © 2018 American Association of Gynecologic Laparoscopists. Published by Elsevier Inc. All rights reserved.

 

 

 

Fertil Steril. 2018 Feb 7. pii: S0015-0282(17)32052-6. doi: 10.1016/j.fertnstert.2017.11.009. [Epub ahead of print]

Mycoplasma genitalium can modulate the local immune response in patients with endometriosis.

Campos GB¹, Marques LM², Rezende IS³, Barbosa MS³, Abrão MS⁴, Timenetsky J³.

Abstract

OBJECTIVE:

To detect Mollicutes in women with endometriosis and healthy peritoneal tissues and evaluate the participation of these bacteria in the immune response during endometriosis.

DESIGN:

Cross-sectional study.

SETTING:

University hospitals.

PATIENT (S):

Women with endometriosis (n = 73) and without endometriosis (n = 31).

INTERVENTION(S):

Endocervical swabs, peritoneal fluid, and biopsied lesions of endometriosis of women with endometriosis(study group) and healthy peritoneal tissues (control group) were collected during surgery. Clinical characteristics were registered before surgery.

MAIN OUTCOME MEASURE(S):

We determined the infectious agents with the use of quantitative polymerase chain reaction (PCR). The cytokine secretion profile was determined with the use of Luminex. The expression of immune response related genes was determined with the use of a PCR array kit.

RESULT(S):

All target microorganisms were detected at least once in the swab samples analyzed. It was possible to observe higher diversity of microorganisms in the samples of swab and peritoneal fluid in the study group compared with the control. Ureaplasma parvum was associated with the severity of the symptom dyspareunia. Mycoplasma genitalium was associated with higher production of interferon-γ and interleukin-1β. Genes of inflammatory response activation and antigen presentation were up-regulated in biopsied tissue of women with endometriosis. In women with endometriosis, peritoneal fluid cells showed a down-regulation of genes associated with the inflammatory response. This down-regulation profile was higher in presence of M. genitalium.

CONCLUSION(S):

Mycoplasma genitalium may play a key role in the immune tolerance process and, especially, the aggravation of this profile. More studies are needed to understand this immune tolerance profile of bacterial infections.

 

 

 

Acta Obstet Gynecol Scand. 2018 Feb 12. doi: 10.1111/aogs.13328. [Epub ahead of print]

Medical treatment in the management of deep endometriosis infiltrating the proximal rectum and sigmoid colon: a comprehensive literature review.

Vercellini P^1,2, Buggio L², Borghi A¹, Monti E², Gattei U², Frattaruolo MP².

 

Abstract

A comprehensive literature review was performed to evaluate the effect of various hormonal therapies, in terms of variations of intestinal and pain complaints and of patient satisfaction with treatment, in women with symptomatic, non-severely sub-occlusive endometriosis infiltrating the proximal rectum and sigmoid colon. A MEDLINE search through PubMed from 2000 to 2018 was conducted to identify all original English language articles published on medical treatment for colorectal endometriosis. Additional reports were identified by systematically reviewing reference lists and using the “similar articles” function in PubMed. A total of 420 women with colorectal endometriosis treated with combined oral contraceptives, progestins, gonadotropin releasing-hormone (GnRH) agonists and aromatase inhibitors have been described in eight case series, two retrospective cohort studies and four case reports. Published data consistently suggest that several hormonal medications can control most symptoms associated with intestinal endometriosis, provided the relative bowel lumen stenosis is less than 60%. Patients with irritative-type symptoms appear to respond better than those with constipation. Overall, about two-thirds of women were satisfied with the treatment received, independently of the drug used. Progestins are the compound supported by the largest body of evidence. The addition of aromatase inhibitors or, alternatively, the use of GnRH agonists does not seem to be associated with better outcomes. Long-term treatment with a progestin should be proposed as an alternative to surgery to patients with non-severely sub-occlusive endometriosis infiltrating the proximal rectum and sigmoid colon who are not seeking conception. The final decision should be shared together with the woman, respecting her preferences and priorities.

 

 

 

J Minim Invasive Gynecol. 2018 Feb 9. pii: S1553-4650(18)30114-6. doi: 10.1016/j.jmig.2018.02.002. [Epub ahead of print]

Anterior Focal Adenomyosis and Bladder Deep Infiltrating Endometriosis: Is There a Link?

Marcellin L¹, Santulli P¹, Bortolato S², Morin C³, Millischer AE⁴, Borghese B¹, Chapron C⁵.

Abstract

STUDY OBJECTIVE:

To evaluate the association between bladder deep infiltrating endometriosis (DIE) and anterior focal adenomyosis of the outer myometrium (aFAOM) diagnosed by preoperative magnetic resonance imaging (MRI).

DESIGN:

An observational, cross-sectional study using prospectively collected data (Canadian Task Force classification II-2).

SETTING:

Single university tertiary referral center.

PATIENTS:

All nonpregnant women younger than 42 years who had undergone complete surgical exeresis of endometriotic lesions. For each patient a standardized questionnaire was completed during a face-to-face interview conducted by the surgeon during the month preceding the surgery. Only women with preoperative standardized uterine MRI were retained for this study.

INTERVENTIONS:

Thirty-nine women with histologically proven bladder DIE and an available preoperative MRI were enrolled in the study. Patients were divided into 2 groups: women with aFAOM (aFAOM (+), n = 19) and women without aFAOM (aFAOM (-), n = 20). Both groups were compared for general characteristics, medical history, MRI findings, and disease severity.

MEASUREMENTS AND MAIN RESULTS:

Nineteen patients (48.7%) with bladder DIE had aFAOM at preoperative MRI. The rate of associated diffuse adenomyosis was similar in the 2 groups (63.2% [n = 12] vs 73.7% [n = 14]; p = .48). The rate of an associated ovarian endometrioma (OMA) was significantly lower in the aFAOM (+) group (10.5% [n = 2] vs 40.0% [n = 8]; p = .03). There were fewer associated intestinal DIE lesions in the aFAOM (+) group compared with the aFAOM (-) group (26.3% vs 75.0%; p = .02), with lower involvement of the pouch of Douglas (26.3% vs 70%; p < .01). Total American Society for Reproductive Medicine score was significantly lower in the aFAOM (+) group (13.8 ± 12.2 vs 62.2 ± 46.2; p < .01).

CONCLUSION:

aFAOM is present in only half of women with bladder DIE and appears to be associated with lower associated posterior DIE.

 

 

 

Yonago Acta Med. 2018 Feb 5;60(4):227-233. doi: 10.24563/yam.2017.12.003. eCollection 2017 Dec.

SR-16234, a Novel Selective Estrogen Receptor Modulator for Pain Symptoms with Endometriosis: An Open-label Clinical Trial.

Harada T¹, Ohta I², Endo Y³, Sunada H³, Noma H⁴, Taniguchi F¹.

Abstract

BACKGROUND:

SR-16234 is a selective estrogen receptor modulator (SERM) structurally different from approved SERM and has been reported to have estrogen receptor (ER) α antagonistic activity and strong affinity with a weak partial agonistic activity to ERβ receptor. SR-16234 showed strong inhibitory effects on transplanted endometrial cysts in the endometriosis model of rat and mouse. In this clinical trial, efficacy and safety of SR-16234 have been evaluated in endometriosis patients.

METHODS:

This trial was an open-label single arm clinical trial. Ten patients with dysmenorrhea and pelvic pain associated with endometriosis and adenomyosis were enrolled in this trial, and received 40 mg of SR-16234 once daily for 12 weeks. The primary endpoint was the visual analogue scale (VAS) of pelvic pain. The secondary endpoints included dysmenorrhea score, pelvic pain score, objective observations (stiffness of Douglas’ pouch, limitation of uterine movement, size of ovarian chocolate cysts, thickness of endometrium, and serum CA125 concentration) and safety.

RESULTS:

After oral administration of SR-16234 40 mg for 12 weeks, there were statistically significant decreases in pelvic pain VAS, total pelvic pain score, total dysmenorrhea score, stiffness of Douglas’ pouch, limitation of uterine movement compared with the baseline values.

CONCLUSION:

The present trial suggested that a selective estrogen receptor modulator could be used for treatment of pain associated with endometriosis for the first time.

 

 

 

Oncol Lett. 2018 Feb;15(2):1529-1532. doi: 10.3892/ol.2017.7449. Epub 2017 Nov 20.

Co-existence of benign gynecological tumors with endometriosis in a group of 1,000 women.

Matalliotaki C¹, Matalliotakis M¹, Ieromonachou P², Goulielmos GN³, Zervou MI³, Laliotis A⁴, Spandidos DA⁵, Arici A⁶, Matalliotakis I¹.

 

Abstract

The purpose of this study was two-fold, first to investigate the association between endometriosis and the risk of benign gynecologic tumors and, secondly, to evaluate the distribution of endometrioma and ovarian cysts in women with endometriosis. The medical and pathological reports of 1,000 women with endometriosis were retrospectively reviewed. The incidence of ovarian cysts, uterine leiomyomas and adenomyosis, as well as the side of ovarian cysts were further compared. A total of 295 cases of endometriomas, 172 cases of adenomyosis, 173 cases of ovarian cysts and 89 cases of uterine leiomyomas were confirmed histologically in patients with endometriosis. Serous cysts represented the most frequent diagnosis (n=81, 8.1%) in women with ovarian cysts, followed by dermoid cysts (n=15, 1.2%). In women with unilateral endometriomas, the observed proportion of left-sided cysts was found in 65.6% (164 of 250), significantly higher compared with right-sided cysts (86 out of 250, 34.4%) (P<0.001). Moreover, patients with other ovarian cysts were recognized as left-sided in 60% (96 out of 160) of cases, significantly higher compared with right-sided cysts (64 out of 160, 40%) (P<0.01). On the whole, the current study indicates that endometriosis may be associated with an increased risk of benign gynecological tumors, such as ovarian cysts, adenomyosis and leiomyomas. The results of this study confirm a left lateral predisposition of endometriomas and ovarian cysts.

 

 

 

Oncotarget. 2017 Dec 28;9(4):5344-5367. doi: 10.18632/oncotarget.23747. eCollection 2018 Jan 12.

Expression and function of nuclear receptor coactivator 4 isoforms in transformed endometriotic and malignant ovarian cells.

Rockfield S¹, Flores I², Nanjundan M¹.

 

Abstract

Iron is proposed to contribute to the transition from endometriosis to specific subtypes of ovarian cancers (OVCAs). Regulation of intracellular iron occurs via a ferritinophagic process involving NCOA4 (Nuclear Receptor Coactivator 4), represented by two major isoforms (NCOA4α and NCOA4β), whose contribution to ovarian cancer biology remains uninvestigated. We thus generated transformed endometriotic cells (via HRAS^V12A, c-MYC^T58A, and p53 inactivation) whose migratory potential was increased in response to conditioned media from senescent endometriotic cells. We identified elevated NCOA4 mRNA in transformed endometriotic cells (relative to non-transformed). Knockdown of NCOA4 increased ferritin heavy chain (FTH1) and p21 protein which was accompanied by reduced cell survival while NCOA4β overexpression reduced colony formation. NCOA4α and NCOA4β mRNA were elevated in malignant versus non-malignant gynecological cells; NCOA4α protein was increased in the assessed malignant cell lines as well as in a series of OVCA subtypes (relative to normal adjacent tissues). Further, NCOA4 protein expression was regulated in a proteasome- and autophagy-independent manner. Collectively, our results implicate NCOA4 in ovarian cancer biology in which it could be involved in the transition from precursors to OVCA.

 

 

 

Endocrinology. 2018 Apr 1;159(4):1630-1641. doi: 10.1210/en.2017-03227.

Hypoxia Promotes Ectopic Adhesion Ability of Endometrial Stromal Cells via TGF-β1/Smad Signaling in Endometriosis.

Lin X^1,2, Dai Y^1,2, Xu W^1,2, Shi L^1,2, Jin X^1,2, Li C^1,2, Zhou F^1,2, Pan Y^1,2, Zhang Y^1,2, Lin X^1,2, Zhang S^1,2.

 

Abstract

Hypoxia plays a vital role in the progression of endometriosis. Additionally, integrin-mediated aberrant adhesion is also essential for establishment of endometriotic lesions. In this study, we sought to determine the function of hypoxia in integrin-mediated adhesion of endometrial stromal cells (ESCs) in endometriosis. The expressions of adhesion molecule integrins (integrin α5, integrin αV, integrin β3, and integrin β5) were determined in 15 normal endometria and 15 paired eutopic and ectopic endometria by immunohistochemistry. Thirteen primary ESCs from patients with peritoneal endometriosis in the proliferative phase were cultured under a hypoxic (1% O2) or normoxic (21% O2) environment, and the expression levels of hypoxia-inducible factor (HIF)-1α, transforming growth factor (TGF)-β1, and integrins were detected by quantitative reverse transcription polymerase chain reaction and western blot. The alteration of integrins in endometriotic mouse models were also explored. Our results demonstrated that HIF-1α and integrins were highly expressed in ESCs of endometriotic lesions compared with ESCs of eutopic and normal endometrium. Hypoxia treatment significantly increased ESC adhesion abilities and integrin expression, which were positively correlated with TGF-β1 expression. Both TGF-β1 and hypoxia enhanced ESC adhesion properties, whereas hypoxia combined with TGF-β1 receptor inhibitor inhibited ESC adhesion. Knockdown of HIF-1α attenuated TGF-β1/Smad signaling activation and integrin expression and reduced ESC adhesion. Higher expression levels of HIF-1α, TGF-β1, and integrins were detected in endometriotic cysts from mice models. Our findings provide a novel insight of endometriosis that the hypoxic microenvironment stimulates ESCs to produce excessive TGF-β1 and activates the TGF-β1/Smad signaling pathway, thus enhancing integrin expression and the adhesion ability of ESCs.

 

 

 

Reprod Sci. 2018 Jan 1:1933719118756755. doi: 10.1177/1933719118756755. [Epub ahead of print]

Caloric Restriction Dramatically Stalls Lesion Growth in Mice With Induced Endometriosis.

Yin B¹, Liu X^1,2, Guo SW^1,2.

 

Abstract

Caloric restriction (CR) has been demonstrated to have many health-beneficial effects in many species, but whether CR can impede the development of endometriosis is unknown. To test the hypothesis that CR can impede the growth of endometriotic lesions and fibrogenesis, we conducted 2 experiments. In experiment 1, 20 female Balb/C mice were randomly assigned to either ad libitum (AL) group that was fed AL or to CR group that was fed 30% less calories than that of AL mice. Two weeks after the implementation of the dietary intervention, endometriosis was induced by intraperitoneal injection of endometrial fragments. Two weeks after the induction, all mice were sacrificed and their lesion samples were evaluated. In experiment 2, another 20 mice were used and CR was implemented 2 weeks after induction of endometriosis and lasted for 4 weeks. Caloric restriction instituted before the induction of endometriosis reduced the lesion weight by 88.5%, whereas CR implemented well after lesions were established reduced the lesion weight by 93.0%. In both cases, CR significantly increased staining levels of markers of autophagy but reduced proliferation, angiogenesis, steroidogenesis, and fibrosis in lesions as compared with the AL group. Consequently, CR, instituted either before or after the induction of endometriosis, dramatically curbs the growth of endometriotic lesions and fibrogenesis through multiple mechanisms. Caloric restriction and CR mimetics, a family of compounds mimicking the beneficial effect of CR, even when instituted well after lesions are established, may stall the development of endometriosis. Given the scarcity in research on how lifestyle can impact on the development of endometriosis, our study should hopefully stimulate more research in this area.

 

 

 

Sci Rep. 2018 Feb 13;8(1):2917. doi: 10.1038/s41598-018-21318-9.

The Primodos components Norethisterone acetate and Ethinyl estradiol induce developmental abnormalities in zebrafish embryos.

Brown S¹, Fraga LR^1,2, Cameron G³, Erskine L¹, Vargesson N⁴.

 

Abstract

Primodos was a hormone pregnancy test used between 1958-1978 that has been implicated with causing a range of birth defects ever since. Though Primodos is no longer used, it’s components, Norethisterone acetate and Ethinyl estradiol, are used in other medications today including treatments for endometriosis and contraceptives. However, whether Primodos caused birth defects or not remains controversial, and has been little investigated. Here we used the developing zebrafish embryo, a human cell-line and mouse retinal explants to investigate the actions of the components of Primodos upon embryonic and tissue development. We show that Norethisterone acetate and Ethinyl estradiol cause embryonic damage in a dose and time responsive manner. The damage occurs rapidly after drug exposure, affecting multiple organ systems. Moreover, we found that the Norethisterone acetate and Ethinyl estradiol mixture can affect nerve outgrowth and blood vessel patterning directly and accumulates in the forming embryo for at least 24 hrs. These data demonstrate that Norethisterone acetate and Ethinyl estradiol are potentially teratogenic, depending on dose and embryonic stage of development in the zebrafish. Further work in mammalian model species are now required to build on these findings and determine if placental embryos also are affected by synthetic sex hormones and their mechanisms of action.

 

 

 

Adv Clin Exp Med. 2017 Dec;26(9):1431-1435. doi: 10.17219/acem/41149.

Relationship between resistin and IL-23 levels in follicular fluid in infertile patients with endometriosis undergoing IVF-ET.

Zhang QF¹, Chen GY², Liu Y², Huang HJ², Song YF².

Abstract

BACKGROUND:

Endometriosis (EM) interferes with the reproductive process and affects the success rate of in vitro fertilization (IVF). Inflammatory cytokines are suggested to play a role in infertility in patients with EM.

OBJECTIVES:

In this study, we aimed to investigate the relationship between resistin and interleukin 23 (IL-23) levels in follicular fluid (FF) and serum together with the severity of endometriosis and in vitro fertilization/ embryo transfer (IVF-ET) outcome.

MATERIAL AND METHODS:

Samples from 116 infertile women were studied using enzyme-linked immunosorbent assay (ELISA). The study group consisted of 76 infertile patients diagnosed with EM (40 with stages I-II and 36 with stages III-IV) undergoing IVF-ET. The control group included 40 women with tubal factor infertility. FF and serum samples were collected on the day of follicle aspiration and hCG administration, respectively.

RESULTS:

The serum and FF resistin levels were significantly higher in the EM group than in the control group (p-value <0.05). The FF resistin and IL-23 levels were significantly higher in EM stages III-IV than in stages I-II (p-value <0.05), and the serum resistin and IL-23 levels were also significantly (p-value <0.01) higher in stages III-IV than in stages I-II. The E2 level on the day of hCG administration and the implantation rate were both significantly lower in the EM group than in the control group. However, there were no differences in the Gn duration and dose, and the cleavage, implantation and clinical pregnancy rates between the 2 groups.

CONCLUSIONS:

Our results suggest that patients with EM exhibit increased resistin level in FF and serum. Advanced EM may contribute to infertility via decreased embryo implantation rates because of inflammation and immune rejection. No influence was observed on pregnancy outcomes after IVF-ET.

 

 

 

Asian J Endosc Surg. 2018 Feb;11(1):7-14. doi: 10.1111/ases.12464. Epub 2018 Feb 14.

Laparoscopic surgery with urinary tract reconstruction and bowel endometriosisresection for deep infiltrating endometriosis.

Ota Y¹, Andou M¹, Ota I².

 

Abstract

Deep infiltrating endometriosis (DIE) is the most severe form of endometriosis. It causes chronic pelvic pain, severe dysmenorrhea, deep dyspareunia, dyschezia, and dysuria, markedly impairing the quality of life of women of reproductive age. A number of randomized controlled trials on surgical and medical treatments to reduce the pain associated with endometriosis have been reported, but few have focused on this in DIE. DIE causes not only pain but also functional invasion to the urinary organs and bowel, such as hydronephrosis and bowel stenosis. In addition to DIE resection, surgical treatment involves adhesion separation as well as resection and reconstruction of the urinary organs and bowel; high-level skills are required. The severity of DIE should be evaluated preoperatively as accurately as possible. Using ENZIAN in conjunction with the AFS (The revised American Fertility Society classification of endometriosis) classification makes a more detailed assessment of DIE possible. The operative procedures used for laparoscopic resection of urinary DIE and reconstruction of the urinary organs are chosen based on the type of lesion (intrinsic/extrinsic) and length of stenosis. In addition to ureteroneocystostomy, the psoas bladder hitch and Boari bladder flap procedures are applied when necessary to extend the urinary tract. Bowel resection for bowel endometriosis is classified into classic segmental resection and conservative approaches (shaving/discoid). When these procedures are employed, it is advisable to work in consultation with urologists and gastroenterologists and to inform the patients of the associated risks and outcomes. Furthermore, postoperative medication is essential because it is difficult to conduct repeated surgeries.

 

 

 

Med J Islam Repub Iran. 2017 Sep 6;31:56. doi: 10.14196/mjiri.31.56. eCollection 2017.

Comparison of intramuscular progesterone with oral nifedipine for treating threatened preterm labor: A randomized controlled trial.

Haghighi L¹, Rashidi M², Najmi Z³, Homam H⁴, Hashemi N⁴, Mobasseri A⁴, Moradi Y⁵.

 

Abstract

Background: Threatened preterm labor (TPL) is the leading cause of hospitalization during pregnancy. Tocolytic agents are the primary therapeutic options for TPL. The aim of this study is to compare intramuscular progesterone with oral nifedipine as a tocolytic agent. Methods: This randomized controlled trial was carried out in a teaching hospital (Shahid Akbarabadi) in Tehran, Iran, from December 2011 to November 2012. Three hundred and fifteen singleton pregnant women aged >18 yrs at 26-34 weeks’ gestation with the diagnosis of threatened preterm labor (TPL) were randomly received either intramuscular progesterone or oral nifedipine for tocolysis. Maternal and neonatal outcomes were then compared between the two interventions. P value less than 0.05 was considered statistically significant. IRCT registration number of this study is IRCT201112198469N1 Results: The success rate of progesterone and nifedipine in treating TPL were 83% and 82.7%, respectively. There was no significant difference between the two interventions with regard to gestational age at delivery, type of delivery, the time interval until the delivery, birth weight, NICU admission rate and hospital stays. Progesterone administration was associated with lower duration of NICU stay as compared with nifedipine (0.33±0.77 days vs.1.5±3.2 days, p<0.05). None of the two drugs caused any major side effects. Conclusion: Single dose intramuscular progesterone is as effective as oral nifedipine in treating TPL. It also significantly reduces the NICU stay.

 

 

 

Gynecol Endocrinol. 2018 Feb 15:1-4. doi: 10.1080/09513590.2017.1397116. [Epub ahead of print]

Operation, hormone therapy and recovery of the patients with severe forms of adenomyosis.

Tskhay V¹, Schindler AE², Мikailly G¹.

 

Abstract

Endometriosis is among the prevalent gynecological diseases and diagnosed in 10% of women of reproductive age. Endometriosis/adenomyosis is becoming increasingly a health-social problem, which is associated with severe clinical manifestations and recurrent disease which has a negative effect on quality of life, women ability to work and her reproductive function. This article presents modern approaches of drug therapy to treat severe forms of adenomyosis. We have reviewed recent major studies in the field of surgical treatment of this disease, analyzed the main stages of disease progress and the results of our surgeries. Here, we are presenting our own results of long-term post-operative hormonal therapy and complex medical treatment.

 

 

 

Pain Med. 2018 Feb 13. doi: 10.1093/pm/pny001. [Epub ahead of print]

Small Fiber Polyneuropathy Is Prevalent in Patients Experiencing Complex Chronic Pelvic Pain.

Chen A¹, De E², Argoff C³.

Abstract

OBJECTIVE:

To demonstrate the prevalence of small fiber polyneuropathy (SFPN) in patients with refractory chronic pelvic pain (CPP).

DESIGN:

Retrospective study of prospective database.

SUBJECTS:

Participants were complex CPP patients recruited from subspecity referral clinics defined as those who were refractory to initial treatment and/or exhibited comorbid pain syndromes at initial presentation.

METHODS:

Comprehensive treatment history for CPP was obtained, and participants referred as above; 3-mm punch biopsies were obtained of the lower extremity and sent to diagnostic reference labs to evaluate for SFPN. The reported lab sensitivity and specificity for SFPN are 78-92% and 65-90%, respectively.

RESULTS:

Twenty-five of 39 patients (64%) were positive for SFPN. Comorbid conditions noted in our population included gastroesophageal reflux disease (46%), migraine (38%), irritable bowel syndrome (33%), lower back pain (33%), fibromyalgia (38%), endometriosis (15%), interstitial cystitis (18%), vulvodynia (5%), and other chronic pain syndromes (36%).

CONCLUSIONS:

The prevalence of SFPN in our specialty referral patients with complex CPP is remarkably high vs published general population prevalence data (53/100,000). Identification of SFPN in this complex population shifts the focus from undefined syndromes to symptom complexes with linked potentially treatable mechanisms (e.g., SFPN, central sensitization). Most CPP patients with SFPN are undiagnosed. Considering the diagnosis may expand treatment options beyond conventional or so-called adjuvant analgesics. Treatment may expand to therapies such as IV lidocaine, IVIG, or other immunomodulatory options. In addition, the value to the patient of receiving a diagnosis for a multisystem or refractory pain syndrome, often attributed to negative psychologic factors, cannot be underestimated. Identifying SFPN should be contemplated in CPP patients who present with multisystem pain or who have not responded to initial evaluation and management.

 

 

 

Hum Reprod Update. 2018 Feb 13. doi: 10.1093/humupd/dmy003. [Epub ahead of print]

Sirtuins in gamete biology and reproductive physiology: emerging roles and therapeutic potential in female and male infertility.

Tatone C^1,2, Di Emidio G^1,2, Barbonetti A³, Carta G^1,2, Luciano AM⁴, Falone S¹, Amicarelli F^1,5.

Abstract

BACKGROUND:

Sirtuins (SIRT1-7) are a family of NAD+-dependent deacetylases that catalyze post-translational modifications of proteins. Together, they respond to metabolic challenges, inflammatory signals or hypoxic/oxidative stress, and are associated with aging and longevity. The role of Sirtuins in the regulation of fertility emerged in 2003 when a defective reproductive phenotype was observed in SIRT1-null mice. Although studies on Sirtuins in reproductive biology have been increasing in the last years, a recent comprehensive update on this issue is still lacking.

OBJECTIVE AND RATIONALE:

This review is aimed to provide knowledge on the activation mechanism and cellular role of Sirtuins and to give an update of the rapid development of Sirtuin research in female and male reproduction under physiological and pathological conditions. The final goal is to assess whether strategies aimed to improve Sirtuin expression or activity could have therapeutic potential for infertility associated with polycystic ovarian syndrome (PCOS), endometriosis, diabetes, xenobiotic stress and aging.

SEARCH METHODS:

The MEDLINE database was examined for peer-reviewed original articles. The following keywords were searched: ‘Sirtuin’, ‘ovary’, ‘oocyte’, ‘ovarian follicle’, ‘embryo’, ‘endometrium’, ‘sperm’ and ‘testis’. These keywords were combined with other search phrases relevant to the topic.

OUTCOMES:

Our knowledge of Sirtuins in reproductive functions has grown exponentially over the last few years. The majority of the work carried out so far has focused on SIRT1 with a prevalence of studies on female reproduction. Numerous studies have provided evidence that down-regulation of SIRT1 is associated with physiological or pathological reduction of ovarian reserve. SIRT1 has also been shown to regulate proliferation and apoptosis in granulosa cells whereas SIRT3 was found to promote luteinisation. Biochemical modulation of Sirtuin activity has led to discoveries of the roles of SIRT1, SIRT2, SIRT3 and SIRT6 in improving the competence of oocytes grown or matured in vitro in humans and animal models. Recently, SIRT1, SIRT2 and SIRT3 have emerged as protectors of oocyte against postovulatory aging. Transgenic models provide strong evidence that SIRT1 is involved in spermatogenesis by influencing specific functions of male germ cell, Sertoli cells and Leydig cells. When our attention moves to post-fertilization events, maternally derived SIRT3 appears crucial in the protecting early embryos against stress conditions. Finally, increasing SIRT1 activity may have the potential to ameliorate fertility in PCOS, diabetes, endometriosis, xenobiotic stress and aging. Overall, these effects have been ascribed to Sirtuin-mediated regulation of energy homoeostasis, mitochondrial biogenesis, chromatin remodelling and protection against oxidative stress.

WIDER IMPLICATIONS:

The present review provides challenges and opportunities to stimulate research and exploit Sirtuin-based signalling as diagnostic tools and potential targets for therapeutic applications in reproductive medicine.

© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

 

 

 

Cell Physiol Biochem. 2018;45(3):1172-1190. doi: 10.1159/000487450. Epub 2018 Feb 9.

Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy.

Zhao Q¹, Ye M¹, Yang W¹, Wang M^1,2, Li M¹, Gu C^1,3, Zhao L⁴, Zhang Z¹, Han W⁵, Fan W¹, Meng Y¹.

Abstract

BACKGROUND/AIMS:

Mitochondrial homeostasis is implicated in the development and progression of endometriosis through poorly defined mechanisms. Mst1 is the major growth suppressor related to cancer migration, apoptosis and proliferation. However, whether Mst1 is involved in endometriosis apoptosis and migration via regulating the mitochondrial function remains to be elucidated.

METHODS:

Expression of Mst1 in endometriosis was examined via western blots. Cellular apoptosis was detected via MTT and TUNEL assay. Gain of function assay about Mst1 was conducted via adenovirus over-expression. Mitochondrial functions were evaluated via mitochondrial membrane potential JC-1 staining, ROS flow cytometry analysis, mPTP opening assessment and immunofluorescence of HtrA2/Omi. The mitophagy activity were examined via western blots and immunofluorescence.

RESULTS:

First, we found that Mst1 was significantly downregulated in the ectopic endometrium of endometriosis compared to the normal endometrium. However, the recovery of Mst1 function was closely associated with the inability of endometrial stromal cells (ESCs) to migrate and survive. A functional study indicated that regaining Mst1 enhanced Drp1 post-transcriptional phosphorylation at Ser616 and repressed Parkin transcription activity via p53, leading to mitochondrial fission activation and mitophagy inhibition. Excessive Drp1-related fission forced the mitochondria to liberate HtrA2/Omi into the cytoplasm. Moreover, Mst1-induced defective mitophagy evoked cellular oxidative stress, energy metabolism and calcium overload. Through excessive mitochondrial fission and aberrant mitophagy, Mst1 launched caspase 9-related mitochondrial apoptosis and abrogated F-actin/lamellipodium-dependent cellular migration. Notably, we also defined NR4A/miR181c as the upstream signal for Mst1 dysfunction in endometriosis.

CONCLUSION:

Collectively, our results comprehensively described the important role of the NR4A-miR181c-Mst1 pathway in endometriosis, which handled mitochondrial apoptosis and F-actin/ lamellipodium-based migration via the regulation of Drp1-related mitochondrial fission and Parkin-required mitophagy, with a potential application in endometriosis therapy by limiting ESCs migration and promoting apoptosis.

 

 

 

Reprod Sci. 2018 Jan 1:1933719118757682. doi: 10.1177/1933719118757682. [Epub ahead of print]

Circulating Neutrophil Extracellular Traps Are Elevated in Patients With Deep Infiltrating Endometriosis.

Munrós J¹, Tàssies D², Reverter JC², Martin L², Pérez A¹, Carmona F¹, Martínez-Zamora MÁ¹.

 

Abstract

Neutrophil extracellular traps (NETs) have been described to be related to the pathogenesis of inflammatory and autoimmune conditions. Endometriosis is currently considered a chronic inflammatory condition. Therefore, we performed a preliminary case-control study to compare the circulating plasma NET levels in patients with surgically confirmed endometriosis (E group, n = 82) and those of patients without surgical findings of endometriosis (C group, n = 35). Venous blood samples were obtained at the time of surgery. Circulating plasma NET levels were assessed as histone-DNA complexes (ie, nucleosomes) by a quantitative sandwich enzyme-linked immunosorbent assay. The results were expressed in arbitrary units. Circulating plasma NET levels were significantly higher in the E group compared with the C group (median [25th; 75th percentiles]): E group: 0.734 [0.484; 1.363]; C group: 0.541 [0.411; 0.653]; P = .005). The subanalysis of E group patients with deep infiltrating endometriosis (DIE group) or without DIE (non-DIE group) showed that plasma NET levels were higher in the DIE group ( P = .02). No differences were observed in NET levels among patients with and without severe pelvic pain or in patients with and without infertility, regardless of the presence of endometriotic lesions. Therefore, our study shows significantly higher NET levels in patients with endometriosis, which seem to be attributed to increased levels in the subgroup of patients with DIE, suggesting that the presence of elevated circulating plasma NET levels may reflect an inflammatory status in this gynecological condition. Further research is warranted to confirm our findings and to assess the exact role of NETs in the pathophysiological mechanisms of endometriosis.

 

 

 

Insights Imaging. 2018 Feb 15. doi: 10.1007/s13244-017-0591-0. [Epub ahead of print]

Endometriosis: clinical features, MR imaging findings and pathologic correlation.

Foti PV¹, Farina R², Palmucci S², Vizzini IAA², Libertini N², Coronella M², Spadola S³, Caltabiano R³, Iraci M⁴, Basile A², Milone P², Cianci A⁴, Ettorre GC².

Abstract

OBJECTIVE:

We illustrate the magnetic resonance imaging (MRI) features of endometriosis.

BACKGROUND:

Endometriosis is a chronic gynaecological condition affecting women of reproductive age and may cause pelvic pain and infertility. It is characterized by the growth of functional ectopic endometrial glands and stroma outside the uterus and includes three different manifestations: ovarian endometriomas, peritoneal implants, deep pelvic endometriosis. The primary locations are in the pelvis; extrapelvic endometriosis may rarely occur. Diagnosis requires a combination of clinical history, invasive and non-invasive techniques. The definitive diagnosis is based on laparoscopy with histological confirmation. Diagnostic imaging is necessary for treatment planning. MRI is as a second-line technique after ultrasound. The MRI appearance of endometriotic lesions is variable and depends on the quantity and age of haemorrhage, the amount of endometrial cells, stroma, smooth muscle proliferation and fibrosis. The purpose of surgery is to achieve complete resection of all endometriotic lesions in the same operation.

CONCLUSION:

Owing to the possibility to perform a complete assessment of all pelvic compartments at one time, MRI represents the best imaging technique for preoperative staging of endometriosis, in order to choose the more appropriate surgical approach and to plan a multidisciplinary team work.

TEACHING POINTS:

• Endometriosisincludes ovarian endometriomas, peritoneal implants and deep pelvic endometriosis. • MRI is a second-line imaging technique after US. • Deep pelvic endometriosis is associated with chronic pelvic pain and infertility. • Endometriosis is characterized by considerable diagnostic delay. • MRI is the best imaging technique for preoperative staging of endometriosis.

 

 

 

Adv Ther. 2018 Mar;35(3):408-423. doi: 10.1007/s12325-018-0667-3. Epub 2018 Feb 15.

Real-World Evaluation of Direct and Indirect Economic Burden Among EndometriosisPatients in the United States.

Soliman AM¹, Surrey E², Bonafede M³, Nelson JK⁴, Castelli-Haley J⁵.

Abstract

INTRODUCTION:

The prevalence of endometriosis and the need for treatment in the USA has led to the need to explore the contemporary cost burden associated with the disease. This retrospective cohort study compared direct and indirect healthcare costs in patients with endometriosis to a control group without endometriosis.

METHODS:

Women aged 18-49 years with endometriosis (date of initial diagnosis = index date) were identified in the Truven Health MarketScan^® Commercial database between 2010 and 2014 and female control patients without endometriosis were matched by age and index year. The following outcomes were compared: healthcare resource utilization (HRU) during the 12-month pre- and post-index periods (including inpatient admissions, pharmacy claims, emergency room visits, physician office visits, and obstetrics/gynecology visits), annual direct (medical and pharmacy) and indirect (absenteeism, short-term disability, and long-term disability) healthcare costs during the 12-month post-index period (in 2014 US$). Multivariate analyses were conducted to estimate annual total direct and indirect costs, controlling for demographics, pre-index clinical characteristics, and pre-index healthcare costs.

RESULTS:

Overall, 113,506 endometriosis patients and 927,599 controls were included. Endometriosis patients had significantly higher HRU during both the pre- and post-index periods compared to controls (p < 0.0001, all categories of HRU). Approximately two-thirds of endometriosis patients underwent an endometriosis-related surgical procedure (including laparotomy, laparoscopy, hysterectomy, oophorectomy, and other excision/ablation procedures) in the first 12 months post-index. Mean annual total adjusted direct costs per endometriosis patient during the 12-month post-index period was over three times higher than that for a non-endometriosis control [$16,573 (standard deviation (SD) = $21,336) vs. $4733 (SD = $14,833); p < 0.005]. On average, incremental direct and indirect 12-month costs per endometriosis patient were $10,002 and $2132 compared to their matched controls (p < 0.005).

CONCLUSIONS:

Endometriosis patients incurred significantly higher direct and indirect healthcare costs than non-endometriosispatients.

 

 

 

Am J Reprod Immunol. 2018 Feb 16. doi: 10.1111/aji.12828. [Epub ahead of print]

Unexplained infertility patients present the mostly impaired levels of progesterone receptors: Prospective observational study.

Petousis S^1,2, Prapas Y^1,2, Margioula-Siarkou C^1,2, Ravanos K², Milias S³, Mavromatidis G¹, Kalogiannidis I¹, Haitoglou C⁴, Athanasiadis A¹, Prapas N^1,2, Rousso D¹.

Abstract

PROBLEM:

Τo assess the endometrial expression of progesterone receptors in various subgroups of infertile women during implantation window. ΜETHODS: A prospective observational study was performed during March 2013-February 2017. Infertile women were categorized to those with tubal factor, ovarian failure, endometriosis or unexplained infertility. Endometrial biopsy was obtained on 7th-8th postovulatory day. Total progesterone receptors’ PR(A + B) and type-B receptors’ (PR-B) expression were compared between all categories of infertile and fruitful controls.

RESULTS:

There were overall 30 patients with tubal factor infertility (group 1), 30 with ovarian failure (group 2), 20 with endometriosis (group 3) and 20 with unexplained infertility (group 4). The control group consisted of 30 fertile patients. Patients with unexplained infertility presented the lowest levels of epithelial endometrial expression both regarding PR(A + B) and PR-B receptors. PgR(A + B) h-score in luminal epithelial cells was 106.4 ± 14.7 for cases with unexplained infertility vs 219.7 ± 15.8 for controls (P < .001). Similarly, PgR(A + B) h-score in glandular epithelial cells was 109.7 ± 13.9 vs 220.1 ± 17.2 (P < .001). Relative remarks were made for type-B progesterone receptors.

CONCLUSION:

Εndometrial expression of progesterone receptors is impaired in women with unexplained infertility. Therapeutic strategies targeting on improving progesterone receptors’ expression may significantly affect final reproductive outcome.

© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

 

 

 

Stem Cells. 2018 Feb 16. doi: 10.1002/stem.2804. [Epub ahead of print]

Hematogenous Dissemination of Mesenchymal Stem Cells from Endometriosis.

Li F¹, Alderman MH 3rd¹, Tal A¹, Mamillapalli R¹, Coolidge A¹, Hufnagel D¹, Wang Z¹, Neisani E¹, Gidicsin S¹, Krikun G¹, Taylor HS¹.

 

Abstract

Endometriosis is ectopic growth of endometrial tissue traditionally thought to arise through retrograde menstruation. We aimed to determine if cells derived from endometriosis could enter vascular circulation and lead to hematogenous dissemination. Experimental endometriosis was established by transplanting endometrial tissue from DsRed+ mice into the peritoneal cavity of DsRed- mice. Using flow cytometry, we identified DsRed+ cells in blood of animals with endometriosis. The circulating donor cells expressed CXCR4 and mesenchymal stem cell (MSC) biomarkers, but not hematopoietic stem cell markers. Nearly all the circulating endometrial stem cells originated from endometriosis rather than from the uterus. Cells expressing DsRed, CXCR4, and MSCs markers were identified in the peritoneal wall and surrounding vessels of recipient mice, contributing to both endometriosis and angiogenesis. Cells originating in endometriosis lesions migrated and implanted in lung tissue and displayed makers of differentiation, indicating retained multipotency. In vitro these cells demonstrated multipotency and were able to differentiate into adipogenic, osteogenic, and chondrogenic lineages. Endometriosis lesions also expressed high levels of CXCL12, the CXCR4 receptor ligand. Serum CXCL12 levels were greater than in sham control mice. In humans with endometriosis, serum CXCL12 levels were significantly higher than controls, suggesting that the CXCL12/CXCR4 axis is operational in women with spontaneous endometriosis as well. Stem cells, rather than differentiated cells from endometriosis, enter the circulation in response to CXCL12. We identify an endometriosis-derived stem cell population, a potential mechanism of dissemination of this disease and a potential target for treatment of endometriosis. Stem Cells 2018.

 

 

J Minim Invasive Gynecol. 2018 Feb 14. pii: S1553-4650(18)30119-5. doi: 10.1016/j.jmig.2018.02.006.

Natural Orifice Specimen Extraction (NOSE) during Laparoscopic Bowel Resection for Colorectal Endometriosis: Technique and Outcome.

Bokor A¹, Lukovich P², Csibi N³, D’Hooghe T⁴, Lebovic D⁵, Brubel R³, Rigo J³.

 

Abstract

STUDY OBJECTIVE We first present a detailed description of a modified NOSE-colectomy technique. Secondly, we report the postoperative outcomes of our prospective case series when compared to conventional laparoscopic bowel resection in a relatively large series of patients. DESIGN Canadian Task Force Classification II-1. SETTING University tertiary referral center. PATIENTS Patient selection The last 90 consecutive patients in our care with DIE of the bowel are presented in this study. Patients were diagnosed at the 1^st Department of OB/GYN Semmelweis Universtiy Budapest, Hungary. INTERVENTIONS We performed laparoscopic bowel resection using the transrectal NOSE-technique and compared the results of the new operative method (n=30) to traditional laparoscopic bowel resection (n=60). MEASUREMENTS AND MAIN RESULTS Duration of operations The median duration of surgery was 121 minutes in the control group and 96 minutes in the NOSE-group (p=.005). Postoperative complications According to Clavien-Dindo classification, we observed a severe, grade IIIb or higher, overall complication rate of 3.3% among all 90 patients. In the control group anastomosis insufficiency occurred in 3.3% of patients (2/60 cases) and in one patient with anastomotic leakage a rectovaginal fistula was observed (1.7%). There was no significant difference in rates of severe postoperative complications (p=0.55). Hospital stay The length of hospital stay in the control group was a median of 7 (5-13) days whereas in the NOSE-group this was 6 (3-11) days (p<.001). CONCLUSION According to our findings, the use of NOSE-colectomy offers shorter recovery and can eventually lead to shorter surgery duration compared to traditional laparoscopic bowel resection.

 

 

 

Reprod Sci. 2018 Jan 1:1933719118756744. doi: 10.1177/1933719118756744. [Epub ahead of print]

Optimization of Endometrial Decidualization in the Menstruating Mouse Model for Preclinical Endometriosis Research.

Peterse D^1,2, De Clercq K², Goossens C², Binda MM², Dorien FO^1,2, Saunders P³, Vriens J², Fassbender A^1,2, D’Hooghe TM^2,4.

Abstract

BACKGROUND:

To induce endometrial decidualization in rodents, an intrauterine oil stimulus can be delivered via the nontraumatic vagina or via the traumatic laparotomy. However, there is considerable variation in amount of decidualization using these inducing methods. Therefore, we studied which oil delivery route could achieve the highest rate of endometrial decidualization along the full length of both uterine horns.

METHODS:

To induce decidualization, ovariectomized C57Bl/6J mice were injected with estrogen (100 ng/day; 3 days). A progesterone pellet (5 mg) was implanted subcutaneously, followed by estrogen injections (5 ng/day; 3 days). Oil (20 µL/horn) was injected in the uterus via laparotomy, laparoscopy, or vagina. Four days later, the pellet was removed, followed by hysterectomy after 4 to 6 hours. Endometrial decidualization was evaluated macroscopically and microscopically using hematoxylin and eosin and desmin staining. Furthermore, uterine weight and hormone levels were measured.

RESULTS:

The proportion of animals with macroscopic bicornuate decidualization was higher after laparoscopic (83%) and laparotomic (89%) injection than after sham injection (11%). Furthermore, macroscopic bicornuate decidualization was significantly higher after laparotomic injection (89%) compared to the vaginal injection (38%). Uterine weight and endometrial surface area were significantly higher in both laparotomy and laparoscopy groups compared to the sham group, while the relative desmin-positive endometrial surface area was only significantly different between the laparotomy and the sham animals.

CONCLUSION:

Methods using laparoscopic and laparotomic intrauterine oil injection resulted in a higher amount of decidualized endometrium compared to sham injection, although further optimization is needed to reach full bicornuate decidualization.

 

 

 

Reprod Biomed Online. 2018 Feb 5. pii: S1472-6483(18)30047-6. doi: 10.1016/j.rbmo.2018.01.012. [Epub ahead of print]

The prognostic capacity of transvaginal hydrolaparoscopy to predict non-IVF conception.

van Kessel M¹, Tros R², Oosterhuis J³, Kuchenbecker WH⁴, Vernooij EM³, Bongers MY⁵, Mol BWJ⁶, Koks CA⁷.

 

Abstract

Transvaginal hydrolaparoscopy (THL) is performed to investigate tubal pathology in subfertile women. This retrospective multicentre cohort study investigated the results of THL and subsequent pregnancy rates. Between 2000 and 2011, 1033 subfertile women participated in the study. The primary outcome measure was intrauterine pregnancy, either after natural conception or after treatment with intrauterine insemination or ovulation induction. Cumulative intrauterine pregnancy rates were calculated using Kaplan-Meier analysis and fecundity rate ratios (FRR) were established. THL showed bilateral patent tubes in 83%, one-sided tubal occlusion in 12.4% and bilateral tubal occlusion in 4.6% of women. Cumulative intrauterine pregnancy rates after 36 months were 52% for women with bilateral patent tubes, 44% for one-sided tubal occlusion (FRR 1.04; 95% confidence interval [CI], 0.78 to 1.39) and 7% for bilateral tubal occlusion (FRR 0.13; 95% CI, 0.04 to 0.43). Endometriosis was diagnosed in 6.4%, and adhesions in 9.1%, while 3.9% of women had both. Corresponding FRR were 0.73 (95% CI, 0.49 to 1.09), 0.68 (95% CI, 0.46 to 1.02) and 0.42 (95% CI, 0.20 to 0.84). In conclusion, women with bilateral tubal occlusion or a combination of endometriosis and adhesions found on THL significantly reduced chances of natural conception.

 

 

 

J Res Med Sci. 2018 Jan 29;23:7. doi: 10.4103/jrms.JRMS_628_17. eCollection 2018.

Role of granulocyte colony-stimulating factor in human reproduction.

Eftekhar M¹, Naghshineh E^1,2, Khani P¹.

 

Abstract

As new research reveals, granulocyte colony-stimulating factor (G-CSF) plays an effective role in pregnancy success, considering that it not only affects the embryo implantation and ovarian function but also it promotes endometrial thickening and improves the pathophysiology of endometriosis, which all fundamentally lead to reducing pregnancy loss. In this review, we focus on the role of G-CSF in human reproduction. We summarized its role in ovulation, luteinized unruptured follicle syndrome, poor responders, improving repeated in vitro fertilization failure, endometrial receptivity and treatment of thin endometrium, and recurrent spontaneous abortion.

 

 

 

Evid Based Complement Alternat Med. 2017;2017:8563909. doi: 10.1155/2017/8563909. Epub 2017 Dec 31.

The Root Aqueous Extract of Entada africana Guill. et Perr. (Mimosaceae) Inhibits Implant Growth, Alleviates Dysmenorrhea, and Restores Ovarian Dynamic in a Rat Model of Endometriosis.

Mvondo MA¹, Minko Essono S¹, Bomba Tatsinkou FD¹, Ateba SB², Njamen D².

 

Abstract

Entada africana (Mimosaceae) was reported to have analgesic and antioxidant properties. The present study is aimed at investigating the effects of the root aqueous extract of Entada africana (EA) on an experimental model of endometriosis. The study was performed in rats orally treated with EA at doses of 127.5, 255, and 510 mg/kg. Microgynon® 30 served as the reference substance. Estradiol valerate and oxytocin were used to induce dysmenorrhea. Endometrial implant levels of catalase and malondialdehyde (MDA) allowed estimating tissue oxidative status. Ovarian dynamic and rat sexual behavior were assessed through histological analysis of ovaries, uterus, and vagina. EA decreased dysmenorrhea at tested doses following a 7-day treatment (p < 0.001). Endometrial implant volume decreased following the three treatment periods (p < 0.05). Catalase activity (p< 0.001) and MDA level (p < 0.01) increased only following a 3-day treatment. EA also increased antral follicles, reduced luteinized unruptured follicle number (p < 0.001), and induced animals to be in the estrus phase. In conclusion, EA prevented the progress of endometriosis, reduced dysmenorrhea, promoted ovarian follicle growth, prevented anovulation, and stimulated the special period of rat sexual desire. These results suggest that Entada africana could be a promising alternative option for the treatment of endometriosis.

 

 

 

Ecancermedicalscience. 2018 Jan 25;12:803. doi: 10.3332/ecancer.2018.803. eCollection 2018.

Endometriosis and endometriosis-associated cancers: new insights into the molecular mechanisms of ovarian cancer development.

Dawson A¹, Fernandez ML¹, Anglesio M^1,2, Yong PJ¹, Carey MS^1,3.

 

Abstract

Endometriosis is a fascinating disease that we strive to better understand. Molecular techniques are shedding new light on many important aspects of this disease: from pathogenesis to the recognition of distinct disease variants like deep infiltrating endometriosis. The observation that endometriosis is a cancer precursor has now been strengthened with the knowledge that mutations that are present in endometriosis-associated cancers can be found in adjacent endometriosis lesions. Recent genomic studies, placed in context, suggest that deep infiltrating endometriosis may represent a benign neoplasm that invades locally but rarely metastasises. Further research will help elucidate distinct aberrations which result in this phenotype. With respect to identifying those patients who may be at risk of developing endometriosis-associated cancers, a combination of molecular, pathological, and inheritance markers may define a high-risk group that might benefit from risk-reducing strategies.

 

 

 

Exp Ther Med. 2018 Mar;15(3):3000-3005. doi: 10.3892/etm.2018.5779. Epub 2018 Jan 19.

Discrimination of malignant transformation from benign endometriosis using a near-infrared approach.

Kawahara N¹, Yamada Y¹, Ito F¹, Hojo W², Iwabuchi T², Kobayashi H¹.

 

Abstract

The aim of the present single-center retrospective study was to investigate the discrimination of malignant transformation from ovarian endometrioma (OE) using a near-infrared approach ex vivo. Cystic fluid samples were collected from patients with OE (n=34) and endometriosis-associated ovarian cancer (EAOC) (n=12). The light reflected from each sample of cystic fluid [change in luminance, Δl (cd/m²) = background luminance-cystic fluid luminance at 800 nm] was spectrally measured by a near-infrared CCD camera with band-path filter (800 nm). The Δl in EAOC was significantly lower compared with that in OE. On regression analysis, a positive correlation was observed between the Δl and Hb level in the cystic fluid, and this association was exponential. The diagnostic sensitivity and specificity of Δl was 83.3 and 94.1% at the cutoff value of 21.5 cd/m², with an area under the ROC curve of 0.897. The present ex vivo study potentially provides a powerful near-infrared approach for quantitative discrimination between EAOC and benign OE, with high sensitivity and specificity, which may have clinical applications.

 

 

 

Br J Pharmacol. 2018 Feb 19. doi: 10.1111/bph.14170. [Epub ahead of print]

In vitro and in vivo effects of MK2206 and chloroquine combination therapy on endometriosis: Autophagy may be required for regrowth of endometriosis.

Matsuzaki S^1,2, Pouly JL^1,2, Canis M^1,2.

Abstract

BACKGROUND AND PURPOSE:

A high recurrence rate after medical treatment is a major clinical problem for patients with endometriosis. In the present study, we evaluated the in vitro effects of combined treatment with MK2206 (an AKT inhibitor) + chloroquine on cell growth and regrowth of endometriotic stromal cells, and the in vivo effects on endometriotic implants in a mouse xenograft model of endometriosis.

EXPERIMENTAL APPROACH:

We evaluated the effects of autophagy inhibition by knockdown of the ATG13, Beclin-1, and ATG12 genes and pharmacologic agents (chloroquine, bafilomycin A1, or 3-methyalanine) individually and in combination with MK2206 on cell growth and/or cell regrowth of endometriotic stromal cells in vitro. Furthermore, we evaluated combined treatment with MK2206 + chloroquine on endometriotic implants in a mouse xenograft model of endometriosis.

KEY RESULTS:

Combined treatment with MK2206 and chloroquine markedly reduced cell growth and regrowth after discontinuation of treatment in endometriotic stromal cells compared to cells treated with either drug alone. Autophagy inhibition by either ATG13, Beclin-1, or ATG12 gene knockdown only affected regrowth of endometriotic stromal cells, but not endometrial stromal cells within the same patients, after a 72-h discontinuation of the combined treatment. Furthermore, combined treatment significantly reduced the size of endometriotic implants, whereas no significant effects on endometriotic implants treated with either drug alone were observed in a mouse xenograft model of endometriosis.

CONCLUSIONS AND IMPLICATIONS:

The present findings suggest that a novel strategy for treatment of endometriosis may involve decreasing the number of endometriotic cells that can survive treatment and then preventing regrowth by autophagy inhibition.

 

 

 

Taiwan J Obstet Gynecol. 2018 Feb;57(1):153-156. doi: 10.1016/j.tjog.2017.12.027.

Pregnancy following robot-assisted laparoscopic partial cystectomy and gonadotropin-releasing hormone agonist treatment within three months in an infertile woman with bladder endometriosis.

Tan SJ¹, Chen CH¹, Yeh SD², Lin YH³, Tzeng CR⁴.

Abstract

OBJECTIVE:

To report an infertility case of deep-infiltrating bladder endometriosis conceiving following robot-assisted surgery and modified gonadotropin-releasing hormone agonist (GnRHa) treatment.

CASE REPORT:

A 33 year-old infertile female presenting with dysmenorrhea was found to have a bladder mass by pelvic ultrasound. Cystoscopy revealed a protruding tumor from the posterior bladder wall, and endometriosis was highly suspected. Robot-assisted laparoscopic partial cystectomy was performed for the deep-infiltrating bladder endometriosis. With postoperative half-dose GnRHa treatment and timed intercourse, she got pregnant within 3 months.

CONCLUSION:

Robot-assisted complete resection of deep-infiltrating endometriosis and bladder repair immediately followed by GnRHa therapy and medical assistance improves reproductive outcomes efficiently in women with endometriosis-associated infertility.

Copyright © 2018. Published by Elsevier B.V.

 

 

J Pediatr Urol. 2018 Feb 9. pii: S1477-5131(18)30038-X. doi: 10.1016/j.jpurol.2018.01.011. [Epub ahead of print]

Screening for Mullerian anomalies in patients with unilateral renal agenesis: Leveraging early detection to prevent complications.

Friedman MA¹, Aguilar L², Heyward Q³, Wheeler C⁴, Caldamone A².

Abstract

BACKGROUND:

Mullerian anomalies have a known association with renal agenesis yet, to date, there are no formal recommendations for screening women with certain renal anomalies for associated genital tract disorders.

OBJECTIVE:

The objective of this study is to review current data regarding the association between renal and Mullerian anomalies, and propose screening recommendations.

STUDY DESIGN:

A comprehensive review of the literature was performed to identify relevant articles using the keywords “unilateral renal agenesis,” “renal anomalies,” and “Mullerian anomalies.”

RESULTS:

Over 30% of patients with unilateral renal agenesis have an associated Mullerian anomaly. However, diagnosis is frequently delayed in this population until after menarche when complications of retrograde menstruation with obstructive anomalies lead to significant problems including endometriosis, pelvic inflammatory disease, and infertility. No clear guidelines exist for communication among the antenatal sonographer, the obstetrician, the parents, and the child’s pediatrician, which creates a barrier to effective screening and follow-up. Further, no current guidelines exist for screening women with certain renal anomalies for Mullerian anomalies.

DISCUSSION:

The complications of Mullerian anomalies are easily preventable if identified early. We propose new guidelines for education and screening for Mullerian anomalies in patients with unilateral renal agenesis (URA) and multicystic dysplastic kidney (MCDK) to guide providers, patients, and parents on proper identification and management (Table).

CONCLUSIONS:

Screening young women with URA and MCDK for Mullerian anomalies has the potential to prevent long-term complications from untreated obstructive malformations. Identification of unilateral renal agenesis on antenatal ultrasound must be clearly articulated with parents and the child’s pediatrician so that proper screening can be performed before menarche. Pelvic sonography is a low-cost, high-yield screening tool to identify these anomalies.

Published by Elsevier Ltd.

 

 

 

Cell Death Dis. 2018 Feb 19;9(3):291. doi: 10.1038/s41419-018-0317-3.

Calpain7 impairs embryo implantation by downregulating β3-integrin expression via degradation of HOXA10.

Yan Q¹, Huang C¹, Jiang Y¹, Shan H¹, Jiang R¹, Wang J¹, Liu J¹, Ding L, Yan G¹, Sun H².

 

Abstract

Endometriosis (ENDO) is a common gynecological disease that causes infertility in many women. Previous studies noted that the dysregulation of Homeo box A10 (HOXA10) in the endometrium of women with ENDO was involved in the failure of embryo implantation. However, the mechanism by which HOXA10 expression is reduced in women with ENDO is still poorly understood. Here we found that a member of the calcium (Ca²⁺)-dependent cysteine protease family calpain7 (CAPN7), negatively correlated with HOXA10, was highly expressed in the endometrium of infertile women with ENDO and was significantly downregulated during the window of embryo implantation in mice. Overexpression of CAPN7 in Ishikawa cells or in the uterus of mice inhibited embryo implantation in vitro and in vivo. In the current study, we identified a sequence rich in proline, glutamic acid, serine, and threonine (PEST sequence) that enhanced the Ca²⁺-dependent degradation of HOXA10 by CAPN7. Furthermore, the interaction between HOXA10 and CAPN7 repressed the transcriptional activity and protein stability of HOXA10. In contrast, the administration of the calpain inhibitor ALLN reversed the CAPN7-induced HOXA10 degradation. Moreover, truncation of the PEST motif in HOXA10 abolished its CAPN7-dependent proteolysis. These studies reveal a novel pattern of HOXA10 regulation via PEST sequence-mediated calpain proteolysis that was demonstrated to be reversed by a calpain inhibitor. Thus, the inhibition of CAPN7-induced HOXA10 degradation may represent a novel potential therapeutic method to improve impaired embryo implantation in women with ENDO.

 

 

 

Eur J Immunol. 2018 Feb 20. doi: 10.1002/eji.201747417. [Epub ahead of print]

MDSCs drive the process of endometriosis by enhancing angiogenesis and are a new potential therapeutic target.

Zhang T¹, Zhou J², Man GCW¹, Leung KT³, Liang B¹, Xiao B², Ma X², Huang S⁴, Huang H⁵, Hegde VL⁶, Zhong Y⁶, Li Y², Kong GWS¹, Yiu AKW¹, Kwong J¹, Ng PC³, Lessey BA⁶, Nagarkatti PS⁷, Nagarkatti M⁷, Wang CC^1,8,9.

 

Abstract

Endometriosis affects women of reproductive age via unclear immunological mechanism(s). Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells with potent immunosuppressive and angiogenic properties. Here, we found MDSCs significantly increased in the peripheral blood of patients with endometriosis and in the peritoneal cavity of a mouse model of surgically induced endometriosis. Majority of MDSCs were granulocytic, produced ROS, and arginase, and suppressed T-cell proliferation. Depletion of MDSCs by antiGr-1 antibody dramatically suppressed development of endometrial lesions in mice. The chemokines CXCL1, 2, and 5 were expressed at sites of lesion while MDSCs expressed CXCR-2. These CXC-chemokines promoted MDSC migration toward endometriotic implants both in vitro and in vivo. Also, CXCR2-deficient mice show significantly decreased MDSC induction, endometrial lesions, and angiogenesis. Importantly, adoptive transfer of MDSCs into CXCR2-KO mice restored endometriotic growth and angiogenesis. Together, this study demonstrates that MDSCs play a role in the pathogenesis of endometriosis and identifies a novel CXC-chemokine and receptor for the recruitment of MDSCs, thereby providing a potential target for endometriosis treatment.

 

 

 

Hum Reprod. 2018 Feb 15. doi: 10.1093/humrep/dex372. [Epub ahead of print]

Endometriosis induces gut microbiota alterations in mice.

Yuan M¹, Li D², Zhang Z³, Sun H¹, An M¹, Wang G¹.

Abstract

STUDY QUESTION:

What happens to the gut microbiota during development of murine endometriosis?

SUMMARY ANSWER:

Mice with the persistence of endometrial lesions for 42 days develop a distinct composition of gut microbiota.

WHAT IS KNOWN ALREADY:

Disorders in the immune system play fundamental roles in changing the intestinal microbiota. No study has used high-throughput DNA sequencing to show how endometriosis changes the gut microbiota, although endometriosis is accompanied by abnormal cytokine expression and immune cell dysfunction.

STUDY DESIGN, SIZE, DURATION:

This study includes a prospective and randomized experiment on an animal endometriosismodel induced via the intraperitoneal injection of endometrial tissues.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

The mice were divided into endometriosis and mock groups and were sacrificed at four different time points for model confirmation and fecal sample collection. To detect gut microbiota, 16S ribosomal-RNA gene sequencing was performed. Alpha diversity was used to analyze the complexity and species diversity of the samples through six indices. Beta diversity analysis was utilized to evaluate the differences in species complexity. Principal coordinate analysis and unweighted pair-group method with arithmetic means clustering were performed to determine the clustering features. The microbial features differentiating the fecal microbiota were characterized by linear discriminant analysis effect size method.

MAIN RESULTS AND THE ROLE OF CHANCE:

The endometriosis and mock mice shared similar diversity and richness of gut microbiota. However, different compositions of gut microbiota were detected 42 days after the modeling. Among the discriminative concrete features, the Firmicutes/Bacteroidetes ratio was elevated in mice with endometriosis, indicating that endometriosis may induce dysbiosis. Bifidobacterium, which is known as a commonly used probiotic, was also increased in mice with endometriosis.

LARGE SCALE DATA:

N/A.

LIMITATIONS, REASONS FOR CAUTION:

More control groups should be further studied to clarify the specificity of the dysbiosis induced by endometriosis. This study was performed only on mice. Thus, additional data acquired from patients with endometriosis are needed in future research. We only detected the changes of gut microbiota at 42 days after the modeling, while the long-term effect of endometriosis on gut microbiota remains poorly understood. Moreover, we only revealed a single effect of endometriosis on gut microbiota.

WIDER IMPLICATIONS OF THE FINDINGS:

This study provided the first comprehensive data on the association of endometriosisand gut microbiota from high-throughput sequencing technology. The gut microbiota changed with the development of endometriosis in a murine model. The communication between the host and the gut microbiota is bidirectional, and further studies should be performed to clarify their relationship.

STUDY FUNDING/COMPETING INTEREST(S):

This research was supported by Grant (81571417) from the National Science Foundation of China and Grant (2015GSF118092) from the Technology Development Plan of Shandong Province. The authors report no conflict of interest.

 

 

 

Hum Reprod. 2018 Feb 15. doi: 10.1093/humrep/dey026. [Epub ahead of print]

Secreted frizzled-related protein 2 (SFRP2) expression promotes lesion proliferation via canonical WNT signaling and indicates lesion borders in extraovarian endometriosis.

Heinosalo T¹, Gabriel M^1,2, Kallio L¹, Adhikari P¹, Huhtinen K^1,3,4, Laajala TD^5,6,7, Kaikkonen E¹, Mehmood A^1,8, Suvitie P², Kujari H^3,4, Aittokallio T^5,6,7, Perheentupa A^1,2, Poutanen M^1,7,9.

Abstract

STUDY QUESTION:

What is the role of SFRP2 in endometriosis?

SUMMARY ANSWER:

SFRP2 acts as a canonical WNT/CTNNB1 signaling agonist in endometriosis, regulating endometriosislesion growth and indicating endometriosis lesion borders together with CTNNB1 (also known as beta catenin).

WHAT IS KNOWN ALREADY:

Endometriosis is a common, chronic disease that affects women of reproductive age, causing pain and infertility, and has significant economic impact on national health systems. Despite extensive research, the pathogenesis of endometriosis is poorly understood, and targeted medical treatments are lacking. WNT signaling is dysregulated in various human diseases, but its role in extraovarian endometriosis has not been fully elucidated.

STUDY DESIGN, SIZE, DURATION:

We evaluated the significance of WNT signaling, and especially secreted frizzled-related protein 2 (SFRP2), in extraovarian endometriosis, including peritoneal and deep lesions. The study design was based on a cohort of clinical samples collected by laparoscopy or curettage and questionnaire data from healthy controls and endometriosispatients.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

Global gene expression analysis in human endometrium (n = 104) and endometriosis (n = 177) specimens from 47 healthy controls and 103 endometriosis patients was followed by bioinformatics and supportive qPCR analyses. Immunohistochemistry, Western blotting, primary cell culture and siRNA knockdown approaches were used to validate the findings.

MAIN RESULTS AND THE ROLE OF CHANCE:

Among the 220 WNT signaling and CTNNB1 target genes analysed, 184 genes showed differential expression in extraovarian endometriosis (P < 0.05) compared with endometrium tissue, including SFRP2 and CTNNB1. Menstrual cycle-dependent regulation of WNT genes observed in the endometrium was lost in endometriosis lesions, as shown by hierarchical clustering. Immunohistochemical analysis indicated that SFRP2 and CTNNB1 are novel endometriosislesion border markers, complementing immunostaining for the known marker CD10 (also known as MME). SFRP2 and CTNNB1 localized similarly in both the epithelium and stroma of extraovarian endometriosis tissue, and interestingly, both also indicated an additional distant lesion border, suggesting that WNT signaling is altered in the endometriosis stroma beyond the primary border indicated by the known marker CD10. SFRP2 expression was positively associated with pain symptoms experienced by patients (P < 0.05), and functional loss of SFRP2 in extraovarian endometriosis primary cell cultures resulted in decreased cell proliferation (P < 0.05) associated with reduced CTNNB1 protein expression (P = 0.05).

LIMITATIONS REASONS FOR CAUTION:

SFRP2 and CTNNB1 improved extraovarian endometriosis lesion border detection in a relatively small cohort (n = 20), although larger studies with different endometriosis subtypes in variable cycle phases and under hormonal medication are required.

WIDER IMPLICATIONS OF THE FINDINGS:

The highly expressed SFRP2 and CTNNB1 improve endometriosis lesion border detection, which can have clinical implications for better visualization of endometriosis lesions over CD10. Furthermore, SFRP2 acts as a canonical WNT/CTNNB1 signaling agonist in endometriosis and positively regulates endometriosis lesion growth, suggesting that the WNT pathway may be an important therapeutic target for endometriosis.

STUDY FUNDING/COMPETING INTEREST(S):

This study was funded by the Academy of Finland and by Tekes: Finnish Funding Agency for Innovation. The authors have no conflict of interest to declare.

 

 

 

J Pediatr Adolesc Gynecol. 2018 Feb 17. pii: S1083-3188(18)30160-8. doi: 10.1016/j.jpag.2018.02.127. [Epub ahead of print]

Post-insertional pain following intrauterine device placement among nulliparous adolescents.

Sinning KM¹, Jude DC¹, Yoost JL².

Abstract

STUDY OBJECTIVE:

To quantify the “normal” adolescent experience after IUD insertion, in order to provide appropriate counseling for future adolescents.

DESIGN:

Prospective cohort study.

SETTING:

Marshall University Department of Obstetrics and Gynecology generalist and adolescent gynecology clinics.

PARTICIPANTS:

Nulliparous adolescents age 13-18 and parous adults ≥18 years receiving a levonorgestrel intrauterine system (LNG-IUS).

INTERVENTIONS:

Visual analog scale pain score (VAS) and medication log was used for data collection for two weeks after LNG-IUS. A separate chart review was completed for demographic factors and indications for procedure.

MAIN OUTCOME MEASURES:

VAS pain scores and medication use was compared between groups.

RESULTS:

93 subjects returned the VAS record and medication log (46 adolescents and 47 adults). There was no difference in the incidence of endometriosis or dysmenorrhea, but there was a higher prevalence of menorrhagia among adolescents (65.2% vs 21.3%, p= <.001). 45 (95.7%) adults vs 25 (54.3%) adolescents had contraception as an indication for IUD use (p= <.001). Pain scores were statistically higher among the adolescent group each day (p=<.05) in the two week study period. The greatest mean differences occurred in the first four days. 32.6% of adolescents vs 12.8% of adults had a pain score >5 during the first three days, p=0.022. A statistical difference in amount of ibuprofen recorded was only noted on day 1 (p=.023) and day 4 (p=.046).

CONCLUSION:

Nulliparous adolescents undergoing LNG-IUS placement experience more post-insertional discomfort compared to parous adults; however, this method should still be considered first-line in this age group.

 

 

 

Int J Mol Sci. 2018 Feb 17;19(2). pii: E599. doi: 10.3390/ijms19020599.

The miRNA Mirage: How Close Are We to Finding a Non-Invasive Diagnostic Biomarker in Endometriosis? A Systematic Review.

Agrawal S¹, Tapmeier T², Rahmioglu N³, Kirtley S⁴, Zondervan K^5,6, Becker C⁷.

Abstract

BACKGROUND:

Endometriosis is a common disorder of the reproductive age group, characterised by the presence of ectopic endometrial tissue. The disease not only causes enormous suffering to the affected women, but also brings a tremendous medical and economic burden to bear on society. There is a long lag phase between the onset and diagnosis of the disease, mainly due to its non-specific symptoms and the lack of a non-invasive test. Endometriosis can only be diagnosed invasively by laparoscopy. A specific, non-invasive test to diagnose endometriosis is an unmet clinical need. The recent discovery of microRNAs (miRNAs) as modulators of gene expression, and their stability and specificity, make them an attractive candidate biomarker. Various studies on miRNAs in endometriosis have identified their cardinal role in the pathogenesis of the disease, and have proposed them as potential biomarkers in endometriosis. Rationale/Objectives: The aims of this review were to study the role of circulatory miRNAs in endometriosis, and bring to light whether circulatory miRNAs could be potential non-invasive biomarkers to diagnose the disease.

SEARCH METHODS:

Three databases, PubMed, EMBASE, and BIOSIS were searched, using a combination of Mesh or Emtree headings and free-text terms, to identify literature relating to circulating miRNAs in endometriosis published from 1996 to 31 December 2017. Only peer-reviewed, full-text original research articles in English were included in the current review. The studies meeting the inclusion criteria were critically assessed and checked using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) tool. The dysregulated miRNAs were assessed regarding the concordance between the various studies and their role in the disease.

OUTCOMES:

Nine studies were critically analysed, and 42 different miRNAs were found to be dysregulated in them, with only one common miRNA (miR-20a) differentially expressed in more than one study. miR-17-5p/20a, miR-200, miR-199a, miR-143, and miR-145 were explored for their pivotal role in the aetiopathogenesis of endometriosis. Wider implications: It is emerging that miRNAs play a central role in the pathogenesis of endometriosis and have the potential of being promising biomarkers. Circulating miRNAs as a non-invasive diagnostic tool may shorten the delay in the diagnosis of the disease, thus alleviating the suffering of women and reducing the burden on health care systems. However, despite numerous studies on circulating miRNAs in endometriosis, no single miRNA or any panel of them seems to meet the criteria of a diagnostic biomarker. The disagreement between the various studies upholds the demand of larger, well-controlled systematic validation studies with uniformity in the research approaches and involving diverse populations.

 

 

 

Cell Tissue Res. 2018 Feb 20. doi: 10.1007/s00441-018-2805-2. [Epub ahead of print]

Peritoneal fluid of women with endometriosis reduces SOD1 in bovine oocytes in vitro maturation.

Malvezzi H¹, Da Broi MG², Meola J², Rosa-E-Silva JC², Ferriani RA^2,3, Navarro PA^2,3.

 

Abstract

Studies have demonstrated oxidative stress in peritoneal fluid (PF) from women with endometriosis and the importance of enzymatic antioxidant machinery to avoid oocyte oxidative damage. Considering that PF constantly surrounds the ovaries and has direct contact with the oocyte at ovulation, we wonder if PF from women with endometriosis may affect antioxidant enzyme gene expression. Thus, the present study aims to evaluate the PF impact from infertile women with minimal and mild endometriosis and from fertile control women without endometriosis on SOD1, CAT, GSR gene’s expression in experimental bovine oocytes matured in vitro. Samples of PF were obtained from women who underwent videolaparoscopy-7 infertile with EI/II and 7 fertile without endometriosis. Immature bovine oocytes underwent in vitro maturation in the absence of PF and in the presence of three concentrations (1, 5 and 10%) of PF from fertile and from infertile women with EI/II. After 22 to 24 h of IVM, oocytes were denuded and stored for analysis of SOD1, CAT and GSR by real-time polymerase chain reaction. Oocyte SOD1 expression was significantly lower in the 10% endometriosis group (0.67 ± 0.32) when compared with no-peritoneal fluid (1.05 ± 0.24, p < 0.008) and 10% control groups (1.06 ± 0.22, p < 0.006). These findings raise the possibility of a deleterious influence of PF from women with EI/II on the oocyte, not only after ovulation but also during the maturation process, which could contribute to worsening oocyte quality, being one of the mechanisms related to infertility in patients with endometriosis.

 

 

 

“You have Endometriosis”: Making Menstruation-Related Pain Legitimate in a Biomedical World.

Wright KO¹.

Abstract

In this essay, the author reflects on how biomedical and gendered perceptions of reproductive health can impact an illness experience. Using a narrative lens, she relays the frustration of attempting to have her excessive menstrual pain legitimated and treated when loved ones and medical professionals trivialized it and refused to let her take on the sick role. She recounts incidents that demonstrate the embedded and limiting persistence of gendered perceptions of pain. In the end, she argues that only through strong patient self-advocacy and knowledge can one rewrite the social scripts assigned to how women cope with menstrual pain.