Knee. 2016 Jun;23(3):559-60.

Monthly swelling of the knee – Case report and review of the literature.

Jelsma J¹, Mayne A², Steffanie B³.

 

Abstract

INTRODUCTION:

We report a 17-year old with monthly swelling of her knee. The complaints are associated with the menstrual cycle. After physical examination, radiographs, MRI and an arthroscopy with biopsies, a diagnosis of intra-articular endometriosis and menstrual arthritis was made.

DISCUSSION:

Both an intra-articular manifestation of endometriosis and menstrual arthritis are very rare diagnoses. Extraperitoneal lesions of endometriosis are rare and the mechanism for spreading outside the retroperitoneal space is unknown. A similar situation exists for menstrual arthritis, it is thought that cytokines, which are produced as a reaction to retrograde menstruation, are the trigger for menstrual arthritis. A review of literature is given.

CONCLUSION:

A monthly recurrent, painful swelling of a joint, can and should give rise to thorough investigation. Differential diagnostic one should think of intra-articular manifestation of endometriosis and menstrual arthritis. We give a proposal for treatment.

 

 

J Pediatr Adolesc Gynecol. 2016 Oct;29(5):e63-e65.

Spontaneous Reformation of Imperforate Hymen after Repeated Hymenectomy.

Ossman AM¹, El-Masry YI¹, El-Namoury MM¹, Sarsik SM².

 

Abstract

BACKGROUND:

Imperforate hymen prevents menstrual blood drainage, which causes cyclic lower abdominal pain and amenorrhea. Untreated patients might develop serious complications such as endometriosis and infertility. Hymenectomy represents the adequate treatment.

CASE:

In a 16-year-old female virgin presented with recurrent lower abdominal pain, urine retention, and secondary amenorrhea after 3 hymenectomy surgeries. The examination revealed imperforate hymen. A fourth hymenectomy was performed with continuous locked sutures over all of the edges.

SUMMARY AND CONCLUSION:

Recurrent imperforate hymen after hymenectomy should be suspected if symptoms recur. Diagnosis can be achieved through meticulous clinical examination and appropriate imaging techniques.

 

 

J Appl Toxicol. 2016 May;36(5):741-7

Stereoselectivity and the potential endocrine disrupting activity of di-(2-ethylhexyl)phthalate (DEHP) against human progesterone receptor: a computational perspective.

Sheikh IA¹.

 

Abstract

Di-(2-ethylhexyl)phthalate (DEHP) is a phthalate plasticizer and is one of the very common endocrine-disrupting chemicals (EDCs) contaminating our ecosystem. It is used for imparting flexibility to plastics and frequently used in personal and industrial products. Clinical and experimental studies have indicated that exposure to DEHP is associated with developmental abnormalities of the reproductive system particularly of male neonates, endometriosis and miscarriage in women, low sperm counts and lower sperm motility and DNA integrity in men, and placental problems with higher rates of low birth weight, premature birth, and fetal loss in laboratory animals. Binding of DEHP to progesterone receptor (PR) represents a potential mechanism of interference in the reproductive functions. DEHP is a chiralmolecule and is available commercially as a racemic mixture of RR, SS and RS stereoisomers. The ability of individual stereoisomers of DEHP to interfere with the reproductive functions of humans and animals is not known and molecular interactions of DEHP stereoisomers with PR are not available. In the present study, in silico approaches were adopted for molecular simulation studies of the three stereoisomers of DEHP with PR. The study suggested that all three stereoisomers of DEHP have the potential to compete with the normal substrate binding of PR. However, the binding of DEHP to PR was stereoselective with RR stereoisomer of DEHP having the best binding characteristics compared with SS, and RS stereoisomers. It has been suggested that stereoselectivity may be employed for improving the safety of the commercial compounds using pure stereoisomers instead of racemic mixtures.

 

 

J Med Ultrason (2001). 2016 Jul;43(3):395-400.

The utility of ultrasound elastography in differentiation of endometriomas and hemorrhagic ovarian cysts.

Batur A¹, Yavuz A², Ozgokce M², Bora A², Bulut MD², Arslan H², Alpaslan M².

 

Abstract

PURPOSE:

To investigate the feasibility of acoustic radiation force impulse imaging in differentiation of endometriomas and hemorrhagic ovarian cysts.

MATERIALS AND METHODS:

We evaluated 84 ovarian cysts with high internal echogenicity diagnosed in 70 consecutive women. We excluded simple cysts and hemorrhagic cysts containing septations or mural nodules with detectable flow on Doppler ultrasonography. We obtained the elastographic shear wave velocity (SWV) value of the cysts that could be endometriomas or hemorrhagic ovarian cysts.

RESULTS:

Among the 78 ovarian cysts in 70 women without any septation or mural nodule, there were 42 endometriomas and 36 hemorrhagic ovarian cysts. Analysis of median SWV values of the ovarian cysts showed that the endometriomas had considerably higher levels of stiffness compared to the hemorrhagic ovarian cysts [median SWV 4.20 ± 0.42 vs 2.54 ± 1.04 m/s, p < 0.001]. A SWV cutoff value greater than 3.81 m/s yielded sensitivity and specificity values of 82.1 and 79.2 % respectively, for differentiation of endometriomas from hemorrhagic ovarian cysts.

CONCLUSION:

Sonoelastography is a novel imaging technique that enables us to evaluate the stiffness of adnexal lesions. The accurate discrimination of endometriomas and hemorrhagic ovarian cysts is important for avoiding unnecessary surgical procedures. ARFI imaging has a high sensitivity and specificity for distinguishing endometrioma from hemorrhagic ovarian cysts.

 

 

Gastroenterol Res Pract. 2016;

Capsule Endoscopy for Ileitis with Potential Involvement of Other Sections of the Small Bowel.

Lee HS¹, Lim YJ².

 

Abstract

Ileitis is defined as inflammation of the ileum. This condition includes ulcers, aphthous ulcers, erosions, and nodular or erythematous mucosa. Various etiologies are associated with ileitis. Crohn’s disease, ulcerative colitis, medications such as nonsteroidal anti-inflammatory drugs, infectious conditions, neoplasms, infiltrative disorders, vasculitides, spondyloarthritis, endometriosis, and radiation therapy-related conditions involve the ileum. However, the differential diagnosis of terminal ileitis can be difficult in many cases. Video capsule endoscopy (VCE) has become a useful tool for the diagnosis of a variety of small bowel lesions. This review describes each of the various conditions associated with ileitis and the diagnostic value of VCE for ileitis, which may help identify and evaluate these conditions in clinical practice. Based on the information provided by VCE, a definitive diagnosis could be made using the patients’ medical history, clinical course, laboratory and ileocolonoscopic findings, radiologic imaging findings, and histologic findings.

 

 

Biomed Res Int. 2015;2015:934164.

Treatment of Endometriosis with the GnRHa Deslorelin and Add-Back Estradiol and Supplementary Testosterone.

Agarwal SK¹, Daniels A², Drosman SR³, Udoff L⁴, Foster WG⁵, Pike MC⁶, Spicer DV⁷, Daniels JR⁷.

 

Abstract

BACKGROUND:

This randomized, multicenter, open-label clinical trial was intended to generate pilot data on the efficacy and safety of the gonadotropin-releasing hormone agonist (GnRHa) deslorelin (D) with low-dose estradiol ± testosterone (E2  ± T) add-back for endometriosis-related pelvic pain.

METHODS:

Women with pelvic pain and laparoscopically confirmed endometriosis were treated with a six-month course of daily intranasal D with concurrent administration of either transdermal E2, intranasal E2, or intranasal E2  + T. Efficacy data included evaluation of dyspareunia, dysmenorrhea, pelvic pain, tenderness, and induration. Cognition and quality of life were also assessed. Safety parameters included assessment of endometrial hyperplasia, bone mineral density (BMD), and hot flashes.

RESULTS:

Endometriosis symptoms and signs scores decreased in all treatment arms from a baseline average of 7.4 to 2.5 after 3 months of treatment and 3.4 after 6 months. BMD changes and incidence of hot flashes were minimal, and no endometrial hyperplasia was observed. Patient-reported outcomes showed significant improvement across multiple domains.

CONCLUSIONS:

Daily intranasal D with low dose E2  ± T add-back resulted in significant reduction in severity of endometriosis symptoms and signs with few safety signals and minimal hypoestrogenic symptoms that would be expected with the use of a GnRHa alone.

 

 

Int J Clin Exp Med. 2015 Nov 15;8(11):21497-506.

Comparison of complete and incomplete excision of deep infiltrating endometriosis.

Cao Q¹, Lu F², Feng WW¹, Ding JX¹, Hua KQ¹.

 

Abstract

OBJECTIVE:

To compare the efficacy and safety of complete and incomplete excision of deep infiltrating endometriosis (DIE).

METHODS:

Ninety-three women who underwent complete excision (n=55) or incomplete surgery of DIE (n=38) between January 2011 and December 2013 were included in this retrospective cohort study. Surgical data, and follow-up information of the patients were analyzed.

RESULTS:

Eighty-five women (91.4%) returned for their follow-up after the operation. The mean follow-up time was 18.3±8.7 months. The complete excision group had a significantly higher complication rate than the incomplete excision group (9.1% VS 0%, P<0.001). The decrease of visual analog scale (VAS) scores were more significant (5.6±3.9 VS 2.9±3.3, P=0.001), and the postoperative recurrence rate is significantly lower (3.9% VS 35.3%, P=0.000) in the complete excision group than that in the in-complete surgery group. The palliative incomplete excision had a comparable pregnancy rate and comparable quality of life in most aspects, except psychological score. And in the in-complete excision patients, administration of post-operative GnRH agonist had a post-treatment improvement of VAS score similar with the complete excision patient (4.5±3.2 versus 5.6±3.9, P=0.272). However, the recurrence rate were still significantly higher (29.4% VS 3.9%, P=0.000).

CONCLUSIONS:

Comparing with incomplete excision, the complete excision of DIE significantly decreased the post-operative pain and the recurrence rate. Although incomplete excision with post-operative GnRHa is efficient with respect to pain, the side effects of the drugs and the recurrence rate after cessation of the drugs must be considered. So complete excision of DIE is the first surgical treatment of choice.

 

 

Int J Clin Exp Med. 2015 Nov 15;8(11):21703-6.

Clinical analyses of endometriosis after conservative surgery.

Ke X¹, Qian H¹, Kang L¹, Wang J¹, Xie Y¹, Cheng Z¹.

 

Abstract

OBJECTIVE:

To assess the remission rate and outcome of pregnancy of patients who had moderate and severe ovarian endometriosis after conservative surgery. We also wished to analyze the associated factors of recurrence.

METHODS:

Weconducted retrospective analyses of 199 cases with stage II-IV ovarian endometriosis who had preserved fertility under laparoscopic surgical treatment. Postoperatively, the 199 patients were divided into three groups: 43 cases underwent surgical treatment alone (group A); 47 were given a gonadotropin-releasing hormone agonist (GnRH-α) (group B), and 109 were given mifepristone (group C). Ten cases in group A were infertile, 26 cases in group B, and 38 cases in group C. All patients were followed up for 3 years. This study was approved by the Ethics Committee of Yangpu District Central Hospital.

RESULTS:

In groups A, B and C, the remission rate was 58.13%, 70.21% and 60.55% and the difference not significant (P=0.384); Recurrence rates were 27.90%, 12.76% and 24.77%, and the difference between them significant (P<0.05). The recurrence rate in group B was the lowest. The natural pregnancy rate after surgery in the three study groups (untreated, GnRH-α and mifepristone) was 30%, 34.61% and 28.94% but this difference was not significant.

CONCLUSION:

Surgery can improve the symptom remission rate and fertility of patients. Postoperative drug therapy does not improve the chance of pregnancy.

 

 

Int J Clin Exp Med. 2015 Dec 15;8(12):22039-44.

Endometrial stem cells: clinical application and pathological roles.

Xu Y¹, Zhu H¹, Zhao D¹, Tan J¹.

 

Abstract

Adult stem cells occur in human endometrium. Menstrual-blood derived stem cells (MenSCs) are mesenchymal stem cells that can be obtained in a non-invasive manner. Due to their rapid proliferation rate, low immunogenicity, and low tumorigenicity, MenSCs are used extensively in tissue engineering. They can be induced into multiple cell lineages under certain conditions. MenSCs contribute to tissue repair via several different mechanisms, highlighting their great promise in clinical applications. Endometrial stem cells may also be used to shed light on the pathogenesis of endometriosis and endometrial carcinoma. This review will cover recent progress in this field.

 

 

J Endocrinol Invest. 2016 Jul;39(7):785-91.

Aberrant expression and hormonal regulation of Galectin-3 in endometriosis women with infertility.

Yang H¹, Yin J², Ficarrotta K³, Hsu SH⁴, Zhang W⁵, Cheng C⁶.

 

Abstract

OBJECTIVE:

To investigate the role and potential molecular mechanism of Galectin-3 (Gal-3) in the etiology of endometriosis-associated infertility.

METHODS:

We detected Gal-3 expression in eutopic endometrium from women with endometriosis-associated infertility and healthy women without endometriosis or infertility. We then evaluated Gal-3 expression in endometrial glandular epithelial cells (EECs) and endometrial stromal cells (ESCs) and investigated its response to hormone stimulation in EECs and ESCs from both groups of women.

RESULTS:

Results of real-time PCR and western blot analysis showed Gal-3 expression in both proliferative and secretory stages of the menstrual cycle decreased significantly in women with endometriosis-associated infertility compared to healthy women. The changes in expression of Gal-3 were more dramatic in EECs than ESCs. Moreover, estrogen (E2) and progesterone (P4) induced Gal-3 expression in EECs of healthy groups, and P4 was more significant than E2 and combined E2 and P4 (E2P4). However, in the endometriosis group, P4 failed to induce a similar increase in Gal-3 expression.

CONCLUSIONS:

Our results suggest that aberrant expression of Gal-3 might contribute to infertility in patients with endometriosis due to progesterone resistance.

 

 

BJOG. 2017 Feb;124(3):444-452.

Pregnancy outcomes in women with endometriosis: a national record linkage study.

Saraswat L¹, Ayansina DT², Cooper KG¹, Bhattacharya S³, Miligkos D⁴, Horne AW⁵, Bhattacharya S⁶.

 

Abstract

OBJECTIVE:

To determine pregnancy outcomes in women with endometriosis.

DESIGN:

A national population based cohort study using record linkage.

SETTING:

Scotland.

PARTICIPANTS:

A cohort of 14 655 women followed up over a 30-year period (1981-2010).

METHODS:

In a nationwide Scottish study, we compared pregnancy outcomes in 5375 women with surgically confirmed endometriosis with outcomes in 8710 women without endometriosis who were pregnant during the same time period. Data were analysed using univariable and multivariable logistic regression after adjusting for confounding factors.

MAIN OUTCOME MEASURES:

Outcome measures evaluated included miscarriage, ectopic pregnancy, stillbirths and other pregnancy complications such as hypertensive disorders of pregnancy, antepartum and postpartum haemorrhage, operative delivery and preterm births. The outcomes were presented as adjusted odds ratios (OR) with 95% confidence intervals (CI).

RESULTS:

On multivariable analysis, after adjusting for age, parity, socio-economic status and year of delivery, women with endometriosis when compared to women without endometriosis, had a significantly higher risk of early pregnancy complications with adjusted OR (95% CI) of 1.76 (1.44, 2.15) and 2.70 (1.09, 6.72) for miscarriage and ectopic pregnancy, respectively. A previous diagnosis of endometriosis was associated with a significantly increased risk of [adjusted OR (95% CI)] placenta praevia [2.24 (1.52, 3.31)], unexplained antepartum haemorrhage [1.67 (1.39, 2.00)], postpartum haemorrhage [1.30 (1.61, 1.46)] and preterm births [1.26 (1.07, 1.49)] in pregnancies progressing beyond 24 weeks.

CONCLUSION:

Endometriosis predisposes women to an increased risk of early pregnancy loss and later pregnancy complications.

TWEETABLE ABSTRACT:

Endometriosis predisposes women to an increased risk of early pregnancy loss and later pregnancy complications.

 

 

Reprod Sci. 2016 Jul;23(7):924-30.

Adenosine Triphosphate Regresses Endometrial Explants in a Rat Model of Endometriosis.

Zhang C¹, Gao L¹, Yi Y¹, Han H², Cheng H¹, Ye X¹, Ma R¹, Sun K³, Cui H¹, Chang X⁴.

 

Abstract

The aim of this study was to determine the effects of adenosine triphosphate (ATP) in a rat endometriosis model. After surgical induction of endometriosis, 3 rats were killed, and explants were measured in the remaining 19 rats, which were then randomly assigned to 4 groups. Group 1 (n = 4) received normal saline (2 mL/d intragastric [IG]), group 2 (n = 4) gestrinone (0.5 mg/kg/d IG), group 3 (n = 5) ATP (3.4 mg/kg/d IG), and group 4 (n = 6) ATP (1.0 mg/kg/d; intramuscularly), respectively. Four weeks after medication, they were euthanized to evaluate histological features of explants and eutopic uterine tissues. To test the effect of ATP on the growth of eutopic endometrium stromal cells, proliferation rates of hEM15A cells at 24, 48, and 72 hours after treatment with different concentrations of ATP and vehicle control were detected with the Cell Counting Kit-8 (CCK-8) method. There was a significant difference between pretreatment and posttreatment volumes within group 2 (positive control; P = .048) and group 4 (P = .044). On condition that pretreatment implant size was similar in both groups (P = .516), regression of explants in group 4 was significantly higher than that in group 1 (negative control; P = .035). Epithelial cells were significantly better preserved in group 1 than in group 3 (P = .008) and group 4 (P = .037). The CCK-8 assay showed no significant difference in proliferation among hEM15A cells treated with ATP and controls. These results suggest that ATP regresses endometriotic tissues in a rat endometriosis model but has no impact on the growth of eutopic endometrium stromal cells.

 

 

Reprod Sci. 2016 Aug;23(8):1071-9

Elevated Systemic Levels of Endocannabinoids and Related Mediators Across the Menstrual Cycle in Women With Endometriosis.

Sanchez AM¹, Cioffi R², Viganò P², Candiani M², Verde R³, Piscitelli F³, Di Marzo V³, Garavaglia E², Panina-Bordignon P⁴.

 

Abstract

Cannabinoids and modulators of the endocannabinoid system affect specific mechanisms that are critical to the establishment and development of endometriosis. The aim of this study was to measure the systemic levels of endocannabinoids and related mediators in women with and without endometriosis and to investigate whether such levels correlated with endometriosis-associated pain. Plasma and endometrial biopsies were obtained from women with a laparoscopic diagnosis of endometriosis (n = 27) and no endometrial pathology (n = 29). Plasma levels of endocannabinoids (N-arachidonoylethanolamine [AEA] and 2-arachidonoylglycerol [2-AG]) and related mediators (N-oleoylethanolamine [OEA] and N-palmitoylethanolamine [PEA]), messenger RNA expression of some of their receptors (cannabinoid receptor type 1 [CB1], CB2, transient receptor potential vanilloid type [TRPV1]), and the enzymes involved in the synthesis (N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D [NAPE-PLD]) and degradation (fatty acid amide hydrolase 1 [FAAH]) of AEA, OEA, and PEA were evaluated in endometrial stromal cells. The systemic levels of AEA, 2-AG, and OEA were elevated in endometriosis in the secretory phase compared to controls. The expression of CB1 was higher in secretory phase endometrial stromal cells of controls versus endometriosis. Similar expression levels of CB2, TRPV1, NAPE-PLD, and FAAH were detected in controls and endometriosis. Patients with moderate-to-severe dysmenorrhea and dyspareunia showed higher AEA and PEA levels than those with low-to-moderate pain symptoms, respectively. The association of increased circulating AEA and 2-AG with decreased local CB1 expression in endometriosis suggests a negative feedback loop regulation, which may impair the capability of these mediators to control pain. These preliminary data suggest that the pharmacological manipulation of the action or levels of these mediators may offer an alternative option for the management of endometriosis-associated pain.

 

 

Zhonghua Fu Chan Ke Za Zhi. 2015 Nov;50(11):838-42.

Ovarian clear cell carcinoma derived from endometriotic cyst: a clinicopathological analysis of 54 cases.

Zhu Q¹, Lu Y, Rao Y, Ning Y, Qu Y, Wang L, Zhou X².

 

Abstract

OBJECTIVE:

To clarify the clinicopathological features of ovarian clear cell carcinoma derived from endometriotic cyst (EC-OCCC).

METHODS:

Totally 54 cases of EC-OCCC were recruited in the current retrospective study. The relation between ages, clinical symptoms and signs, surgical and pathological stages, serum CA125, findings of ultrasound, treatments and the sites of tumors, macro- and micro-features and expression of immunostainings were analyzed.

RESULTS:

(1) Clinical features: the ages of patients were (50±6) years old (range 31-62 years old). Pelvic mass was the major complaint of 50 patients (93% , 50/54). Forty-five cases belonged to International federation of Gynecology and Obstetrics (FIGO) stage I, 4 cases were stage II and another 5 cases were stage III. Serum CA125 was elevated in 21 cases (54%, 21/39) before therapy. Doppler ultrasound showed 46 cases (85%, 46/54) had solid masses in pelvis. (2) Pathological findings: 52 cases (96%, 52/54) had their tumor unilaterally, and 2 cases (4%, 2/54) occurred bilaterally. The maximal diameters of endometriotic cyst (EC) ranged from 1.5 to 23.0 cm and maximal diameters of ovarian clear cell carcinoma (OCCC) components were from 0.5 to 12.0 cm. Fifty-one cases (94%, 51/54) had their tumor within EC, which showed focally irregular protrudings, grey-white papillae or solid nodules attached to the cyst wall. Three cases (6%, 3/54) appeared as irregular thickened wall of the cysts, ranged from 1.5 to 6.0 cm in the maximal length, with the microscopic features of EC and OCCC and the transitional areas between the 2 morphologies. All cases expressed cytokeratin (CK) 7 and pan-CK AE1/AE3, 17 cases (33%, 17/51) expressed ER and 5 cases (10%, 5/51) expressed PR. TP53 showed mutational phenotype in 19 cases (36%, 19/53). Sixteen cases (30%, 16/54) combined with uterine adenomyosis and 25 cases (46%, 25/54) with endometriosis at other sites. (3) Survival survey: during the period of 39.1 months follow-up, 3 cases relapsed and 2 cases died. (4) There was a significant difference of serum CA125 between patients of early-and advanced-stages (P=0.049). There were no differences identified in ages, diameters of EC and OCCC, the expression level of ER, PR and TP53, the co-existence of adenomyosis and endometrosis, as well as ultrasonic findings (P>0.05).

CONCLUSION:

EC-OCCC could be recognized in early stage by symptoms and ultrasound due to accompanied endometriotic cysts, resulting in relatively good prognosis.

 

 

G Chir. 2015 Nov-Dec;36(6):276-9.

Appendicular mucocele: two case reports and literature review.

Anania G, Giaccari S, Solfrini G, Scagliarini L, Vedana L, Resta G.

 

Abstract

The classification of mucinous tumors of the vermiform appendix is quite controversial, and includes a spectrum of neoplastic lesions ranging from benign proliferations, intraluminal, to invasive adenocarcinomas. Among the complications of appendicular mucinous neoplasms we should mention the “pseudomyxoma peritonei”, a condition caused by cancerous cells (mucinous adenocarcinoma) that produce abundant mucin or gelationous ascites. Mucinous neoplasms of the appendix are rare diseases of unknown etiology. The diagnosis is difficult because of poorly specific clinical, biochemical and imaging parameters, and their detection can be occasional. Most of the reported cases involving women of reproductive age (with a history of endometriosis, abdominal surgery or pelvic inflammatory disease). The definitive diagnosis requires histology and immunohistochemistry. Cytoredutive surgery combined with hyperthermic intraperitoneal chemoterapy (HIPEC) is now considered the best treatment for this disease. We present two cases treated with surgery and HIPEC.

 

 

 

Biol Reprod. 2016 Mar;94(3):70.

Intracellular Wnt/Beta-Catenin Signaling Underlying 17beta-Estradiol-Induced Matrix Metalloproteinase 9 Expression in Human Endometriosis.

Zhang L¹, Xiong W¹, Xiong Y¹, Liu H¹, Li N¹, Du Y¹, Liu Y².

 

Abstract

Extracellular matrix remodeling is necessary for ectopic endometrium implantation. Many studies have shown an increased expression of matrix metalloproteinase 9 (MMP9) in the ectopic endometrium of endometriosis. However, the signaling pathways and cellular effects related to this process remain incompletely elucidated. The objective of our study was to investigate the association between MMP9 and the Wnt signaling pathway under the regulation of 17beta-estradiol (E2) in endometrial stromal cells. We found that MMP9 was elevated in tissues from women with endometriosis compared with normal women. Furthermore, MMP9 and beta-catenin increased concurrently in a time- and dose-dependent manner after E2 treatment. To clarify the relationship between MMP9 and beta-catenin, we performed luciferase promoter reporter and chromatin immunoprecipitation assays. A beta-catenin/TCF3/LEF1 complex bound to a specific site on the MMP9 promoter that promoted MMP9 gene and protein expression. The promotion of MMP9 by the Wnt signaling pathway under the regulation of E2 may contribute to the pathophysiology of this disease.

 

 

J Obstet Gynaecol Res. 2016 Jun;42(6):669-77.

Evaluation of estrogen in endometriosis patients: Regulation of GATA-3 in endometrial cells and effects on Th2 cytokines.

Chen P¹, Wang DB¹, Liang YM¹.

 

Abstract

AIMS:

Endometriosis (EM) is a hormone-dependent chronic inflammatory disease, usually accompanied by a high level of localized estrogen and abnormal levels of cytokines, which are regulated by GATA-3 in lymphocytes. This study aimed to investigate the role of estrogen on GATA-3 expression and the relationship between GATA-3 and cytokine response.

METHODS:

Endometrial tissues collected from 20 patients who underwent laparoscopic or open surgery were used. Immunohistochemistry, quantitative polymerase chain reaction, Western blot analysis, cell transfection, estrogen treatments and enzyme-linked immunosorbent assays were performed to evaluate the effects of estrogen on GATA-3 expression and the relationship between estrogen-induced GATA-3 and the Th2 immune status of EM.

RESULTS:

Estrogen regulated the expression of GATA-3 in a dose and time-dependent manner. GATA-3 was relocated from the cytoplasm to the nucleus. Estrogen and GATA-3 regulated Th2 cytokine expression in eutopic endometrial cells, including interleukin (IL)-6, IL-8 and IL-10. Moreover, interferon-γ and IL-2 were highly expressed in the GATA-3 knockdown groups.

CONCLUSION:

In summary, GATA-3 was induced by estrogen and may promote the occurrence and development of EM by regulating the secretion of cytokines in the eutopic endometrial cells of EM patients.

 

 

Gynecol Endocrinol. 2016 Aug;32(8):646-649.

Postoperative administration of dienogest for suppressing recurrence of disease and relieving pain in subjects with ovarian endometriomas.

Adachi K¹, Takahashi K¹, Nakamura K², Otake A¹, Sasamoto N¹, Miyoshi Y¹, Shioji M¹, Yamamoto Y¹, Fujitani M³, Wakimoto A³, Tokuhira A³, Kobayashi E², Yoshimura A², Sawada K², Kimura T².

 

Abstract

To assess the effect of dienogest on recurrence of ovarian endometriomas and severity of pain after laparoscopic surgery, a retrospective study of 81 patients was performed at three institutions in Osaka, Japan. Patients had a six-month minimum follow-up after laparoscopic surgery for ovarian endometriomas performed between June 2012 and August 2014. Patients who chose to receive 2 mg dienogest daily and those who were managed expectantly postoperatively were included. Recurrence was defined as the presence of endometriomas of more than 2 cm. A visual analog scale (VAS) was used to score the intensity of pelvic pain. The cumulative recurrence rate and absolute VAS score changes between the baseline and at 6, 12, 18 and 24 months after the start of administration were evaluated in both groups. The recurrence rate was 16.5% and 24.0% in the expectant management group at 12 and 24 months, respectively. No recurrences occurred in the dienogest treatment group. The rate of VAS score reduction was significantly higher in the dienogest than in the expectant management group. Dienogest is effective on the recurrence of ovarian endometrioma and relieving pelvic pain after laparoscopic surgery.

 

 

 

Oncology (Williston Park). 2016 Feb;30(2):166-76.

Morphologic, Immunophenotypic, and Molecular Features of Epithelial Ovarian Cancer.

Ramalingam P.

 

Abstract

Epithelial ovarian cancer comprises a heterogeneous group of tumors. The four most common subtypes are serous, endometrioid, clear cell, and mucinous carcinoma. Less common are transitional cell tumors, including transitional cell carcinoma and malignant Brenner tumor. While in the past these subtypes were grouped together and designated as epithelial ovarian tumors, these tumor types are now known to be separate entities with distinct clinical and biologic behaviors. From a therapeutic standpoint, current regimens employ standard chemotherapy based on stage and grade rather than histotype. However, this landscape may change in the era of personalized therapy, given that most subtypes (with the exception of high-grade serous carcinoma) are relatively resistant to chemotherapy. It is now well-accepted that high-grade and low-grade serous carcinomas represent distinct entities rather than a spectrum of the same tumor type. While they are similar in that patients present with advanced-stage disease, their histologic and molecular features are entirely different. High-grade serous carcinoma is associated with TP53 mutations, whereas low-grade serous carcinomas are associated with BRAF and KRAS mutations. Endometrioid and clear cell carcinomas typically present as early-stage disease and are frequently associated with endometriosis. Mucinous carcinomas typically present as large unilateral masses and often show areas of mucinous cystadenoma and mucinous borderline tumor. It must be emphasized that primary mucinous carcinomas are uncommon tumors, and metastasis from other sites such as the appendix, colon, stomach, and pancreaticobiliary tract must always be considered in the differential diagnosis. Lastly, transitional cell tumors of the ovary, specifically malignant Brenner tumors, are quite uncommon. High-grade serous carcinoma often has a transitional cell pattern, and adequate sampling in most cases shows more typical areas of serous carcinoma. Immunohistochemical markers are routinely employed in the diagnosis of epithelial ovarian carcinomas. However, molecular testing of these tumors, unlike in endometrial carcinoma, is not routinely used in clinical practice.

 

 

Arch Gynecol Obstet. 2016 Aug;294(2):299-301.

Adhesions and endometriosis: challenges in subfertility management : (An expert opinion of the ANGEL-The ANti-Adhesions in Gynaecology Expert PaneL-group).

De Wilde RL¹, Alvarez J², Brölmann H³, Campo R⁴, Cheong Y⁵, Lundorff P⁶, Pawelczyk L⁷, Roman H⁸, di Spiezio Sardo A⁹, Wallwiener M¹⁰.

Abstract

There is molecular evidence that endometriosis has a negative impact on the ovaries, although the exact pathophysiology concerning endometriosis-associated subfertility is not known. The negative impact on the tubo-ovarian unit can be directly by distorting the anatomy, indirectly by invoking inflammation or by oxidative damage with poorer-quality oocytes. Endometriosis even seems to have a negative effect on pregnancy outcome after in vitro fertilization.

 

 

Eur J Obstet Gynecol Reprod Biol. 2017 Feb;209:34-38.

Characteristics of follicular fluid in ovaries with endometriomas.

Giacomini E¹, Sanchez AM¹, Sarais V¹, Beitawi SA¹, Candiani M², Viganò P³.

 

Abstract

The study of follicular fluid (FF) content nearby endometriomas may assist in elucidating pathophysiology, possible biomarkers related to this disease and the effect of endometriomas on ovarian physiology. As the question “how endometrioma may intrude the physiology of ovarian tissue?” is still open, we aimed to summarize the molecular evidence supporting the idea that endometriomas can negatively influence the content of the surrounding ovarian follicles. An alteration of the iron metabolism and an increased ROS (reactive oxygen species) generation characterize the intrafollicular environment adjacent to endometriomas. Other potentially negative effects include decreased testosterone and anti-Mullerian hormone FF levels although these have been only partially clarified. Alterations in lipid and proteomic patterns have been also observed in FF samples nearby endometriomas. The possibility that endometriomas per se may influence IVF clinical results as a consequence of the detrimental impact on the local intrafollicular environment is also discussed.

 

 

Eur J Obstet Gynecol Reprod Biol. 2016 Apr;199:42-8.

The association between CYP19 polymorphism and endometriosis risk: a system review and meta-analysis.

Yi K¹, Yang L¹, Lan Z¹, Xi M².

 

Abstract

OBJECTIVE:

Endometriosis is a chronic, inflammatory, estrogen dependent disease. Genetic variation of estrogen biosynthesis and metabolic genes is associated with the risk of endometriosis. The CYP19 gene, encoding aromatase, plays an important role in the conversion of androgens to estrogens. Polymorphisms in the CYP19 gene are associated with circulating estrogen levels and estrogen/testosterone ratio. The aim of present study is to evaluate the impact of the CYP19 rs10046 polymorphism on endometriosis risk.

METHODS:

Embase, PubMed and other databases were searched for eligible case-control studies. A fixed-effects or random effects model was appropriately selected to calculate the pooled odds ratios (ORs).

RESULTS:

A total of 8 case-control studies including 993 cases and 1956 controls were available. Overall, the pooled results indicated that CYP19 rs10046 polymorphism was not associated with endometriosis risk (for heterozygous CC vs. CT carriers OR=1.00, 95% CI: 0.82-1.21; for homozygous CC vs. TT carriers OR=1.06, 95% CI: 0.83-1.35; allele contrast C vs. T OR=1.01, 95% CI: 0.90-1.14; dominant model CC vs. CT+TT OR=1.02, 95% CI: 0.85-1.23; recessive model CC+CT vs. TT OR=1.05, 95% CI: 0.85-1.30). Heterogeneity among studies was founded in dominant model and allele contrast. Galbraith plot analyses were performed to assess the source of heterogeneity and one study was found to be contributor of heterogeneity. The heterogeneity decreased significantly after excluding that study.

CONCLUSION:

Present meta-analysis reveals that CYP19 rs10046 polymorphism may be not correlated to endometriosis risk.

 

 

Biomed Pharmacother. 2016 Mar;78:66-73.

Selection of reliable reference genes in eutopic and ectopic endometrium for quantitative expression studies.

Andrusiewicz M¹, Słowikowski B², Skibińska I³, Wołuń-Cholewa M⁴, Dera-Szymanowska A⁵.

 

Abstract

PURPOSE:

Physiological changes during menstrual cycle cause the endometrium and endometriosis to develop specific kind of tissues, especially in regard to the gene expression profiles, which may include also housekeeping genes, commonly used as reference genes (RGs) in quantitative studies. Reverse transcription, followed by quantitative polymerase chain reaction (RT-qPCR) is the most precise and commonly used method in gene expression studies. In order to reduce effects of technical approaches and biological variability of gene’s expression level, the studies often employ RGs in experimental data normalization. However, the expression of RGs is not always stable and depends on several variables. Thus, the selection of appropriate RG is one of the most significant steps to obtain reliable results in RT-qPCR-based methods.

MATERIAL AND METHODS:

With the usage of RT-qPCR, we researched the expression of seven genes (ACTB, B2M, G6PD, GAPD, GUSB, HPRT and PPIA) as reliable reference genes in eutopic and ectopic endometrial tissue specimens obtained during standard surgery of women of reproductive age. Stability of expression level was analyzed by the most universal MS Excel plug-ins including: geNorm, NormFinder and BestKeeper. The descriptive statistics were evaluated using Statistica software.

RESULTS:

The distribution of threshold (Ct) values was not equal. We identified genes with higher expression level (referring to Ct values) such as ACTB and B2M, medium e.g., GAPD and low expression level, e.g., G6PD and HPRT. We demonstrated that the stability of the analyzed reference genes was not homogenous, and different algorithms pointed to PPIA, GAPD and B2M as the most stable ones in eutopic and ectopic endometrium. On the contrary to these, GUSB and G6PD were the most unstable ones.

CONCLUSIONS:

In RT-qPCR-based analyses of gene expression level in eutopic and ectopic endometrium, we strongly recommend that a minimum of two reference genes are to be used and we determined that the most suitable seem to be PPIA and GAPD.

 

 

Biochimie. 2016 Apr;123:130-7.

Hypoxia-inducible factor-1alpha: A promising therapeutic target in endometriosis.

Zhan L¹, Wang W¹, Zhang Y¹, Song E¹, Fan Y¹, Wei B².

 

Abstract

Endometriosis is a common gynecologic disease defined as the presence of ectopic endometrial tissues on the ovaries and pelvic peritoneum, and it is a significant cause of pelvic pain, dysmenorrhea and infertility of women in their reproductive age. However, the etiology of endometriosis remains obscure. In recent years, a growing body of evidence validated that hypoxia developed a close relationship with endometriosis and the expression of hypoxia-inducible factor-1alpha (HIF-1α) was increased significantly in the development of endometriosis. Furthermore, inhibiting the expression of HIF-1α contributed to suppress endometriosis progression, suggesting HIF-1α plays a critical function in endometriosis. Nevertheless, the mechanisms by which HIF-1α associates with endometriosis are still undefined. In this brief review, we had a general understanding of HIF-1α firstly, and then we tried to sum up the collective knowledge of HIF-1α in endometriosis. Finally, we will discuss kinds of novel therapeutic approaches to endometriosis based on the functions of HIF-1α.

 

J Mol Med (Berl). 2016 Aug;94(8):887-97.

IGF-I stimulates ERβ and aromatase expression via IGF1R/PI3K/AKT-mediated transcriptional activation in endometriosis.

Zhou Y¹, Zeng C¹, Li X¹, Wu PL¹, Yin L¹, Yu XL¹, Zhou YF¹, Xue Q².

 

Abstract

Estrogen receptor beta (ERβ, encoded by ESR2 gene) and cytochrome P450 aromatase (encoded by CYP19A1 gene) play critical roles in endometriosis, and the levels of insulin-like growth factor-I (IGF-I) in the peritoneal fluid are significantly higher in patients with endometriosis compared with those in normal women. However, the effects and mechanisms of IGF-I on ERβ and aromatase expression remain to be fully elucidated. In this study, human endometriotic stromal cells (ESCs) and endometrial cells (EMs) derived from ovarian endometriomas and eutopic endometrial tissues. ESCs were cultured with IGF-I, signal pathway inhibitors, and siRNAs. ERβ and aromatase expression were measured by real-time PCR and Western, respectively. The binding of c-Jun and CREB to the ESR2 and CYP19A1 promoters was assessed by chromatin immunoprecipitation assay. Animal experiments were performed in a xenograft mouse model. Levels of IGF-I mRNA in ESCs were markedly higher than those in EMs. IGF-I upregulated ERβ and aromatase expression in ESCs after stimulation of the IGF1R/PI3K/AKT pathway. Following IGF-I treatment, a marked increase in c-Jun and CREB phosphorylation occurred, enhancing binding to the ESR2 and CYP19A1 promoters. An IGF1R inhibitor in vivo reduced IGF-I-induced endometriosis graft growth and ERβ and aromatase expression. In conclusion, this is the first report to describe a mechanistic analysis of ERβ and aromatase expression regulated by IGF-I in ESCs. Moreover, an IGF1R inhibitor impeded ectopic lesion growth in nude mice. These findings suggest that an inhibitor of IGF1R might have therapeutic potential as an antiendometriotic drug.

KEY MESSAGES:

Level of IGF-I mRNA in ESCs is markedly higher than that in EMs. IGF-I up-regulates ERβ and aromatase expression via IGF1R/PI3K/AKT pathway. C-Jun and CREB are recruited to ESR2 or CYP19A1 promoter by IGF-I stimulation. IGF-1R inhibitors in vivo impede the growth of ectopic lesions in nude mice.

 

 

J Reprod Biol Health. 2015;3

Anxiety, coping skills and hypothalamus-pituitary-adrenal (HPA) axis in patients with endometriosis.

Quiñones M¹, Urrutia R², Torres-Reverón A³, Vincent K⁴, Flores I⁵.

 

Abstract

BACKGROUND:

Endometriosis is an inflammatory disease that is defined by growth of endometrial tissue outside the uterus, resulting in pain, infertility, and emotional distress. Previous studies have shown that the HPA axis is compromised in patients with chronic, painful diseases, including endometriosis. However, the underlying mechanisms and the physiological and emotional consequences of dysfunctions in the HPA axis in these patients are largely unknown. We aimed to understand whether diurnal circulating cortisol levels in women with endometriosis are affected and how this impacts their emotional and behavioral responses.

METHODS:

Thirty-two patients with endometriosis and 36 healthy control women provided saliva samples and completed a series of psychological questionnaires. Salivary cortisol levels were measured in duplicate using a colorimetric immunoassay.

RESULTS:

There were significant differences in average cortisol levels between endometriosis patients and controls. A negative correlation was found between cortisol levels and infertility and dyspareunia. Furthermore, incapacitating pain was found to be a strong predictor of hypocortisolism. Women with endometriosis reported higher levels of trait anxiety, but showed no differences in perceived stress or in coping styles compared to the control group.

CONCLUSIONS:

This study supports previous reports of hypocortisolism as a biomarker of aberrant HPA responses in women with endometriosis. Moreover, it provides further insight into the link between HPA axis dysregulation, emotional responses, and the high comorbidity between endometriosis and other inflammatory conditions.

 

 

Organogenesis. 2016 Jan 2;12(1):33-41.

New theory of uterovaginal embryogenesis.

Makiyan Z¹.

 

Abstract

BACKGROUND:

The explanation of uterine and vaginal embryogenesis in humans still poses many controversies, because it is difficult to assess early stages of an embryo. The literature review revealed many disagreements in Mullerian theory, inciting some authors to propose new embryological hypotheses. In the original Mullerian theory: the paramesonephral ducts form the Fallopian tubes, uterus and vagina; the mesonephral ducts regress in female embryos.

AIMS:

The aim of this article is to investigate the development of Mullerian ducts in humans, using comparative analysis of fundamental embryological theory and various utero-vaginal anomalies.

MATERIAL AND METHODS:

Between 1998 and 2015, 434 patients with various uterovaginal malformations had been operated on at the Scientific Centre of Obstetrics Gynaecology and Perynatology in Moscow. The anatomies of the uterovaginal malformations in these patients were diagnosed with ultrasound and MRI and then verified during surgical correction by laparoscopy.

RESULTS:

A systematic comparison of uterovaginal malformations to those in the literature has allowed us to formulate a new theory of embryonic morphogenesis. The new theory is significantly different: ovary, ovarian ligamentum proprium, and ligamentum teres uteri derive from gonadal ridges; Fallopian tubes and vagina completely develop from mesonephral ducts. The uterus develops in the area of intersection between the mesonephral ducts with gonadal ridges by the fusion of the two.

CONCLUSIONS:

The new theory may to induce future embryological studies. The hypothetic possibility that the ovary and endometrium derive from the gonadal ridges could be the key to understanding the enigmatic aetiologies of extragenital and ovarian endometriosis.

 

 

Am J Obstet Gynecol. 2016 Jul;215(1):68.e1-4.

The gut microbiota: a puppet master in the pathogenesis of endometriosis?

Laschke MW¹, Menger MD².

 

Abstract

Endometriosis is a frequent gynecologic disease with a complex, multifactorial cause. It is characterized by the cyclic estrogen-driven proliferation and bleeding of endometriotic lesions (ie, ectopic endometrial glands and stroma) outside the uterus. These lesions induce a chronic activation of the innate immune system within the peritoneal cavity that is associated with the release of various inflammatory cytokines and angiogenic growth factors into the peritoneal fluid. This stimulates angiogenesis and the further spread of the lesions and triggers the typical pain that is symptomatic of the disease. Moreover, circulating stem and progenitor cells are recruited into the ectopic endometrial tissue and contribute to its growth and vascularization. In recent years, an increasing number of studies have indicated that the gut microbiota is not only essential for a physiologic gastrointestinal function but acts as a central regulator of a variety of inflammatory and proliferative conditions. Besides, the gut flora affects estrogen metabolism and stem-cell homeostasis. Based on these findings, we hypothesize that the gut microbiota may be involved crucially in the onset and progression of endometriosis. In the future, this novel view of the pathogenesis of endometriosis may be verified by analysis of the development of endometriotic lesions in animal models with a defined composition of the gut microbiota and by investigation of the microbiota of patients with endometriosis with modern next-generation sequencing tools. This could open the door for completely new preventive, diagnostic, and therapeutic approaches for endometriosis.

 

 

Eur J Obstet Gynecol Reprod Biol. 2016 Apr;199:69-75.

Molecular detection of intrauterine microbial colonization in women with endometriosis.

Khan KN¹, Fujishita A², Masumoto H³, Muto H³, Kitajima M⁴, Masuzaki H⁴, Kitawaki J⁵.

 

Abstract

OBJECTIVE:

Increased intrauterine microbial colonization by bacteria culture method and occurrence of endometritis have been reported in women with endometriosis. Here we investigated microbial colonization in intrauterine environment and cystic fluid of women with and without endometriosis by molecular approach.

STUDY DESIGN:

This is a case-controlled biological study with a total of 32 women each with and without endometriosis. Among them, 16 each in these two groups of women received treatment with gonadotropin-releasing hormone agonist (GnRHa). Pattern of microbial colonization in endometrial swabs and endometrioma/non-endometrioma cystic fluid was examined using broad-range polymerase-chain reaction (PCR) amplification of bacteria targeting 16S rRNA gene (rDNA). After quantification of index PCR product, 16S rDNA metagenome sequence analysis was done by Illumina Miseq system.

RESULTS:

A wide proportion (0.01-97.8%) of multiple bacteria was detected in both endometrial swabs and cystic fluid collected from women with and without endometriosis. 16S metagenome assay indicated that proportion of Lactobacillacae was significantly decreased (p<0.01) and of Streptococcaceae, Staphylococaceae, Enterobacteriaceae was significantly increased (p<0.05 for each) in GnRHa-treated women with endometriosis than in GnRHa-untreated women. While bacteria culture method failed to detect a single colony, 16S metagenome assay could detect significantly higher percentage of Streptococcaceae (p<0.01) and Staphylococaceae (p<0.05) in the cystic fluid derived from women with ovarian endometrioma comparing to that in cystic fluid collected from non-endometrioma cysts.

CONCLUSION:

These findings indicate the occurrence of sub-clinical infection in intrauterine environment and in the cystic fluid of ovarian endometrioma. Additional side effect of GnRHa treatment in promoting silent intrauterine and/or ovarian infection should be considered.

 

 

Magy Seb. 2016 Mar;69(1):20-6.

Technical questions of the transrectal specimen extraction.

Lukovich P¹, Csibi N², Bokor A².

 

Abstract

INTRODUCTION:

During laparoscopic partial colectomy the specimen can be extracted transrectally. This technique decreases the invasiveness of the surgery, because the abdominal wall incision is avoided. Premises of a new surgical technique are precise technical description as well as a favourable balance of advantages and disadvantages. In this paper the authors review the technique they apply and analyse their first results.

PATIENTS AND METHOD:

45 laparoscopic bowel resections were performed by a multidisciplinary team between 16th April 2014 and 1st November 2015. Indication of surgery was endometriosis, and the specimen was extracted transrectally in 11 patients. Having ligated both bowel ends proximal and distal to the section infiltrated with endometriosis, and the proximal bowel secured with a laparoscopic bulldog. Then the bowel was resected and the specimen was extracted in a camera bag transrectally. A purse-string suture was placed into the proximal bowel end, and the anvil of the circular stapler–which was introduced transrectally–was inserted into the bowel. After closing the rectal stump, the anastomosis was performed with a circular stapler. We used this technique when the upper third of the rectum or sigmoid colon was infiltrated with endometriosis.

RESULTS:

The difference between the operation time of the two techniques (transabdominal vs. transrectal specimen extraction: 108 min vs. 118 min) was not significant. There was not difference in the WBC count between the first and second postoperative day, and there was not any anastomosis leakage detected either.

CONCLUSION:

By using the above technique, postoperative infections could have been reduced to minimum. Transrectal specimen extraction did not increase postoperative complication The authors believe this is a safe way of specimen extraction after partial colectomy.

 

Reprod Sci. 2016 Aug;23(8):1044-52.

Endometriosis-Derived Stromal Cells Secrete Thrombin and Thromboxane A2, Inducing Platelet Activation.

Guo SW¹, Du Y², Liu X³.

 

Abstract

Platelets have been recently revealed to play important roles in the development of endometriosis. However, it is unclear whether endometriotic lesions can secrete any platelet inducers outside the menstruation window. Hence, this study was undertaken to see whether endometriosis-derived stromal cells secrete platelet activators and cause platelet activation. We employed in vitro experimentation using primary ectopic endometrial stromal cells (EESCs) and platelets from healthy male volunteers and evaluated the extent of platelet aggregation by aggregometer and the platelet activation rate by flow cytometry using supernatants harvested from EESCs of different cell densities. We also measured the concentration of thromboxane B2 (TXB2), a metabolite of thromboxane A2 (TXA2), and thrombin activity in supernatants harvested from EESCs of different densities and evaluated the extent of platelet aggregation after treatment of EESCs with hirudin, Ozagrel, and apyrase. Finally, the concentration of TXB2, thrombin, and transforming growth factor β1 (TGF-β1) in platelets cocultured with different densities of EESCs is measured by enzyme-linked immunosorbent assay. We found that EESCs secrete thrombin and TXA2 and induce platelet activation and aggregation in a density-dependent fashion. Treatment of platelets with EESCs resulted in increased concentration of TXB2, thrombin, and TGF-β1 in a density-dependent manner. Treatment of EESCs with hirudin and Ozagrel, but not apyrase, resulted in significant suppression of platelet aggregation. Thus, given recently reported effects of activated platelets on the cell behaviors of EESCs and endometriotic lesions in general, our findings establish that endometriotic lesions and platelets engage active cross-talks in the development of endometriosis, highlighting the importance of lesion microenvironment in endometriosis.

 

 

Biomed Res Int. 2016;2016:3029264.

Use of Modified Polysaccharide 4DryField (®) PH for Adhesion Prevention and Hemostasis in Gynecological Surgery: A Two-Center Observational Study by Second-Look Laparoscopy.

Korell M¹, Ziegler N², De Wilde RL².

 

Abstract

Purpose. This study evaluates both scopes of 4DryField PH, certified for adhesion prevention and hemostasis, in patients undergoing surgery for various and severe gynecological disorders. Methods. This is a two-institutional study. Adhesion prevention efficacy was evaluated using video documentation of first-look laparoscopies (FLL) and second-look laparoscopies (SLL); other patient data were analyzed retrospectively. Twenty patients with various disorders were evaluated, 4 assigned to a uterus pathology, 10 to endometriosis, and 6 to an adhesion disease group. Nine patients received 4DryField primarily for hemostasis and 11 solely for adhesion prevention. Nineteen patients had SLL after 5 to 12 weeks and one after 13 months. Results. At FLL with 4DryField, immediate hemostasis could be achieved in diffuse bleeding. At SLL, effective adhesion prevention was observed in 18 of all 20 women, with only 2 revealing major adhesions. In particular, only 1 of the 6 women with adhesion disease as predominant disorder showed major adhesions at SLL. Conclusions. Modified polysaccharide 4DryField is not only effective in diffuse bleeding. In this cohort with extensive surgery for various gynecological pathologies, 4DryField showed effective adhesion prevention as confirmed at SLL, too. Its use as premixed gel is a convenient variant for treatment of large peritoneal wounds.

 

 

Reprod Sci. 2016 Sep;23(9):1129-38.

Effects of Prenatal Environmental Exposures on the Development of Endometriosis in Female Offspring.

Wei M¹, Chen X², Zhao Y³, Cao B⁴, Zhao W⁵.

 

Abstract

BACKGROUND:

Endometriosis has many hypothesized etiologies. Known risk factors include genetic predisposition, uterine outflow abnormalities, and iatrogenic causes. Of increasing concern is prenatal environmental exposures. However, the findings of studies investigating the relationships between prenatal environmental exposures and the development of endometriosis have not always been conclusive, and therefore, the relationships are debatable.

METHODS:

This review presents a summary and analysis of the current studies that investigated the effects of prenatal environmental exposures on the development of endometriosis in female offspring.

RESULTS:

Prenatal exposure to estrogenic substances (such as ethinyl estradiol and diethylstilbestrol) and environmental toxins (such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, polychlorinated biphenyls, and bisphenol A) may increase the incidence of endometriosis in female offspring. However, exposure to cigarette smoke may protect against the development of endometriosis in female offspring mainly because of its antiestrogenic effects.

CONCLUSION:

Certain prenatal environmental exposures might result in the development of endometriosis in female offspring. In addition to known environmental exposures that predispose the development of endometriosis in adulthood, such as dioxin and radiation exposure (animal models), prenatal exposures are of increasing concern.

 

 

Oncotarget. 2016 Mar 8;7(10):10857-69.

An efficient model of human endometriosis by induced unopposed estrogenicity in baboons.

Nair HB¹, Baker R², Owston MA², Escalona R², Dick EJ², VandeBerg JL², Nickisch KJ¹.

 

Abstract

Endometriosis is a chronic estrogen-dependent disease that occurs in approximately 10% of reproductive age women. Baboons offer a clear benefit for studying the initiation and progression of endometriosis since baboon is very close to humans phylogenetically. Progestins are used in the treatment of endometriosis. The therapeutic window of progestins depends on the ratio of its affinity towards progesterone receptor agonism verses antagonism. The present study is to determine the role of pure antiprogestin in baboon endometriosis. We hypothesize that pure antiprogestin will induce unopposed estrogenicity and spontaneous endometriosis in baboons. The rate of endometrial invasion and attachment through modeled peritoneum in the presence and absence of progesterone and antiprogestin was evaluated in this study. A baboon model of endometriosis induced by unopposed estrogenicity using progesterone receptor antagonist (EC304) was used in this study. We observed EC304 has induced unopposed estrogenicity that deregulated proteins involved in attachment, invasion, cell growth, and steroid hormone receptors in this model. Our data suggest that depleting progesterone levels in the endometrium will increase estrogen hyper-responsiveness that leads to increased endometriotic lesion progression in the baboon (Papio anubis) model. This study reports a refined model of human endometriosis in baboons that could potentially be used to develop new diagnostic and therapeutic strategies for the benefit of women suffering from endometriosis.

 

 

Hum Reprod. 2016 Apr;31(4):734-49.

Corroborating evidence for platelet-induced epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis.

Liu X¹, Shen M², Qi Q², Zhang H³, Guo SW⁴.

 

Abstract

STUDY QUESTION:

Do platelets play any role in the development of adenomyosis?

SUMMARY ANSWER:

As in endometriosis, adenomyotic lesions show significantly increased platelet aggregation, increased expression of transforming growth factor (TGF)-β1, phosphorylated Smad3, markers of epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT), and smooth muscle metaplasia (SMM), in conjunction with increased fibrosis as compared with normal endometrium.

WHAT IS KNOWN ALREADY:

Both EMT and FMT are known to play vital roles in fibrogenesis in general and in endometriosis in particular. EMT has been implicated in the development of adenomyosis. SMM is universally seen in endometriosis and also in adenomyosis, and is correlated positively with the extent of fibrosis. However, there has been no published study on the role of platelets in fibrogenesis in adenomyosis, even though adenomyotic lesions undergo repeated cycles of tissue injury and repair, which suggests the involvement of platelets and their possible roles in fibrogenesis.

STUDY DESIGN, SIZE, DURATION:

Cross-sectional studies of ectopic endometrial and control endometrial tissue samples from three sets of women with and without adenomyosis (n= 34 and 20, 12 and 10, and 8 and 8, respectively) were carried out from 2014 to 2015.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

Immunohistochemistry analysis of ectopic endometrial tissues from women with (n= 34) and without (n= 20) adenomyosis with respect to biomarkers of EMT, FMT and highly differentiated smooth muscle cells as well as TGF-β1, phosphorylated Smad3, markers of proliferation, angiogenesis and extracellular matrix (ECM) deposits. Masson trichrome staining, Van Gieson staining and Pico-Sirius staining were performed to evaluate and quantify the extent of fibrosis in lesions. Progesterone receptor isoform B (PR-B) staining also was performed. In addition, CD42b-positive platelets in ectopic (n= 12) and control (n= 10) endometrium were counted by confocal microscopy and compared. The protein expression levels of TGF-β1 and phosphorylated Smad3 in both ectopic (n= 8) and control (n= 8) endometrium were measured by western blot analysis. Immunofluorescent staining of both platelets and hepatocyte growth factor (HGF) was also performed for adenomyotic tissue samples (n= 10).

MAIN RESULTS AND THE ROLE OF CHANCE:

Adenomyotic lesions had a significantly higher extent of platelet aggregation and increased staining for TGF-β1 and phosphorylated Smad3 (both P-values <0.001 versus control). In addition, E-cadherin staining was decreased while vimentin staining in adenomyotic epithelial cells was increased, along with increased staining of proliferating cell nuclear antigen, vascular endothelial growth factor and CD31 (all P-values <0.001), markers of proliferation and angiogenesis. Staining for α-SMA, a marker for myofibroblast, desmin, smooth muscle myosin heavy chain and oxytocin receptor was significantly increased in adenomyotic lesions versus control, concomitant with increased staining of collagen I and lysyl oxidase (all P-values <0.001). Histochemistry analysis indicates that the extent of fibrosis is high in adenomyotic lesions (P < 0.001), and the extent appeared to correlate negatively with the microvessel density (P < 0.05). PR-B staining was significantly decreased in adenomyotic lesion as compared with control endometrium (P < 0.001). Platelets and HGF were co-localized mostly in the stromal component of adenomyotic lesions, near the glandular epithelium.

LIMITATIONS, REASONS FOR CAUTION:

The results are limited by the cross-sectional nature of the study and the use of histochemistry and immunohistochemistry analyses only, but nonetheless is a validation of our previous finding in mouse experiments.

WIDER IMPLICATIONS OF THE FINDINGS:

The data presented are consistent with the notion that platelet-induced activation of the TGF-β/Smad signaling pathway may be a driving force in EMT, FMT and SMM in the development of adenomyosis, leading to fibrosis. This study provides the first piece of evidence that adenomyotic lesions are wounds that undergo repeated injury and healing, and, as such, platelets play critical roles in the development of adenomyosis by promoting proliferation, angiogenesis, increasing ECM deposits, and SMM, resulting in fibrosis. Platelets may also be involved in uterine hyperactivity and myometrial hyperinnervation. Our results provide one explanation as to why adenomyosis is a challenge for medical treatment, and shed new light onto the pathophysiology of adenomyosis.

STUDY FUNDING/COMPETING INTERESTS:

Support for data collection and analysis was provided by grants from the National Science Foundation of China. None of the authors has anything to disclose.

 

 

Hum Reprod Update. 2016 Jun;22(4):497-515.

The role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding.

Schatz F¹, Guzeloglu-Kayisli O¹, Arlier S¹, Kayisli UA¹, Lockwood CJ².

 

Abstract

BACKGROUND:

Human pregnancy requires robust hemostasis to prevent hemorrhage during extravillous trophoblast (EVT) invasion of the decidualized endometrium, modification of spiral arteries and post-partum processes. However, decidual hemorrhage (abruption) can occur throughout pregnancy from poorly transformed spiral arteries, causing fetal death or spontaneous preterm birth (PTB), or it can promote the aberrant placentation observed in intrauterine growth restriction (IUGR) and pre-eclampsia; all leading causes of perinatal or maternal morbidity and mortality. In non-fertile cycles, the decidua undergoes controlled menstrual bleeding. Abnormal uterine bleeding (AUB) accompanying progestin-only, long-acting, reversible contraception (pLARC) accounts for most discontinuations of these safe and highly effective agents, thereby contributing to unwanted pregnancies and abortion. The aim of this study was to investigate the role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding.

METHODS:

We conducted a critical review of the literature arising from PubMed searches up to December 2015, regarding in situ and in vitro expression and regulation of several specific proteins involved in uterine hemostasis in decidua and cycling endometrium. In addition, we discussed clinical and molecular mechanisms associated with pLARC-induced AUB and pregnancy complications with abruptions, chorioamnionitis or pre-eclampsia.

RESULTS:

Progestin-induced decidualization of estradiol-primed human endometrial stromal cells (HESCs) increases in vivo and in vitro expression of tissue factor (TF) and type-1 plasminogen activator inhibitor (PAI-1) while inhibiting plasminogen activators (PAs), matrix metalloproteinases (MMPs), and the vasoconstrictor, endothelin-1 (ET-1). These changes in decidual cell-derived regulators of hemostasis, fibrinolysis, extracellular matrix (ECM) turnover, and vascular tone prevent hemorrhage during EVT invasion and vascular remodeling. In non-fertile cycles, progesterone withdrawal reduces TF and PAI-1 while increasing PA, MMPs and ET-1, causing menstrual-associated bleeding, fibrinolysis, ECM degradation and ischemia. First trimester decidual hemorrhage elicits later adverse outcomes including pregnancy loss, pre-eclampsia, abruption, IUGR and PTB. Decidual hemorrhage generates excess thrombin that binds to decidual cell-expressed protease-activated receptors (PARs) to induce chemokines promoting shallow placentation; such bleeding later in pregnancy generates thrombin to down-regulate decidual cell progesterone receptors and up-regulate cytokines and MMPs linked to PTB. Endometria of pLARC users display ischemia-induced excess vasculogenesis and progestin inhibition of spiral artery vascular smooth muscle cell proliferation and migration leading to dilated fragile vessels prone to bleeding. Moreover, aberrant TF-derived thrombin signaling also contributes to the pathogenesis of endometriosis via induction of angiogenesis, inflammation and cell survival.

CONCLUSION:

Perivascular decidualized HESCs promote endometrial hemostasis during placentation yet facilitate menstruation through progestational regulation of hemostatic, proteolytic, and vasoactive proteins. Pathological endometrial hemorrhage elicits excess local thrombin generation, which contributes to pLARC associated AUB, endometriosis and adverse pregnancy outcomes through several biochemical mechanisms.

 

 

Eur Rev Med Pharmacol Sci. 2016;20(3):399-406.

Hypoxia responsive miR-210 promotes cell survival and autophagy of endometriotic cells in hypoxia.

Xu TX¹, Zhao SZ, Dong M, Yu XR.

 

Abstract

OBJECTIVE:

Hypoxia may play a role in the survival of ectopic endometrial cells. This study aimed to explore how hypoxia responsive miR-210 is involved in cell survival and autophagic response of endometriotic cells.

MATERIALS AND METHODS:

The expression of hypoxia-inducible factor 1-alpha (HIF-1α) and miR-210 in eutopic and ectopic endometrial tissues were measured. The expression changes of HIF-1α and miR-210 in ovarian endometriotic cell line CRL-7566 after hypoxic culture were further explored. The influence of miR-210 on cell viability and apoptosis was quantified using CCK-8 assay and flow cytometry analysis. The effect of miR-210 on Bcl-2 expression and the effect of miR-210/Bcl-2 axis on autophagy in the cells were measured by Western blot analysis.

RESULTS:

Ectopic lesion had stronger HIF-1α positive signals, as well as more HIF-1α positive cells per visual field than the eutopic endometrium. MiR-210 expression was also elevated in the ectopic lesions. In in-vitro models, CRL-7566 cells had significantly higher expression of HIF-1α and miR-210 after hypoxic treatment. MiR-210 overexpression partly preserved cell viability in hypoxia, while miR-210 knockdown facilitated the loss of cell viability. In addition, miR-210 significantly attenuated hypoxia-induced apoptosis in CRL-7566 cells. Enforced miR-210 overexpression significantly promoted autophagy in hypoxia. Knockdown of endogenous Bcl-2 significantly enhanced autophagy, the effect of which was similar to that of miR-210.

CONCLUSIONS:

The hypoxia-induced higher miR-210 expression may contribute to pathological development of endometriosis at least through enhancing cell survival and promoting autophagy via Bcl2/Beclin-1 axis.

 

 

Curr Mol Med. 2016;16(3):288-98.

Ten-Eleven Translocation Genes are Downregulated in Endometriosis.

Roca FJ, Loomans HA, Wittman AT, Creighton CJ, Hawkins SM¹.

 

Abstract

Our previous whole genome expression analysis of endometriomas suggested dysregulation of the ten-eleven translocation genes (TET1, TET2, and TET3), involved in converting 5- methylcytosine to 5-hydroxymethylcytosine (5-hmC). The objective of this study was to validate the expression of TET genes in ectopic and eutopic endometrium and in primary cultures of human endometrial stromal fibroblasts (HESF) during in vitro decidualization and to quantify 5-hmC levels in patients with endometriosis. Blood, eutopic endometrium, and endometriotic tissues were collected at time of gynecologic surgery. HESF cultures were created from eutopic endometrium of women without (HESF-CONTROL) and with endometriosis (HESF-ENDO) and underwent in vitro decidualization. Genomic DNA from blood and tissues underwent quantification of the absolute amount of 5-hmC using ELISA. The expression of TET1, TET2, and TET3 was decreased in endometriosis compared to non-endometriosis control eutopic endometrium. Surprisingly, the global amount of 5-hmC was higher in ectopic endometrium than control eutopic endometrium, while genomic DNA from blood of women with endometriosiscontained statistically significantly less 5-hmC than women without endometriosis. Expression of TET1, TET2, and TET3 was decreased in non-decidualized HESFENDO. Upon in vitro decidualization, control HESF showed decreased expression of TET3, while decidualized HESF-ENDO showed no statistically significant change in expression of TET1, TET2, or TET3. These results indicate that the TET genes are downregulated in ectopic endometrium and in HESF-ENDO, and suggest for the first time that TET genes play a role in endometriosis. High global amounts of 5-hmC in endometriotic tissues suggest unique epigenetic regulation in these tissues.

 

 

Curr Mol Med. 2016;16(3):276-87.

cAMP-Response Element-Binding 3-Like Protein 1 (CREB3L1) is Required for Decidualization and its Expression is Decreased in Women with Endometriosis.

Ahn JI, Yoo JY, Kim TH, Kim YI, Ferguson SD, Fazleabas AT, Young SL, Lessey BA, Ahn JY, Lim JM¹, Jeong JW².

 

Abstract

Endometriosis is a major cause of infertility and pelvic pain, affecting more than 10% of reproductive-aged women. Progesterone resistance has been observed in the endometrium of women with this disease, as evidenced by alterations in progesterone-responsive gene and protein expression. cAMPResponse Element-Binding 3-like protein 1 (Creb3l1) has previously been identified as a progesterone receptor (PR) target gene in mouse uterus via high density DNA microarray analysis. However, CREB3L1 function has not been studied in the context of endometriosis and uterine biology. In this study, we validated progesterone (P4) regulation of Creb3l1 in the uteri of wild-type and progesterone receptor knockout (PRKO) mice. Furthermore, we observed that CREB3L1 expression was significantly higher in secretory phase human endometrium compared to proliferative phase and that CREB3L1 expression was significantly decreased in the endometrium of women with endometriosis. Lastly, by transfecting CREB3L1 siRNA into cultured human endometrial stromal cells (hESCs) prior to hormonal induction of in vitro decidualization, we showed that CREB3L1 is required for the decidualization process. Interestingly, phosphorylation of ERK1/2, critical factor for decidualization, was also significantly reduced in CREB3L1-silenced hESCs. It is known that hESCs from patients with endometriosis show impaired decidualization and that dysregulation of the P4-PR signaling axis is linked to a variety of endometrial diseases including infertility and endometriosis. Therefore, these results suggest that CREB3L1 is required for decidualization in mice and humans and may be linked to the pathogenesis of endometriosis in a P4-dependent manner.

 

 

Curr Mol Med. 2016;16(3):266-75.

c-Fos-Regulated Matrix Metalloproteinase-9 Expression is Involved in 17β-Estradiol-Promoted Invasion of Human Endometrial Stromal Cell.

Pan H, Zhang P, Li JR, Wang H, Jin MF, Feng C, Huang HF¹.

 

Abstract

Endometriosis is a frequent gynecological disease associated with severe pain and infertility. Although its dependency on estrogen is well recognized, the molecular mechanism along the estrogenic pathway has not been fully understood. This study investigates the effect of 17β-estradiol (E2) on human endometrial stromal cell (HESC) invasion and the role of c-fos and matrix metalloproteinase-9 (MMP-9) in mediating the biological function of 17β-E2. It is found that 17β-E2 promotes not only HESC invasion, but also c-fos and MMP-9 expression in HESC. Further experiments demonstrate that the estrogen receptor inhibitor ICI 182780 and siRNA-mediated c-fos or MMP-9 knockdown are able to block the effect of 17β-E2 on HESC invasion. Moreover, siRNA-mediated c-fos knockdown suppresses the effect of 17β-E2 on MMP-9 expression. Our results indicate that 17β-E2-induced HESC invasion is dependent on c-fos-mediated MMP-9 expression. These findings facilitate our understanding on the pathogenesis of endometriosis and may provide data potentially useful for the development of new treatment modalities for better management of endometriosis.

 

 

 

 

Zhonghua Fu Chan Ke Za Zhi. 2016 Feb;51(2):98-102.

Research of gestrinone-related abnormal uterine bleeding and the intervention in the treatment: a multi-center, randomized, controlled clinical trial.

Duan H¹, Wang S, Hao M, Chen L, Tang J, Wang X, Peng YZ, Zhang SC, Cao LR, Yu JJ.

 

Abstract

OBJECTIVE:

To investigate the incidence, influencing factors and intervention of gestrinone-related abnormal uterine bleeding at different dosage of gestrinone in the clinical treatment.

METHODS:

This was a multicenter, randomized, control study of 195 Chinese women with endometriosis or adenomyosis from June 2011 to November 2013. The subjects were randomized into three groups with oral administration of gestrinone, 2.5 mg dose at one time; twice a week group: 67 cases with oral administration twice a week last three months; double dose first month group: 67 cases with oral administration triple times a week at first month, then twice a week for two months; three times a week group: 61 cases with oral administration three times a week last three months. The improvement of the abnormal uterine bleeding, the changes in estrogen, liver function and blood coagulation were evaluated. At the same time, B-ultrasound examination evaluation were performed.

RESULTS:

(1) Three months later, the incidence of abnormal uterine bleeding in twice a week group was 30% (20/67), in double dose first month group and three times a week group were 7%(5/67) and 16% (10/61) respectively, there were significant difference between three groups (P<0.05). The incidence in double dose first month group was the most lower. (2) Univariate analysis showed that the dosage and ovarian size were the significant factors for abnormal uterine bleeding (OR=0.461,P= 0.003;OR=0.303,P=0.016); logistic regression analysis demonstrated that the risk of abnormal uterine bleeding in double dose first month group was the lowest when compared with twice a week group and three times a week group, the risk in twice a week group was 5-fold higher than that in double dose first month group (OR=0.211,P=0.011). The incidence of abnormal uterine bleeding in participants with abnormal ovarian volume results from ovarian cyst or ovarian surgery was significantly lower than those with normal ovarian volume (OR=0.304,P=0.018). (3) After the treatment of three months, there were no significant difference in alanine transaminase level between the groups (P>0.05). The body mass index significantly increased in three group (P<0.05), but there were no significant differences between the groups (P>0.05). As for blood coagulation, there were also no significant differences between the groups (P>0.05).

CONCLUSIONS:

Double dose of gestrinone in the first month could significantly decrease the incidence of gestrinone-related abnormal uterine bleeding. It is a more optimied dosage of gestrinone and without severe side effects.

 

 

 

Clin Med Insights Reprod Health. 2016 Feb 21;10:1-8

Relevance of Imaging Examinations in the Surgical Planning of Patients with Bowel Endometriosis.

Trippia CH¹, Zomer MT², Terazaki CR¹, Martin RL², Ribeiro R², Kondo W².

 

Abstract

Endometriosis is a benign gynecologic disease characterized by the presence of endometrial tissue outside the uterine cavity. The complexity of the disease results from its multiple clinical presentations, the multifocal pattern of distribution of the lesions, the presence of extra pelvic sites of the disease (mainly affecting the urinary and the intestinal tracts), and the difficulty in the preoperative diagnosis (by means of imaging studies) and in the surgical treatment. The preoperative mapping of the lesions, either by ultrasound or by magnetic resonance imaging, allows for an adequate surgical planning and a better preoperative patient counseling, especially in those women with deep infiltrating endometriosis affecting the bowel. Also, the choice of the surgical team that is going to perform the procedure may be based on the preoperative workup. In this paper, we highlight the important findings that should be described in the imaging examination reports for the preoperative workup of patients with deep infiltrating endometriosis of the intestine.

 

 

Eur J Obstet Gynecol Reprod Biol. 2016 Apr;199:110-5

Immunohistochemical expression pattern of metastasis suppressors KAI1 and KISS1 in endometriosis and normal endometrium.

Timologou A¹, Zafrakas M², Grimbizis G¹, Miliaras D³, Kotronis K¹, Stamatopoulos P¹, Tarlatzis BC¹.

 

Abstract

OBJECTIVE:

To analyze the expression pattern of metastasis suppressors KAI1 and KISS1 in the endometrium of patients with and without endometriosis.

STUDY DESIGN:

In this pilot study, tissue samples were prospectively collected from 38 patients with endometriosis and 29 without endometriosis, undergoing operative laparoscopy in the proliferative phase of the menstrual cycle; diagnosis or absence of endometriosis was confirmed histologically. Protein expression of KAI1 and KISS1 were analyzed immunohistochemically in endometriotic lesions and the eutopic endometrium of patients with endometriosis and without endometriosis.

RESULTS:

KAI1 expression was significantly decreased in the glandular eutopic endometrium of endometriosispatients as compared with that of patients without endometriosis (p=0.008). On the other hand, in endometriosispatients, KAI1 expression was significantly increased in the ectopic as compared with the eutopic endometrial stroma (p=0.021). There were no other significant differences in KAI1 expression between different groups. KISS1 expression in the ectopic glandular endometrium was significantly increased as compared with the eutopic glandular endometrium from patients with (p=0.004) and without endometriosis (p=0.008). There was no significant difference in KISS1 protein expression in the stromal endometrium between the three groups.

CONCLUSIONS:

KAI1 and KISS1 are implicated in the pathogenesis and maintenance of endometriosis. Future studies should investigate whether KAI1 and KISS1 could be used as markers for early and minimally invasive detection of endometriosis based on their differential protein expression pattern in the eutopic endometrium of patients with and without endometriosis.

 

 

Cochrane Database Syst Rev. 2016 Feb 26;2:

Imaging modalities for the non-invasive diagnosis of endometriosis.

Nisenblat V¹, Bossuyt PM, Farquhar C, Johnson N, Hull ML.

 

Abstract

BACKGROUND:

About 10% of women of reproductive age suffer from endometriosis. Endometriosis is a costly chronic disease that causes pelvic pain and subfertility. Laparoscopy, the gold standard diagnostic test for endometriosis, is expensive and carries surgical risks. Currently, no non-invasive tests that can be used to accurately diagnose endometriosis are available in clinical practice. This is the first review of diagnostic test accuracy of imaging tests for endometriosis that uses Cochrane methods to provide an update on the rapidly expanding literature in this field.

OBJECTIVES:

• To provide estimates of the diagnostic accuracy of imaging modalities for the diagnosis of pelvic endometriosis, ovarian endometriosisand deeply infiltrating endometriosis(DIE) versus surgical diagnosis as a reference standard.• To describe performance of imaging tests for mapping of deep endometriotic lesions in the pelvis at specific anatomical sites.Imaging tests were evaluated as replacement tests for diagnostic surgery and as triage tests that would assist decision making regarding diagnostic surgery for endometriosis.

SEARCH METHODS:

We searched the following databases to 20 April 2015: MEDLINE, CENTRAL, EMBASE, CINAHL, PsycINFO, Web of Science, LILACS, OAIster, TRIP, ClinicalTrials.gov, MEDION, DARE, and PubMed. Searches were not restricted to a particular study design or language nor to specific publication dates. The search strategy incorporated words in the title, abstracts, text words across the record and medical subject headings (MeSH).

SELECTION CRITERIA:

We considered published peer-reviewed cross-sectional studies and randomised controlled trials of any size that included prospectively recruited women of reproductive age suspected of having one or more of the following target conditions: endometrioma, pelvic endometriosis, DIE or endometriotic lesions at specific intrapelvic anatomical locations. We included studies that compared the diagnostic test accuracy of one or more imaging modalities versus findings of surgical visualisation of endometriotic lesions.

DATA COLLECTION AND ANALYSIS:

Two review authors independently collected and performed a quality assessment of data from each study. For each imaging test, data were classified as positive or negative for surgical detection of endometriosis, and sensitivity and specificity estimates were calculated. If two or more tests were evaluated in the same cohort, each was considered as a separate data set. We used the bivariate model to obtain pooled estimates of sensitivity and specificity when sufficient data sets were available. Predetermined criteria for a clinically useful imaging test to replace diagnostic surgery included sensitivity ≥ 94% and specificity ≥ 79%. Criteria for triage tests were set at sensitivity ≥ 95% and specificity ≥ 50%, ruling out the diagnosis with a negative result (SnNout test – if sensitivity is high, a negative test rules out pathology) or at sensitivity ≥ 50% with specificity ≥ 95%, ruling in the diagnosis with a positive result (SpPin test – if specificity is high, a positive test rules in pathology).

MAIN RESULTS:

We included 49 studies involving 4807 women: 13 studies evaluated pelvic endometriosis, 10 endometriomas and 15 DIE, and 33 studies addressed endometriosis at specific anatomical sites. Most studies were of poor methodological quality. The most studied modalities were transvaginal ultrasound (TVUS) and magnetic resonance imaging (MRI), with outcome measures commonly demonstrating diversity in diagnostic estimates; however, sources of heterogeneity could not be reliably determined. No imaging test met the criteria for a replacement or triage test for detecting pelvic endometriosis, albeit TVUS approached the criteria for a SpPin triage test. For endometrioma, TVUS (eight studies, 765 participants; sensitivity 0.93 (95% confidence interval (CI) 0.87, 0.99), specificity 0.96 (95% CI 0.92, 0.99)) qualified as a SpPin triage test and approached the criteria for a replacement and SnNout triage test, whereas MRI (three studies, 179 participants; sensitivity 0.95 (95% CI 0.90, 1.00), specificity 0.91 (95% CI 0.86, 0.97)) met the criteria for a replacement and SnNout triage test and approached the criteria for a SpPin test. For DIE, TVUS (nine studies, 12 data sets, 934 participants; sensitivity 0.79 (95% CI 0.69, 0.89) and specificity 0.94 (95% CI 0.88, 1.00)) approached the criteria for a SpPin triage test, and MRI (six studies, seven data sets, 266 participants; sensitivity 0.94 (95% CI 0.90, 0.97), specificity 0.77 (95% CI 0.44, 1.00)) approached the criteria for a replacement and SnNout triage test. Other imaging tests assessed in small individual studies could not be statistically evaluated.TVUS met the criteria for a SpPin triage test in mapping DIE to uterosacral ligaments, rectovaginal septum, vaginal wall, pouch of Douglas (POD) and rectosigmoid. MRI met the criteria for a SpPin triage test for POD and vaginal and rectosigmoid endometriosis. Transrectal ultrasonography (TRUS) might qualify as a SpPin triage test for rectosigmoid involvement but could not be adequately assessed for other anatomical sites because heterogeneous data were scant. Multi-detector computerised tomography enema (MDCT-e) displayed the highest diagnostic performance for rectosigmoid and other bowel endometriosis and met the criteria for both SpPin and SnNout triage tests, but studies were too few to provide meaningful results.Diagnostic accuracies were higher for TVUS with bowel preparation (TVUS-BP) and rectal water contrast (RWC-TVS) and for 3.0TMRI than for conventional methods, although the paucity of studies precluded statistical evaluation.

AUTHORS’ CONCLUSIONS:

None of the evaluated imaging modalities were able to detect overall pelvic endometriosis with enough accuracy that they would be suggested to replace surgery. Specifically for endometrioma, TVUS qualified as a SpPin triage test. MRI displayed sufficient accuracy to suggest utility as a replacement test, but the data were too scant to permit meaningful conclusions. TVUS could be used clinically to identify additional anatomical sites of DIE compared with MRI, thus facilitating preoperative planning. Rectosigmoid endometriosis was the only site that could be accurately mapped by using TVUS, TRUS, MRI or MDCT-e. Studies evaluating recent advances in imaging modalities such as TVUS-BP, RWC-TVS, 3.0TMRI and MDCT-e were observed to have high diagnostic accuracies but were too few to allow prudent evaluation of their diagnostic role. In view of the low quality of most of the included studies, the findings of this review should be interpreted with caution. Future well-designed diagnostic studies undertaken to compare imaging tests for diagnostic test accuracy and costs are recommended.

 

 

Reprod Sci. 2016 Sep;23(9):1139-47.

Fenretinide: A Potential Treatment for Endometriosis.

Pavone ME¹, Malpani SS², Dyson M², Kim JJ², Bulun SE².

 

Abstract

OBJECTIVE:

Fenretinide is a synthetic retinoid analogue that promotes apoptosis but has decreased toxicity when compared to other retinoids. We have previously shown that retinoic acid (RA) production in endometriotic tissue is decreased, resulting in reduced estrogen metabolism and apoptotic resistance. We hypothesize fenretinide may induce apoptosis in endometriotic cells and tissues, thereby reducing disease burden.

MATERIALS AND METHODS:

Primary endometriotic stromal cells were collected, isolated, cultured, and treated with fenretinide in doses from 0 to 20 µmol/L. Cell count, viability, and immunoblots were performed to examine apoptosis. Quantitative reverse transcription-polymerase chain reaction from endometriotic cells treated with fenretinide was used to examine expression of genes involved in RA signaling including stimulated by RA 6 (STRA6), cellular RA binding protein 2 (CRABP2), and fatty acid binding protein 5 (FABP5). Endometriotic tissue was xenografted subcutaneously into the flanks of mice which were treated with fenretinide for 2 weeks, after which the mice were killed and lesion volumes calculated. Statistical analysis was performed using t test and analysis of variance.

RESULTS:

Treatment with fenretinide significantly decreased total cell count (doses 5-20 µL) and viability (doses 10-20 µmol/L). Fenretinide increased protein levels of the apoptotic marker poly (ADP ribose) polymerase (starting at 10 µmol/L) and decreased proliferation marker proliferating cell nuclear antigen (10 µmol/L, starting at 8-day treatment). Examination of genes involved in retinoid uptake and action showed that treatment induced STRA6 expression while expression of CRABP2 and FABP5 remained unchanged. Fenretinide also significantly decreased the endometriotic lesion xenograft volume.

CONCLUSIONS:

Fenretinide increases STRA6 expression thereby potentially reversing the pathological loss of retinoid availability. Treatment with this compound induces apoptosis. In vivo treatments decrease lesion volume. Targeting the RA signaling pathway may be a promising novel treatment for women with endometriosis.