Womens Health (Lond). 2015 Aug;11(5):711-5.
Endometriosis after menopause.
Endometriosis is a common but an enigmatic disease in which endometrial glands and stroma are found outside the uterus. Worldwide, 80 million women are affected by the disease. It has generally been accepted as a problem of reproductive ages and affects 6-10% of those women. It is more common in women with infertility. Moreover, since it is an estrogen dependent problem, it is generally believed that endometriosis connotes ‘active ovarian function’ and is ‘healed’ after the menopause. However, there are reports on endometriosis beyond the reproductive ages. In this article, endometriosis after the menopause will be discussed.
Womens Health (Lond). 2015 Aug;11(5):671-5.
Endometriosis and ovarian reserve.
Endometriosis is characterized by development of the endometrial tissue outside the uterus like ovary, pelvic peritoneum, pelvic organs, and affects 6-10% of reproductive-aged women. The prevalence of endometrioma is 17-44% of women with endometriosis. Since endometriosis is mainly a disease for the women at their reproductive ages, it is important to consider ovarian reserve when managing the cases with ovarian endometriosis. There has been a long debate whether the endometrioma per se decreases the ovarian reserve and/or surgery for endometrioma – either by laparoscopy or by laparotomy – decreases it. Although the dispute for these questions is not totally settled down, in this article, we would like to give some clues for the answers in view of the literature.
Eur J Obstet Gynecol Reprod Biol. 2015 Nov;194:260-1
Primary umbilical endometriosis.
Cutaneous endometriosis is a rare condition, especially when it occurs without previous surgery. We report a case of a 27-year old woman with catamenial bleeding from her umbilicus. A MRI, cytological and pathological examination confirmed the diagnosis of endometriosis. We also present a brief review of the literature.
Hum Reprod. 2015 Nov;30(11):2686-92.
Diminished ovarian reserve is not observed in infertility patients with high normal CGG repeats on the fragile X mental retardation 1 (FMR1) gene.
Does an association exist between high normal numbers of CGG trinucleotide repeats on the fragile X mental retardation 1 (FMR1) gene and diminished ovarian reserve (DOR)?
This large data set demonstrated that a high normal number of CGG repeats (35-54 repeats) on the FMR1 gene was not significantly correlated with DOR.
WHAT IS KNOWN ALREADY:
The FMR1 premutation (55-200 repeats) is a known cause of primary ovarian insufficiency. However, the relationship between high normal CGG repeat numbers (35-54 repeats) and ovarian reserve has yet to be conclusively demonstrated.
STUDY DESIGN, SIZE, DURATION:
This is a retrospective data analysis conducted between January 2012 and February 2014 that included 1287 women. Over 1140 women had complete data.
PARTICIPANTS/MATERIALS, SETTING, METHODS:
All women, excluding oocyte donors, who presented to a large private practice specializing in reproductive endocrinology and infertility for treatment and who underwent both fragile X and ovarian reserve testing were included. All fragile X testing was performed using triplet repeat PCR, with confirmation of positives by Southern blot. CGG repeat numbers from both alleles were recorded, and the allele with the higher number of repeats was used for statistical calculations. We did not differentiate between patients with one or two high normal alleles. Women with >54 CGG repeats were excluded from the analysis. For our analysis, we considered both a ‘high normal’ number of CGG repeats (35-44) and an intermediate number of GCC repeats (45-54) as ‘high normal’. Ovarian reserve testing was carried out on Cycle Day 2 or 3 and included measurements of FSH, anti-Müllerian hormone (AMH) and antral follicle count (AFC). A generalized linear regression model assuming gamma distribution and log link function that controlled for age was used to assess correlation between CGG repeat number and FSH, AMH and AFC.
MAIN RESULTS AND THE ROLE OF CHANCE:
As expected, there was a significant correlation between increasing age and increasing FSH and decreasing AFC and AMH for the patients in this study. For every 1-year increase in age, FSH increased by a factor of 1.04, AFC decreased by a factor of 0.93 and AMH decreased by a factor of 0.89. After controlling for age, there was no significant correlation between FMR1 CGG trinucleotide repeat number and FSH (P = 0.23), AFC (P = 0.14) or AMH (P = 0.53). Three subgroup analyses were also performed. We found a significant relationship between increasing CGG repeat number and decreasing AMH levels (P = 0.01) in women >44 years old. The second subgroup analysis included only Caucasian patients and found no significant correlation between CGG repeat number and DOR. In a subgroup analysis comparing women with at least one allele <26 repeats, at least one allele >35 and women with both alleles between 29 and 32, there were no significant associations regarding ovarian reserve in any of these groups.
LIMITATIONS, REASONS FOR CAUTION:
One limitation of this study is that it involved a heterogeneous population of infertile women with mixed diagnoses. Factors that could affect ovarian reserve, such as medical comorbidities, prior surgeries, family history and endometriosis, were not accounted for. Finally, there was a lack of racial diversity, with Caucasians representing 67.8% of the total population.
WIDER IMPLICATIONS OF THE FINDINGS:
The findings of this study are generalizable to an infertility population and are in line with several previously published studies. Women who are found to have high normal CGG repeat numbers can be counseled that this is not causative for DOR. Further studies are needed to investigate whether increasing CGG repeat numbers are associated with ovarian responsiveness to gonadotrophin stimulation or IVF outcome.
Case Rep Obstet Gynecol. 2015;2015:761348.
Acute Renal Failure due to Obstructive Uropathy Secondary to Ureteral Endometriosis.
Ureteral involvement by endometriosis is a rare and often silent disease but capable of producing significant morbidity and leading to hydronephrosis and to renal failure. Surgery is the treatment of choice to remove endometriotic lesions and relieve ureteral obstruction if the kidney is still functional or a nephrectomy is performed if there is a complete loss of renal function. We report a case of acute renal failure induced ureteral endometriosismanaged with laparoscopic unilateral nephrectomy and endometrioma cystectomy. Differential diagnosis is important to confirm diagnosis for patients with ureteral obstruction presenting nonspecific symptoms.
Dis Colon Rectum. 2015 Oct;58(10):957-66
Full-Thickness Disc Excision in Deep Endometriotic Nodules of the Rectum: A Prospective Cohort.
To date, a majority of patients presenting with large endometriosis of the rectum are managed worldwide by colorectal resection. However, postoperative rectal function may be impacted by radical rectal surgery.
The purpose of this study was to assess the postoperative outcomes of patients with rectal endometriosis who are managed by full-thickness disc excision and to compare outcomes of the 2 procedures using a transanal approach.
This was a prospective study.
The study was conducted at a university hospital.
Fifty patients with colorectal endometriosis that was managed by disc excision between June 2009 and November 2014 were included in the study.
The procedure included laparoscopic deep shaving, followed by full-thickness disc excision to remove the shaved rectal area. Disc excision was performed using a semicircular transanal stapler (the Rouen technique) in 20 patients, an end-to-end anastomosis circular transanal stapler in 28 patients, and transvaginal excision in 2 patients.
MAIN OUTCOMES MEASURES:
Preoperative and postoperative assessments of pelvic symptoms and digestive function using standardized gastrointestinal questionnaires were the main measures.
The largest diameter of specimens achieved was significantly higher using the Rouen technique (58 ± 9 mm) than the end-to-end anastomosis stapler (34 ± 6 mm). Two rectovaginal fistulas were recorded (4%), and 8 patients presented with transitory bladder voiding (16%). Median postoperative values for the Gastrointestinal Quality of Life Index and the Knowles-Eccersley-Scott-Symptom Questionnaire improved progressively 1 and 3 years after surgery. For patients intending to get pregnant, the cumulative pregnancy rate was 80%, and 63% of pregnancies were spontaneous.
The study sample size is small and the design is not comparative; however, direct comparison of patients managed by disc excision and colorectal resection would be inappropriate, because of differences regarding nodule localization and size.
Disc excision is a valuable alternative to colorectal resection in selected patients presenting with rectal endometriosis, achieving better preservation of rectal function. The Rouen technique allows for successful removal of large nodules of the low and midrectum, with favorable postoperative outcomes. (See video abstract, http://links.lww.com/DCR/A208.).
Fertil Steril. 2015 Oct;104(4):802-812
Beyond infertility: obstetrical and postpartum complications associated with endometriosis and adenomyosis.
The risk of pregnancy and neonatal complications in women with endometriosis and adenomyosis is debatable. A literature review looking at rates, presentation, and management of spontaneous hemoperitoneum, enlargement, abscess, and rupture of an endometrioma, uterine rupture, and bowel perforation in pregnant women with endometriosis was conducted. Moreover, studies addressing differences in early pregnancy (miscarriage), late pregnancy (gestational diabetes mellitus, preeclampsia, prematurity, placenta previa, placental abruption, cesarean section, hemorrhages) and neonatal outcomes (weight at birth) between endometriosis and adenomyosis patients versus control subjects were reviewed. The overall prevalence of endometriosis-related spontaneous hemoperitoneum in pregnancy is estimated to be ∼0.4%. Only four cases of endometrioma rupture in pregnancy have been reported. Although during pregnancy there is no way to anticipate the onset of complications from preexisting endometriosis, it is important, when a specific abdominal pain occurs, to suspect rare but potentially life-threating events. Population-based studies suggest a possible association of endometriosis with preterm birth and placenta previa. Limits of the published studies are noted and discussed.
J Biomed Nanotechnol. 2015 May;11(5):789-804.
Nanoparticle-Assisted Combinatorial Therapy for Effective Treatment of Endometriosis.
Endometriosis is characterized by the presence of endometrial glands and stroma outside the uterine cavity. Conventional treatment modalities for endometriosis are unsatisfactory; therefore, there is a need to treat the underlying causes and mechanism. Oxidative stress, extracellular matrix degradation, and angiogenesis are associated with the pathogenesis of endometriosis. The anti-angiogenic and antioxidant properties of epigallocatechin gallate and the matrix metalloproteinase inhibitory activity of the antibiotic doxycycline are well established. However, epigallocatechin gallate and doxycycline have several limitations when used in their native forms. This motivated us to synthesize dual drug-loaded (epigallocatechin gallate and doxycycline) nanoparticles and check their therapeutic efficacy in mice with induced endometriosis. The synthesized nanoparticles displayed features of a promising drug-delivery system, such as small size, high encapsulation efficiency, controlled drug release, and low toxicity. The serum of endometriosis-induced mice and controls was assessed for various oxidative stress markers, matrix-degrading enzymes, and angiogenic markers before and after nanoparticle administration. Endometrial glands, stroma, and new microvessels were determined using histochemistry and immunohistochemistry. Treatment with dual drug-loaded nanoparticles markedly decreased oxidative stress, matrix metalloproteinase activity, and angiogenesis, as well as endometrial gland presence and microvessel density. Mitigation of endometriosis-related adverse effects further produced an improvement in the quality of oocytes, which is critical for successful pregnancy outcomes. Our observations suggest that owing to their combinatorial effect, poly(lactic-co-glycolic) acid nanoparticles loaded with epigallocatechin gallate and doxycycline in a single vehicle appear to be promising for the treatment of endometriosis.
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2015 May;44(3):269-77.
Role of mast cells in estrogen-mediated experimental endometriosis in rats.
To investigate the role of mast cells in the pathogenesis of estrogen-mediated experimental endometriosis in rats.
Endometriosis model was established by transplanting autologous fragments of uterus to the inner surface of the abdominal wall in 24 un-pregnant female Sprague Dawley rats. The rats were divided randomly into three groups (n=8 in each group), and were injected with different doses of estrogen: high-dose group (200 μg·kg⁻¹·d⁻¹), low-dose group (100 μg·kg⁻¹·d⁻¹) and the control group (0 μg·kg⁻¹·d⁻¹). The ovaries were surgically removed in high-dose and low-dose groups. Four rats were sacrificed in each group at 2 and 4 weeks after surgery. Their serum estradiol levels, size of lesions, total number of mast cells and degranulations, serum TNF-α levels, expression of tryptase and NGF in tissues were analyzed and compared among groups.
The mean levels of serum estradiol 2 weeks and 4 weeks after model established and serum TNF-α at 4 weeks in estrogen-treated groups were significantly higher than those in control group (all P<0.05). The mean size of endometriotic lesions in the estrogen-treated groups was also significantly larger than that in the control group 2 weeks and 4 weeks after model established (all P<0.05). Meanwhile, both at week 2 and week 4, the mean ratio of degranulation/total number of mast cells by toluidine blue staining in low-dose estrogen group was significantly higher than that in the control group (P<0.05). The expression of NGF in high-dose estrogen group was significantly higher than that in the control group at week 4(P<0.05).
Estrogen can promote the growth of endometriotic lesions and may mediate the pathogenesis of endometriosis by activating mast cells, which may be associated with increasing TNF-α and NGF levels.
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2015 May;44(3):278-84.
Sodium cromoglycate attenuates experimental endometriosis in rats by regulating mast cells.
To investigate the effect of sodium cromoglycate on experimental endometriosis in rats.
Endometriosis model was established in 36 unpregnant female SD rats by transplanting autologous fragments of endometrium to the inner surface of the abdominal wall. The endometriotic lesions were measured by a second laparotomy 2 weeks after surgery. Then the rats were randomly divided into four groups (n=8 in each group) to receive intraperitoneal injection of different doses of sodium cromoglycate for 2 weeks: high-dose group (20 mg·kg⁻¹·d⁻¹); low-dose group (10 mg·kg⁻¹·d⁻¹); the negative control group and the blank control group. The animals were sacrificed and the size of the lesions were measured. The endometriosis model of SD rats was identified by HE staining and immunohistochemical staining of keratin and vimentin. The total number of mast cells and their degranulation were measured by Toluidine blue staining; the concentrations of TNF-α in serum were measured by enzyme linked immunosorbent assay; the concentrations of estradiol in serum were measured by enzyme immunoassay; the expression of tryptase and nerve growth factor (NGF) were measured by immunohistochemical staining.
The number of activated mast cells (MC) by Toluidine blue staining in high-dose group was significantly lower than that in negative control group (P<0.05), and its ratio of degranulation/total number of MC was significantly lower than that in negative control group or blank control group (P<0.05). The serum TNF-α levels and tryptase expression in tissues in high-dose group were significantly lower than those in negative control group or blank control group (P<0.05). However, no significant difference in the size of endometriotic lesions and expression of NGF was found among groups (P>0.05).
Sodium cromoglycate can stabilize mast cells from degranulation, which may relieve the clinical symptoms of endometriosis by reducing TNF-α and tryptase levels.
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2015 May;44(3):285-92.
AQP5 gene silencing inhibits proliferation and migration of ectopic endometrial glandular epithelial cells in endometriosis.
To investigate the effect of aquaporin 5(AQP5) on proliferation and migration of ectopic endometrial epithelial cells.
AQP5 shRNA interference fragments were designed and transfected into ectopic endometrial epithelial cells stably by lentivirus technology. Fluorescence quantitative RT-PCR and Western blotting were used to detect the AQP5 mRNA and protein expression, respectively. The cell proliferation and migration were determined by using MTT method and Transwell system, respectively. Levels of phosphorylated AKT(p-AKT) and total AKT were examined by Western blotting. The nude mice model of endometriosis was constructed and the endometrial cell nodule formation was observed.
AQP5 shRNA transfection inhibited cell proliferation and migration compared with control group (both P<0.05). The activation of AKT in AQP5 shRNA transfected cells was lower than that in control cells (P<0.01). Compared to control group, the endometrial cells nodule formation was suppressed in mice inoculated with AQP5 shRNA-silencing ectopic endometrial epithelial cells.
Down-regulation of AQP5 expression can suppress the proliferation and migration of ectopic endometrial epithelial cells and endometrial cell nodule formation in nude mice, in which AKT pathway may be involved.
J Assist Reprod Genet. 2015 Oct;32(10):1531-5.
Glutathione S-transferase M1 and T1 gene polymorphisms in Brazilian women with endometriosis.
The glutathione family (GST) genes appear to play a role in the genesis of endometriosis. This case-control study aimed to compare the frequencies of GSTM1 and GSTT1 polymorphisms in women with endometriosis and women without endometriosis.
Polymerase chain reaction was performed to analyze the GSTM1 and GSTT1 genotypes among women with surgically and histologically confirmed endometriosis (case group n = 121) and in women without evidence of endometriosis confirmed by laparoscopy for investigation the infertility or for laparoscopic tubal sterilization (control group n = 97).
No differences in the frequencies of GSTM1 polymorphism (null genotype) were observed between the cases and controls: odds ratio (OR) = 1.13; 95 % CI 0.656-1.93 (p = 0.659). The GSTT1 polymorphism (null genotype) was more prevalent in the endometriosis group than in the control group (OR = 0.53; 95 % CI 0.94-0.29 (p = 0.039). No relationship between menstrual cycle interval and GSTM1 null genotype frequency was observed in either cases or controls (p = 0.370 and p = 0.664, respectively). In addition, no relationship between menstrual cycle interval and GSTT1 null genotype was observed in cases (p = 0.797) or controls (p = 0.052).
GSTM1 null genotype frequency was similar between cases and controls. The GSTT1 null genotype was more frequent in the control group.
Fertil Steril. 2015 Oct;104(4):793-801.
Prevention of the recurrence of symptom and lesions after conservative surgery for endometriosis.
Although surgical excision of endometriosis both improves pain and enhances fertility, recurrence can further exacerbate pain and reduce fertility, which in turn impacts the quality of life and increases personal as well as social costs. Therefore, it is crucial to prevent the recurrence of symptoms and lesions after conservative surgery. This article reviews evidence regarding the prevention of postoperative recurrence of endometriosis reported since the 1990s. Over the past 5 years, many new studies have been conducted and have demonstrated that long-term postoperative medication markedly reduces the recurrence. Most of these studies used oral contraceptives (OC), with either the cyclic or continuous regimen, while some used oral or intrauterine progestin. Continuous OC is more efficacious than cyclic OC, especially for dysmenorrhea. The levonorgestrel-releasing intrauterine system is also shown to prevent recurrence of dysmenorrhea and possibly endometriosis lesions. Dienogest, a new progestin, is shown to reduce the recurrence of endometrioma. Similar to the case of ovarian endometriosis, long-term postoperative medication after conservative surgery for deep infiltrating or extragenital endometriosis seems important, although data are limited. Regardless of the lesion and the medication type, patients who discontinued medication experienced a higher incidence of recurrence, indicating that the protective effect of these medications seems to vanish rapidly after the discontinuation. On the basis of these facts, together with the pathogenesis of recurrence (retrograde menstruation and ovulation), regular and prolonged medication until the patient wishes to conceive is highly recommended to prevent the postoperative recurrence of endometriosis.
Arch Gynecol Obstet. 2016 Apr;293(4):797-804
Molecular mechanisms underlying endometriosis pathogenesis revealed by bioinformatics analysis of microarray data.
To identify differentially expressed genes (DEGs) in endometriosis and further analyze molecular mechanisms implicated in disease pathogenesis.
MATERIALS AND METHODS:
Gene expression data (ID: GSE7846) of human endometrial endothelial cells (HEECs) collected from eutopic endometria tissue of patients with and without endometriosis were downloaded from Gene Expression Omnibus. DEGs were screened using Limma package, followed by enrichment analysis using clusterProfiler package in R. Thereafter, protein-protein interactions (PPIs) were analyzed using STRING (Search Tool for the Retrieval of Interacting Genes) database and visualized by Cytoscape software. Meanwhile, transcription factors were screened from the DEGs based on TRANSFA database, followed by construction of regulatory network using Cytoscape.
A total of 2255 up- and 408 down-regulated genes were identified in endometriosis patients as compared with control patients. Those DEGs were predominantly enriched in focal adhesion (e.g., FN1, EGF, FYN, EGFR, RAC1, CCND1 and JUN), regulation of actin cytoskeleton (e.g., FN1, EGF, EGFR, RAC1 and JUN) and MAPK signaling pathway (e.g., EGF, EGFR, RAC1, JUN, TGFB1 and MYC). Importantly, EGF, EGFR, JUN, FN1, RAC1, TGFB1, CCND1 and FYN were hub nodes in the PPI network. Additionally, TGFB1, SMAD1 and SMAD4 showed up-regulation in TGFB signaling pathway. Transcription factor MYC had a regulatory effect on the most DEGs, including TGFB1, RAC1 and CCND1.
Focal adhesion, regulation of actin cytoskeleton, MAPK and TGFB/SMAD signaling pathway may be important molecular mechanism underlying the pathogenesis of endometriosis.
Biomed Res Int. 2015;2015:340218.
MiR-183 Regulates ITGB1P Expression and Promotes Invasion of Endometrial Stromal Cells.
We applied in the previous study miRNA microarray screening analysis to identify several differentially expressed miRNAs, including miR-183 in normal, eutopic, and ectopic endometrium. Knockdown of miR-183 expression induced the invasiveness and inhibition of apoptosis in endometrial stromal cells. The current study aims to identify the miR-183 targets with relevance to cell functions in endometrial stromal cells, to verify the interaction of miR-183 with its target genes, and to confirm the role of miR-183 in the process of endometriosis. Using microarray analysis, we identified 27 differentially expressed genes (19 were upregulated and 8 downregulated), from which we selected 4 downregulated genes (ITGB1, AMIGO2, VAV3, and PSEN2) based on GO databases for functional analysis and significant pathway analysis. Western blotting analyses showed that integrin β1 (ITGB1), but not AMIGO2, was affected by miR-183 overexpression, whereas no protein expression of VAV3 and PSEN2 was detected. Luciferase reporter assay verified that ITGB1 is a target gene of miR-183. Moreover, we found that ITGB1 is overexpressed in the endometrium of endometriosis patients. Furthermore, overexpression of ITGB1 rescued the repressive effects of miR-183 on the invasiveness of endometrial stromal cells. These findings, together with the fact that ITGB1 is a critical factor for cell adhesion and invasiveness, suggest that miR-183 may be involved in the development of endometriosis by regulating ITGB1 in endometrial stromal cells.
BMC Womens Health. 2015 Sep 10;15:74.
The impact of previous ovarian surgery on ovarian reserve in patients with endometriosis.
To investigate the impact of previous ovarian surgery on ovarian reserve in patients with endometriosis.
A total of 829 female patients were recruited. Their medical records were reviewed retrospectively. Patients who had diagnoses of endometriosis or endometrioma were defined as the endometriosis group, and those without endometriosis were as the control group. We further divided these patients into four groups according to whether they had received ovarian surgeries before. Group 1: control group without previous surgery; Group 2: control group with previous surgery; Group 3: endometriosis group without previous surgery; Group 4: endometriosis group with previous surgery. The subgroups with endometrioma or not and different operative procedures were also analyzed. The parameters for comparison included age, body mass index, serum estradiol, follicle-stimulating hormone, luteinizing hormone, cancer antigen 125, and anti-Müllerian hormone (AMH) level.
The level of serum AMH was highest in group 1 and lowest in group 4. The decline was significant between group 1 and group 4 (p < 0.05). The serum AMH level was lower in group 4 than in group 3 but no significant difference. Serum estradiol level was significantly higher in group 3 than in group 2 (p < 0.05). Cancer antigen 125 levels were both significantly higher in group 3 and group 4 as compared with group 1 and group 2 (p < 0.05).
Performing repeated ovarian surgery in patients with recurrent endometriosis needs careful consideration and adequate patient counselling because of the predictable deteriorating ovarian reserve.
Am J Reprod Immunol. 2015 Dec;74(6):467-79.
TLR4 Activation Promotes the Secretion of IL-8 Which Enhances the Invasion and Proliferation of Endometrial Stromal Cells in an Autocrine Manner via the FAK Signal Pathway.
Chronic inflammation is important for the occurrence of endometriosis, but the molecular mechanisms are still poorly understood. TLR4 is not only expressed on immune cells but is also present in the human endometrium, and its regulation might be crucial for the pathogenesis of endometriosis.
METHOD OF STUDY:
In this study, the expression of TLR4 in normal, eutopic endometrium, and ectopic tissues was analyzed by immunohistochemistry. The expression of the key molecules in endometrial stromal cells (ESCs) was assessed by in-cell Western assays. The invasion of eutopic ESCs from patients with endometriosis was evaluated by Matrigel invasion assay. The effects of CXCL8 on the proliferation of ESCs in vitro were assessed using BrdU assays.
We found that the expression of TLR4 is higher in the eutopic endometrium than the normal endometrium and that ectopic tissue had the highest level of expression. TLR4 activation stimulated IL-8 secretion and the expression of its receptor CXCR1 in ESCs by activating p38/ERK, but not JNK and NK-κB signal pathways. IL-8 could enhance the invasion and proliferation of ESCs through the FAK signal pathway, and these effects could be abolished by an anti-CXCL8 neutralizing antibody or by a FAK inhibitor.
Reprod Sci. 2016 Mar;23(3):379-85. doi
Expression and Significance of WNT4 in Ectopic and Eutopic Endometrium of Human Endometriosis.
The objective was to investigate the expression of the WNT4 gene in ectopic endometrium and eutopic endometrium (EU) during endometriosis and the relationship of WNT4 expression with the menstrual cycle. Ectopic endometrium and EU tissues were collected from 30 women with pathologically confirmed endometriosisand 30 women without endometriosis. The WNT4 protein and messenger RNA (mRNA) expression levels were measured by fluorescence-based quantitative real-time polymerase chain reaction, immunohistochemistry, and Western blot methods. The expression of WNT4 was not significantly correlated with the menstrual cycle, and there were no significant differences when WNT4 expression in proliferative endometrium was compared with that in secretory endometrium within each group. There were no significant differences between the protein and mRNA expression of WNT4 in ectopic endometrium and in EU from participants with endometriosis. The WNT4 expression level in EU was significantly reduced compared with that in normal endometrium of the control group, even when analyzed by the menstrual cycle phase. WNT4 was also downregulated in ectopic lesions. This study provides further evidence supporting the theory of “EU determinism” in the pathogenesis of endometriosis.
Gynecol Endocrinol. 2016;32(1):34-7
Anti-Mullerian hormone trend evaluation after laparoscopic surgery of monolateral endometrioma using a new dual wavelengths laser system (DWLS) for hemostasis.
Operative laparoscopy is the gold standard in the treatment of endometriotic ovarian cysts. Excisional surgery is the best technique to prevent recurrences and improve symptoms but it may result in ovarian reserve damage due to the removal of healthy ovarian cortex. The aim of this study was to assess the impact on ovarian reserve of the use of dual wavelengths laser system (DWLS) hemostasis after stripping technique of monolateral endometrioma, by dosing the anti-Mullerian hormone (AMH). This prospective study was conducted at the Institute of Obstetrics and Gynecology, University of Foggia, from December 2013 to January 2015. Forty-five women underwent excision of monolateral endometriotic ovarian cyst by stripping without using a bipolar coagulation and performing hemostasis with a DWLS. The AMH serum levels were estimated before the surgery (T0), 4-6 weeks (T1) and 6-9 months (T2) after surgery. Our results suggest that an appropriate surgical technique with the use of laser hemostasis does not determine a significant reduction of ovarian reserve. Laser hemostasis could prevent follicular reserve loss after ovarian endometrioma surgery.
Fertil Steril. 2015 Oct;104(4):761-763.
Introduction: Management of endometriosis: moving toward a problem-oriented and patient-centered approach.
Endometriosis is a protean disease, and its manifestations, associated clinical problems, and possible treatments are numerous. Deep endometriosis that infiltrates multiple pelvic organs should be considered the most severe endometriotic form that poses the most difficult therapeutic uncertainties in both infertility and pelvic pain symptoms limiting quality of life. The available evidence demonstrates that endometriosis is not only a gynecologic disorder but, contrary to previous belief, its impact extends into pregnancy, delivery, and the post-partum period. The old clinical tenet that pregnancy is a cure for endometriosis may be revealed as fallacious. Safe and effective modalities to reduce the risk of the recurrence of symptoms and lesions after conservative surgery for endometriosis are now available. These treatment options should be offered post-operatively to women not immediately seeking conception. Endometriosis is associated with a moderate increase in ovarian cancer risk. However, as there are no definitive demonstrations that endometriosis constitutes per se a pre-neoplastic condition, it seems currently unwise to set-up a screening program to detect undiagnosed endometriosis in asymptomatic women. Endometriosis is not a cancer; therefore a paradigm shift from treatment of lesions to treatment of symptoms is warranted. Management should be shaped on the main clinical problem, taking into consideration a woman’s preferences and priorities. Quantitative information should be provided to describe the potential benefits, potential harms, and costs of each treatment alternative. Counseling should be complete and transparent, and the duty of the caring gynecologist is to inform the woman on the pros and cons of each option and support her in the shared decision-making process. The physician should be able to explain in detail all the available treatments, and not only those that the physician prefers or is able to offer.
Fertil Steril. 2015 Oct;104(4):771-792.
Treatment of pain associated with deep endometriosis: alternatives and evidence.
Pain is the most evident clinical manifestation of deep infiltrating endometriosis (DIE). Several hormonal and immunologic mechanisms are markedly altered in DIE compared with superficial peritoneal and ovarian endometriosis, and may explain its most aggressive behavior and the presence of severe pain symptoms. Hormonal therapies, such as combined hormonal contraceptives and progestogens, should be regarded as first-line treatment, as they are efficacious, safe, and well tolerated. Gonadotropin-releasing hormone agonists may be used in patients with symptoms persisting after the administration of first-line therapies. Scanty literature is available for danazol treatment in patients with DIE and, however, it has become less popular due to the high rates of androgenic adverse events (AEs). The partial relief of pain that often is achieved with available therapies and its recurrence after the suspension of the treatment have brought to the development of new therapies (such as aromatase inhibitors, oral GnRH antagonists) that are currently under investigation. Surgical excision of DIE should be considered in patients with pain symptoms persisting after first-line hormonal therapies. The benefits of surgery in terms of pain improvement should be always balanced with the risk of intraoperative complications and for this reason surgical cases should be referred to tertiary centers for the treatment of DIE. A multidisciplinary approach is mandatory in patients with DIE involving the bowel and/or the urinary tract.
Am J Obstet Gynecol. 2016 Feb;214(2):203-211.
Continuous versus cyclic oral contraceptives after laparoscopic excision of ovarian endometriomas: a systematic review and metaanalysis.
In the lack of evidence consistently supporting the use of continuous vs cyclic oral contraceptives after surgery for endometriosis, we conducted a systematic review and metaanalysis with the objective of comparing a continuous vs a cyclic oral contraceptive schedule administered after surgical excision of ovarian endometriomas. A PubMed, MedLine, and Embase search through December 2014 was conducted, with the use of a combination of key words and text words related to endometrioma, endometriosis, oral contraceptives, oral estroprogestins, laparoscopy, and surgery. Studies directly comparing a continuous vs a cyclic schedule administered after surgical treatment of endometriomas were included, with pain and endometrioma recurrence rates as the primary outcomes. Three reviewers independently assessed methodology and extracted data from selected studies. The primary outcomes were considered pain recurrence (evaluated separately for dysmenorrhea, noncyclic chronic pelvic pain, and dyspareunia) and endometrioma recurrence evaluated at ultrasonography. Dichotomous outcomes from each study were expressed as risk ratio (RR) with a 95% confidence interval (CI). Three randomized clinical trials and 1 prospective controlled cohort study were included, for a total of 557 patients with endometriosis, 343 patients of whom had ovarian endometriomas completing the assigned treatment and follow-up. Lower recurrence rates for dysmenorrhea were obtained with a continuous schedule (RR, 0.24; 95% CI, 0.06-0.91; P = .04). Nonsignificant differences were present for chronic pelvic pain and dyspareunia. A continuous oral contraceptive schedule was associated with a nonsignificant reduction of cyst recurrence rates compared with a cyclic schedule (RR, 0.54; 95% CI, 0.28-1.05; P = .07). A continuous oral contraceptive regimen, as opposed to a cyclic regimen, may be suggested after surgery for endometriomas because of lower dysmenorrhea recurrence rates. Due to the small number and small sample sizes of the included studies, further randomized clinical trials are needed to confirm the findings of the present systematic review. Also, outcomes related to patient satisfaction and quality of life should be addressed.
Biomed Res Int. 2015;2015:760698.
Profiling of Selected MicroRNAs in Proliferative Eutopic Endometrium of Women with Ovarian Endometriosis.
It has been well documented that aberrant expression of selected microRNAs (miRNAs) might contribute to the pathogenesis of disease. The aim of the present study is to compare miRNA expression by the most comprehensive locked-nucleic acid (LNA) miRNA microarray in eutopic endometrium of patients with endometriosis and control. In the study we recruited 21 patients with endometriosis and 25 were disease-free women. The miRNA expression profiles were determined using the LNA miRNA microarray and validated for selected molecules by real-time PCR. We identified 1198 human miRNAs significantly differentially altered in endometriosis versus control samples using false discovery rate of <5%. However only 136 miRNAs showed differential regulation by fold change of at least 1.3. By the use of selected statistical analysis we obtained 45 potential pathways that might play a role in the pathogenesis of endometriosis. We also found that natural killer cell mediated cytotoxicity pathway was found to be inhibited which is consistent with previous studies. There are several pathways that may be potentially dysregulated, due to abnormal miRNA expression, in eutopic endometrium of patients with endometriosis and in this way contribute to its pathogenesis.
Eur J Obstet Gynecol Reprod Biol. 2015 Nov;194:119-24.
In search of key genes associated with endometriosis using bioinformatics approach.
The aim of this study was to identify key genes associated with endometriosis.
Microarray data GSE7846 was downloaded from Gene Expression Omnibus. The differentially expressed genes (DEGs) in human endometrial endothelial cells derived from eutopic endometrium of patients with endometriosis compared with controls without endometriosis were identified using Linear Models for Microarray Data (LIMMA) package in R. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology (GO) enrichment analyses were performed using DAVID. Moreover, the protein-protein interaction (PPI) network was constructed by STRING and subsequently significantly enriched modules were mined by ClusterONE. Finally, protein domains and KEGG pathway enrichment analyses were performed for PPI modules.
A total of 687 DEGs were identified, including 584 up- and 103 down-regulated genes. The up-regulated DEGs, such as epidermal growth factor (EGF) and interleukin 1 beta (IL-1β) were significantly enriched in KEGG pathways of focal adhesion, ECM-receptor interaction and calcium signaling pathway. Similarly, only one module was obtained form PPI network, and the genes, like angiotensin II receptor, Type 1 (AGTR1) in the module were mainly enriched in protein domain of rhodopsin-like G protein-coupled receptors and most altered pathways of neuroactive ligand-receptor interaction, calcium signaling pathway and vascular smooth muscle contraction.
Our findings indicate that EGF, IL-1β and AGTR1 may play important roles in the pathogenesis of endometriosis.
J Obstet Gynaecol Res. 2015 Dec;41(12):1921-6.
Use of dienogest over 53 weeks for the treatment of endometriosis.
To evaluate the efficacy and adverse effects of Dienogest (DNG) over 53 weeks for the treatment of endometriosis.
DNG was administered to 75 patients with endometriosis over a period of 53 weeks. Medical charts were retrospectively examined on the efficacy and side effects. Reduction rates of ovarian chocolate cyst, adenomyosis and changes in serum estradiol and cancer antigen 125 concentration were measured. Adverse effects, patient evaluation of their symptoms and willingness to continue taking DNG were assessed by a questionnaire.
The median duration of treatment was 87 weeks, with the longest follow-up duration being 120 weeks. Ovarian chocolate cysts were initially reduced; however, upon cessation of DNG treatment, an increase in size was observed. Adenomyosis lesions were reduced to some extent after 53 weeks of DNG treatment. In terms of adverse events, more than 60% (61.3%, 46/75) of patients experienced atypical genital bleeding. However, this did not prove to be a cause of discontinuation. We ceased DNG treatment in two cases because of lower abdominal pain and shoulder discomfort.
Long term DNG treatment beyond one year for endometriosis proved to be effective and safe. Ovarian chocolate cysts were markedly reduced by short-term use of DNG, while a longer duration was required to reduce the size of adenomyosis. The decision regarding the choice of therapy lies with the individual clinician, considering a balance of efficacy with expense and adverse effects.
Gynecol Endocrinol. 2015;31(12):949-54.
Prevention of ovarian hyperstimulation syndrome in a rat model: comparison of the efficacy of tocilizumab with that of ranibizumab, cabergoline, and a gonadotropin-releasing hormone antagonist.
The aim of the study is to investigate the effects of the interleukin-6 (IL-6) blocker tocilizumab in a hyperstimulated rat model and compare it with ranibizumab, a gonadotropin-releasing hormone antagonist (GnRHA), and cabergoline. Forty-seven rats were randomly divided into the following seven groups: Group 1: OHS; Group 2: OHS+ GnRHA; Group 3: OHS + ranibizumab; Group 4: OHS + cabergoline; Group 5: OHS + low-dose tocilizumab (TL); Group 6: OHS + high-dose tocilizumab (TH); Group 7: sham. Ovarian weight was significantly lower only in the ranibizumab group than in the OHS group. Estrogen levels were significantly lower in the GnRHA group than in the OHS and the treatment groups. Progesterone levels were significantly lower in the ranibizumab, cabergoline, and TL groups than in the OHS group. Among the treatment groups, corpus luteum counts were lower than in the OHS group. Corpus luteum counts were lowest in the tocilizumab groups. IL-6 intensity was lower in all treatment groups than in the OHS group. In the ranibizumab group IL-6 intensity was the lowest. The TL group did not significantly differ from the GnRHA and cabergoline groups regarding IL-6 expression. Ovarian VEGF expression was significantly lower in all treatment groups. For the TL, ranibizumab, and cabergoline groups VEGF intensity was similar. Tocilizumab may be a new strategy for preventing ovarian hyperstimulation syndrome by inhibition of IL-6.
Hum Reprod. 2015 Dec;30(12):2881-91.
Altered expression of microRNA-451 in eutopic endometrium of baboons (Papio anubis) with endometriosis.
Are microRNAs (miRs) altered in the eutopic endometrium (EuE) of baboons following the induction of endometriosis?
Induction of endometriosis causes significant changes in the expression of eight miRs, including miR-451, in the baboon endometrium as early as 3 months following induction of the disease.
WHAT IS KNOWN ALREADY:
Endometriosis is one of the most common gynecological disorders and causes chronic pelvic pain and infertility in women of reproductive age. Altered expression of miRs has been reported in women and has been suggested to play an important role in the pathophysiology of several gynecological disorders including endometriosis.
STUDY DESIGN, SIZE, DURATION:
EuE was obtained from the same group of baboons before and 3 months after the induction of endometriosis. The altered expression of miR-451 was validated in the eutopic and ectopic endometrium of additional baboons between 3 and 15 months following disease induction. Timed endometrial biopsies from women with and without endometriosis were also used to validate the expression of miR-451.
PARTICIPANTS/MATERIALS, SETTING, METHODS:
Total RNA was extracted from EuE samples before and after the induction of endometriosis, and miRNA expression was analyzed using a 8 × 15 K miR microarray. Microarray signal data were preprocessed by AgiMiRna software, and an empirical Bayes model was used to estimate the changes. The present study focused on quantitative RT-PCR validation of the microarray data, specifically on miR-451 and its target genes in both baboons (n = 3) and women [control (n = 7) and endometriosis (n = 19)]. Descriptive and correlative analysis of miR-451 and target gene expression was conducted using in situ hybridization and immunohistochemistry, while functional analysis utilized an in vitro 3′ untranslated region (UTR) luciferase assay and overexpression of miR-451 in human endometrial and endometriotic cell lines.
MAIN RESULTS AND THE ROLE OF CHANCE:
Induction of endometriosis results in the altered expression of miR-451, -141, -29c, -21, -424, -19b, -200a and -181a in the baboon endometrium. In the baboon, induction of endometriosis significantly decreased the expression of miR-451 at 3 months (P < 0.001), which was also associated with increased expression of its target gene YWHAZ (14.3.3ζ). A similar significant (P < 0.0001) decrease in miR-451 expression was observed in women with endometriosis. The 3′ UTR luciferase assay confirmed the regulation of YWHAZ expression by miR-451. Furthermore, overexpression of miR-451 in 12Z cells (immortalized human endometriotic epithelial cell line) led to the decreased expression of its target YWHAZ and this was correlated with decreased cell proliferation.
LIMITATIONS, REASONS FOR CAUTION:
The study focused only on miR-451 and one of its targets, namely YWHAZ. A single miR could target number of genes and a single gene could also be regulated by number of miRs; hence, it is possible that other miRs and their regulated genes may contribute to the pathophysiology of endometriosis.
WIDER IMPLICATIONS OF THE FINDINGS:
Our data suggest that the presence of ectopic lesions in baboon causes changes in EuE miR expression as early as 3 months postinduction of the disease, and some of these changes may persist throughout the course of the disease. We propose that the marked down-regulation of miR-451 in both baboons and women with endometriosis increases the expression of multiple target genes. Increased expression of one of the target genes, YWHAZ, increases proliferation, likely contributing to the pathophysiology of the disease.
Gynecol Endocrinol. 2015;31(11):840-5.
Glutathione-S-transferases M1/T1 gene polymorphisms and endometriosis: a meta-analysis in Chinese populations.
In view of the controversies surrounding the glutathione-S-transferases (GST) M1/T1-endometriosis association, a meta-analysis of the GSTM1/GSTT1 genetic association studies of endometriosis was performed in Chinese populations. PubMed, Springer Link, OvidSP, and Chinese databases were searched for related studies. A total of nine studies on GSTM1-endometriosis involved 874 cases and 997 controls, and five studies on GSTT1 involved 404 cases and 513 controls were included in this meta-analysis. Overall, the null genotype of GSTM1/GSTT1 was significantly related to endometriosis risk in Chinese populations (GSTM1, OR = 2.21, 95% CI: 1.22-4.01; GSTT1, OR = 2.31, 95% CI: 1.34-3.99). In subgroup analyses stratified by ethnicity and source of controls, the same results were observed in Chinese Han and population-based studies. The sensitivity analysis confirmed the reliability and stability of the meta-analysis. No publication bias was found among studies by Egger’s test. In conclusion, our meta-analysis supports that the GSTM1/GSTT1 null genotype might contribute to individual susceptibility to endometriosis in Chinese populations, especially in Chinese Han.
J Obstet Gynaecol Res. 2015 Oct;41(10):1598-606.
Differential mRNA expression profiling in ovarian endometriotic tissue with versus without leuprolide acetate treatment.
Leuprolide acetate, an analog of gonadotropin-releasing hormone (GnRH), regresses endometriotic tissue and reduces pain, resulting in clinical improvement upon treatment. The molecular mechanisms involved in the regression of endometriotic tissue, however, remain to be elucidated. In this study, we performed genome-wide gene expression profiling of clinical specimens of ovarian endometrioma to obtain insight into the effects of leuprolide acetate treatment.
We obtained clinical samples from nine normal eutopic endometrium tissues, eight ovarian endometriotic tissues, and 12 leuprolide acetate-treated endometriotic tissues. We compared the gene expression profiles of the three groups using Affymetrix GeneChip Human genome arrays and bioinformatic analysis, including molecular concept analysis.
Leuprolide acetate-treated endometriotic tissue showed downregulated genes associated with the biological functions of steroid hormone regulation, cell proliferation, inflammation, and intracellular signaling. These genes included PTGDS, GRP, APLP2, PLTP, and FGFRL1. In contrast, genes upregulated by leuprolide acetate treatment were associated with cell growth inhibition and apoptosis. These genes included CARD11 and USP18.
These preliminary results based on GeneChip analysis suggest that leuprolide acetate treatment induces a modulation of gene expression that allows for cooperative alterations in disease state. This study gives new insight into the effects of leuprolide acetate treatment. Further investigations with quantitative reverse transcription-polymerase chain reaction and immunohistochemistry are needed to validate this study and to explore new therapeutic targets and biomarkers of endometriosis.
Semin Reprod Med. 2015 Sep;33(5):333-40.
The Role of Stem Cells in the Etiology and Pathophysiology of Endometriosis.
Human endometrium is a dynamic organ that normally undergoes repetitive cyclic regeneration. To enable this rapid regeneration, it is not surprising that the endometrium contains a reservoir of progenitor stem cells. However, this pool of cells that allows the growth of the endometrium also allows for unrestrained growth that can reach beyond the endometrium. In this review, we will address the role of stem cells in endometriosis. Recent characterization of stem cell populations within human endometrium has opened the possibility of understanding their physiologic as well as their pathologic roles. While stem cells are critical to the cyclic regeneration of a healthy endometrium, we have shown that both endometrium-derived and bone marrow-derived stem cells can migrate to ectopic sites and contribute to the development of endometriosis. Furthermore, endometriosisinterferes with the normal stem cell trafficking to the uterus that is necessary for endometrial growth and repair. Altered stem cell mobility and engraftment characterize this disease.
Obstet Gynecol. 2015 Dec;126(6):1215-8.
Postmenopausal Invasive Endometriosis Requiring Supralevator Pelvic Exenteration.
Endometriosis is rare in postmenopausal women. We report a case of invasive pelvic endometriosis in a postmenopausal woman requiring a supralevator pelvic exenteration for palliation of symptoms and for tissue diagnosis.
A 65-year-old woman with a history of total abdominal hysterectomy and bilateral salpingo-oophorectomy for endometriosis at age 43 years presented with acute vaginal bleeding, hematuria, and a recently diagnosed pelvic mass. Biopsies revealed endometriosis, and she underwent supralevator pelvic exenteration with vaginectomy, end colostomy, ileal conduit, and coagulation of endometriotic implants. Pathologic examination showed invasive endometriosis and no evidence of malignancy.
Endometriosis should remain on the differential diagnosis for pelvic mass in a postmenopausal woman, although suspicion for malignancy should remain high.
Ginekol Pol. 2015 Jul;86(7):547-50.
Endometriosis and carcinosarcoma–a hypothetical correlation or a proven pathogenetic pathway? Colon carcinosarcoma with origin in endometriotic foci–a case report.
We present the first case of a patient with a synchronic occurrence of three neoplasms: non-small cell lung cancer serous cancer of the ovary and carcinosarcoma of the colon. Moreover, the possible origin of the carcinosarcoma is an endometriotic focus, which is an extremely rare occurrence, especially in women with no history of endometriotic treatment. Immunohistochemical staining of the carcinosarcoma was positive for CD10, estrogen receptors and desmin–typical markers for endometriotic foci. The growth of endometriosis depends on estrogen, which is produced at reduced levels after menopause. However, in some cases endometriosis could be diagnosed de novo in postmenopausal women. On the basis of the reported patient we discuss possible correlations between endometriosis and carcinosarcoma, as well as treatment methods of carcinosarcoma.
Cancer Causes Control. 2015 Dec;26(12):1729-36.
PTEN expression in benign human endometrial tissue and cancer in relation to endometrial cancer risk factors.
Clonal loss of PTEN expression occurs frequently in endometrial carcinoma and endometrial hyperplasia. Limited data from immunohistochemical studies suggest that PTEN-null appearing endometrial glands are detectable in women without pathologic abnormalities, but the relationship of PTEN expression to endometrial cancer risk factors has not been extensively explored. We evaluated relationships between endometrial cancer risk factors and loss of PTEN expression in a set of benign endometrial samples prospectively collected from women undergoing hysterectomy and in endometrial cancer tissues from a population-based case-control study.
We used a validated PTEN immunohistochemical assay to assess expression in epidemiological studies designed to assess benign endometrium [Benign Reproductive Tissue Evaluation Study (n = 73); Einstein Endometrium Study (n = 19)], and endometrial cancer [Polish Endometrial Cancer Study (n = 148)] tissues. Associations between endometrial cancer risk factors (collected via study-specific risk factor questionnaires) and PTEN expression in endometrial tissues were determined using Fisher’s exact tests.
PTEN loss was detected in 19% of benign endometrial tissues versus 55% in endometrial cancers. NSAID use was statistically significantly associated with PTEN loss in the benign endometrium (p = 0.02).
Our data demonstrate that PTEN loss is detectable in endometrial tissues that are benign and malignant, with substantially more frequent loss in endometrial cancer compared with benign endometrium. However, alterations in expression were unrelated to most risk factors in this analysis, except for the association with NSAID use, which may represent a chance finding or reverse causality among patients with endometriosiswho may have PTEN pathway abnormalities in eutopic endometrium. Further evaluation of factors associated with PTEN loss and long-term follow-up of women with PTEN-null endometrial glands may be useful in understanding early events in endometrial carcinogenesis.
Reprod Biol Endocrinol. 2015 Sep 17;13:103.
Risk of endometrial polyps in women with endometriosis: a meta-analysis.
Endometrial polyps (EP) and endometriosis are both estrogen-dependent overgrowths of the endometrium. Several studies have shown a higher frequency of EP in endometriosis patients when compared with women without endometriosis. Therefore, we performed a meta-analysis to investigate the risk of EP in women with endometriosis.
This meta-analysis searched for articles published between 1964 and 2014 in PubMed, Embase, and Cochrane Library, as well as in Chinese databases, including CNKI, VIP and Wanfang, regarding the association between endometriosis and EP. Nine cohort studies and one case-control study including 2896 women were included in this meta-analysis. The EP risk was evaluated using relative risk (RR) with a 95% confidence interval (CI). Heterogeneity, small study effect and publication bias were assessed using Higgins I(2), sensitivity analysis and funnel plots, respectively.
The risk of EP increased in women with endometriosis compared with those without endometriosis (the pooled RR, 2.81; 95% CI, 2.48-3.18). No significant heterogeneity, small study effect or publication bias was found. The risk of EP slightly increased in women with endometriosis at stages 2-4 compared with those at stage 1 (Pooled effect size: stage 2 versus stage 1, RR, 1.22, 95% CI, 1.04 – 1.42; stage 3 versus stage 1, RR, 1.23, 95% CI, 1.06-1.42; stage 4 versus stage 1, RR, 1.29, 95% CI, 1.11-1.51; stages 2-4 versus stage 1, RR, 1.24, 95% CI, 1.10-1.40); however, no significantly different risk of EP in women with endometriosis existed between the other stages.
The results suggest that it is important to identify whether patients with endometriosis also have EP and then remove any coexisting EP via hysteroscopy, especially for infertile patients. This process will be clinically helpful to treat endometriosis-related infertility in patients with endometriosis, especially for those with endometriosis that is more serious than stage 1.
PLoS Genet. 2015 Sep 17;11(9):e1005537.
ARID1A Is Essential for Endometrial Function during Early Pregnancy.
AT-rich interactive domain 1A gene (ARID1A) loss is a frequent event in endometriosis-associated ovarian carcinomas. Endometriosis is a disease in which tissue that normally grows inside the uterus grows outside the uterus, and 50% of women with endometriosis are infertile. ARID1A protein levels were significantly lower in the eutopic endometrium of women with endometriosis compared to women without endometriosis. However, an understanding of the physiological effects of ARID1A loss remains quite poor, and the function of Arid1a in the female reproductive tract has remained elusive. In order to understand the role of Arid1a in the uterus, we have generated mice with conditional ablation of Arid1a in the PGR positive cells (Pgrcre/+Arid1af/f; Arid1ad/d). Ovarian function and uterine development of Arid1ad/d mice were normal. However, Arid1ad/d mice were sterile due to defective embryo implantation and decidualization. The epithelial proliferation was significantly increased in Arid1ad/d mice compared to control mice. Enhanced epithelial estrogen activity and reduced epithelial PGR expression, which impedes maturation of the receptive uterus, was observed in Arid1ad/d mice at the peri-implantation period. The microarray analysis revealed that ARID1A represses the genes related to cell cycle and DNA replication. We showed that ARID1A positively regulates Klf15 expression with PGR to inhibit epithelial proliferation at peri-implantation. Our results suggest that Arid1a has a critical role in modulating epithelial proliferation which is a critical requisite for fertility. This finding provides a new signaling pathway for steroid hormone regulation in female reproductive biology and furthers our understanding of the molecular mechanisms that underlie dysregulation of hormonal signaling in human reproductive disorders such as endometriosis.
Int J Clin Exp Med. 2015 Jul 15;8(7):11307-11.
Chinese medicinal plants for advanced endometriosis after conservative surgery: a prospective, multi-center and controlled trial.
The trial was to explore the effects of Chinese medicinal plants (CMP) treatment on the advanced endometriosis(stage III-IV) after conservative surgery. A prospective, multi-center and controlled trial was conducted from June 2012 to September 2013. Sixty-five post-operative women with advanced endometriosis (stage III-IV) after conservative surgery were included in the trial. They had undergone laparoscopic surgical excision of the endometriosis lesions and the diagnosis of endometriosis was confirmed by pathological examination. The patients received either CMP treatment or goserelin acetate sustained-release depot treatment (as comparison) according to the willingness of the patients. In the post-treatment follow-up visit at 6 and 12 months, the patients were respectively undergone ultrasonic and gynecological examinations. The serum levels of cancer antigen 125 (CA-125) and interleukin 18 (IL-18) were also detected in the post-treatment follow-up visit at 12 months. We found that in the post-treatment follow-up visit at 6 months, the recurrence rate of CMP group and comparison group was 1/31 (3.23%) and 1/34 (2.94%), respectively. In the post-treatment follow-up visit at 12 months, the recurrence rate of CMP group and comparison group was 5/31 (16.13%) and 6/34 (17.65%), respectively. There were no significant differences between the two groups (P>0.05). The serum levels of CA-125 and IL-18 significantly decreased in both of the two groups (P<0.05) and no marked differences existed between them on the serum levels of IL-18 (P>0.05). The serum CA-125 levels of CMP group were significantly lower than those of the comparison group (P<0.05). No adverse effect was reported in both of the two groups during the research and the follow-up period. It concluded that CMP showed promise in preventing the recurrence of stage III-IV endometriosis after conservative surgery, although the conclusion is somewhat limited due to the small size of the trial.
Gastroenterol Rep (Oxf). 2017 Nov;5(4):309-312.
The case of the missing appendix: a case report of appendiceal intussusception at the site of colonic mullerianosis.
Right lower quadrant pain is a symptom with an exceptionally broad differential diagnosis. Intussusception of the appendix is a very uncommon condition with many manifestations. Additionally, the pathologic finding of ectopic presence of a mixture of at least two mullerian-derived tissue components is rare. This report presents the case of a 49-year-old woman who presented twice with acute right lower abdominal pain. Diagnosis of appendiceal inversion was made surgically. Pathologic examination of the specimen identified extensive endometriosis, endosalpingiosis and endocervicosis of the colon wall. Appendiceal intussusception and colonic mullerianosis, present together, are discussed, and recommendations for the diagnosis and treatment of appendiceal intussusception are discussed.
Hum Reprod. 2015 Oct;30(10):2252-3.
Safety in reproductive medicine: breadth, depth and discovery.
In this issue of Human Reproduction, a debate article presents a charge to balance effectiveness and safety in Reproductive Medicine. This debate contribution applauds the dialogue opened and constructive opinions that are presented. However, several additional issues are suggested for consideration. Safety must be more broadly considered beyond the achievement of a healthy singleton pregnancy, with reproductive medicine a unique field that has the potential to impact the health and wellbeing of multiple people at one time. Many fields have grappled with the need to balance effective treatment with unintended harms, and reproductive medicine should capitalize upon that body of literature. Finally, to maximize both efficacy and safety in reproductive medicine, there is no replacement for the conduct of well powered, rigorously designed, highly generalizable, multidisciplinary studies.
Reprod Biomed Online. 2015 Nov;31(5):647-54.
Is endometrial receptivity transcriptomics affected in women with endometriosis? A pilot study.
Endometrial receptivity is still questioned today in women with endometriosis. The aim of this study was to assess the endometrial receptivity gene signature in patients with different stages of endometriosis by investigating transcriptomic modifications of their endometrium using the endometrial receptivity array (ERA) test. A prospective, interventional multicentre pilot trial was designed and implemented in two university-affiliated infertility units from Belgium and Spain. Gene expression microarray was used to diagnose the receptivity status by quantifying the expression of 238 specific genes directly related to human endometrial receptivity. Unsupervised hierarchical clustering showed no clustering of samples based on endometriosis stages. Two subgroups of samples clustered together corresponding on the day of the cycle in which the biopsy was taken (day 18 versus days 19-20). None of the 238 genes present in the ERA array were significantly over- or under- expressed in any of different stages of the disease compared with controls. Minimal differences were found when looking at the functional profile, suggesting that the possible effect from a clinical point of view may be meaningless. Endometrial receptivity gene signature during the implantation window does not vary significantly among patients with endometriosis even considering different stages compared with healthy women.
J Med Assoc Thai. 2015 Apr;98 Suppl 3:S96-100.
Recurrence of Endometrioma Following Conservative Ovarian Endometrioma Cystectomy: Laparoscopy versus Laparotomy.
To investigate the recurrence rate and disease-free interval between laparoscopy versus laparotomy for the conservative surgery of endometrioma.
MATERIAL AND METHOD:
A retrospective cohort study was conducted. The medical records of reproductive women who underwent conservative ovarian cystectomy surgery (laparoscopy or laparotomy) for endometrioma at Thammasat University Hospital were retrieved. The patients were followed through 24 months to evaluate the recurrence of endometrioma. Propensity scoring was used to adjust for confounding by indication and confounding by contraindication. Model for competing time to event was used in analysis.
One hundred and twenty-eight and 114 patients were enrolled in laparoscopy and laparotomy groups, respectively. Mean age and body weight in laparotomy group were statistically higher than those in the other group were. Mean height and body mass index were, however not statistically different in either groups. In addition, the stage of disease and bilaterality in both groups were comparable. Diameter ofendometrioma in laparotomy group was significantly larger than that in laparoscopy group (7.0 ± 2.5 vs. 6.2 ± 1.8 cm, respectively; p = 0.004). After adjusting for propensity scoring, the endometrioma recurrence rate was significantly higher in laparoscopy group as compared to laparotomy group (27.3% vs. 14.9%, respectively; p = 0.02). However, the cumulative rate of pregnancy after surgery was not statistically different (4.7% vs. 4.4%, respectively; p = 1.0).
The present study has demonstrated that the surgical technique has a strong impact on the recurrence or disease-free interval. Laparoscopy might not eradicate the disease pathology as effectively as open laparotomy in some situations, such as in cases with complexity of disease.
Am J Reprod Immunol. 2015 Dec;74(6):480-6.
Simultaneous Detection and Evaluation of Four Subsets of CD4+ T Lymphocyte in Lesions and Peripheral Blood in Endometriosis.
The proportion of CD4+ T lymphocytes, Th1, Th2, Th17, and regulatory T cells in endometriosislesions and peripheral blood are not known.
METHOD OF STUDY:
Lymphocytes were isolated from endometriosis lesions (n = 10) and endometrium (n = 10). Lymphocytes in peripheral blood were isolated from patients with and without endometriosis (n = 10, 10). The CD4+ T-lymphocyte profile was analyzed by flow cytometry.
The proportion of Th1 lymphocytes was significantly lower in endometriosis tissue (59.64 ± 9.2%) in comparison with endometrial tissue (79.07 ± 8.97%), whereas the Th17 lymphocyte fraction was significantly higher in endometriosis tissue (6.66 ± 2.53%) in comparison with endometrial tissue (2.27 ± 1.51%). Analysis of peripheral blood indicated that the Th1 proportion was significantly higher in women with endometriosis (10.25 ± 2.82%) in comparison with controls (6.96 ± 4.13%).
The CD4+ T-lymphocyte profile in lesions and peripheral blood is altered in women with endometriosis. These findings may help better understanding of T-lymphocyte involvement in the pathophysiology of endometriosis.
Expert Opin Ther Targets. 2015;19(11):1465-83.
MAP kinases and the inflammatory signaling cascade as targets for the treatment of endometriosis?
The pathogenesis of endometriosis, a common benign disease, remains ill-defined, although it is clear that chronic inflammation plays a crucial role through mitogen-activated protein kinase (MAPK) signaling pathways. All current medical therapies for endometriosis are antigonadotropic, and therefore have a contraceptive effect. A concerted research effort is hence warranted with the aim of delivering novel therapeutics that reduces disease symptoms without blocking ovulation.
The authors review the complex pathogenic mechanisms of chronic inflammation in endometriosis and their relationships with MAPK pathways. The authors conducted a literature search of descriptive and functional targeted validation of MAPK in the pathogenesis of endometriosis. The effects of MAPK inhibitors, which constitute potential agents for future treatments, are also described.
Preliminary studies have highlighted a crucial role for MAPK in driving endometriosis-related inflammation. MAPK inhibitors exhibit potent activity in terms of controlling growth of endometriosis lesions both in vitro and in animal models. As MAPK inhibitors are known to have a multitude of undesirable side effects, their use in humans has to be approached with great care. Indeed, use of these drugs would probably be limited to short exposures prior to surgery in cases involving the most severe disease phenotypes.
Womens Health (Lond). 2015 Aug;11(5):597-601.
Problems with the diagnosis of endometriosis.
Endometriosis is classically defined as the presence of endometrial glands and stroma in outside the uterine cavity. As the definition suggests that confirming the ectopic endometrial stroma and glands in ectopic location histopathologically should be necessary for the diagnosis of endometriosis. Therefore, this situation leads to the need for surgery like laparoscopy for diagnosis. However, this surgical diagnostic approach will not be reliable for all patients with suspected endometriosis. It seems to be an important problem that there is still no reliable clinically diagnostic method or pathognomonic clinical finding, which may allow accurate diagnosis of endometriosis without the need for surgery or histopathologic evaluation. While these clinical features are not pathognomonic for the endometriosis, they should be used as markers for creating high-risk population for endometriosis. Clinical features and the available diagnostic methods, their advantages and limitations for the endometriosis will be discussed in this article. The different options for clinical assessment, laboratory tests and imaging techniques will be summarized and the advantages and disadvantages of these methods will be evaluated. We will also discuss the gold standard definitive diagnostic options with their problematic aspects.
Urologiia. 2015 May-Jun;(3):64-70.
LAPAROSCOPIC URETERO-CYSTO-ANASTOMOSIS IN TREATMENT OF PELVIC URETERAL STRICTURES.
The aim of the paper was to evaluate the efficacy of laparoscopic uretero-cysto-anastomosis (UCA) in patients with lower ureteral strictures of various etiologies. Over the period from 2010 to 2014, 12 patients (8 females and 4 males) aged 19 to 64 years (mean age 35.6 ± 8.5 years) underwent laparoscopic UCA. In all females, iatrogenic ureteral injury occurred during gynecological surgery. Types of gynecological surgeries were an open or laparoscopic hysterectomy (5), excision of endometriosis nodules (2), and resection of the ovaries (1). In men indications for surgery were ureteral strictures after ureteroscopy (3) and neuromuscular dysplasia (1). The operation was performed in lithotomy position by transperitoneal access using 4 trocars. In all cases, extravesical ureteral reimplantation into the bladder was performed. The stent was removed after week four, excretory urography and cystography were conducted. The operation was thought to be successful in all patients. There were no cases of conversion and no need in blood transfusion. In 4 patients we performed psoas-hitch + UCA, in 2–Boari operation, in 5–direct UCA. The patient with neuromuscular dysplasia longitudinal resection of the lower third of the ureter was carried out. Then it was sutured on the stent by interrupted sutures, and extravesical implantation into the bladder was performed. Mean duration of surgery was 145 minutes (110 to 230 minutes), mean blood loss–180 ml (from 120 to 245 ml). Passive asymptomatic vesicoureteral reflux was observed in 3 patients. Laparoscopic UCA is a highly effective intervention with the functional results similar to those of open surgery.
Curr Mol Med. 2015;15(8):697-713.
New Horizons in the Etiopathogenesis and Non-Invasive Diagnosis of Endometriosis.
Endometriosis is one of the most common gynecological inflammatory diseases, occurring in adolescents and women in the reproductive age group and leading to infertility. The precise etiopathogenesis of endometriosis is unknown, but several theories concerning the phenomena involved in its development have been proposed. Beside classic retrograde menstruation, these include lymphatic and vascular metastases, iatrogenic direct implantation, coelomic metaplasia, embryonic remnants and mesenchymal cell differentiation or induction; the persistence of a form of embryonic endometriosis may also be involved, as well as the theory of the possible role of endometrial stem/progenitor cells. This paper deals with other risk factors which may be potentially involved in the etiopathogenesis of endometriosis, including the immune, inflammatory, endocrine, genetic, anatomical and environmental factors. At present, endometriosis can only be diagnosed with surgery, where laparoscopy is considered a gold standard. Therefore, there is an urgent need for a test allowing to detect non-invasive molecular biomarkers to identify the symptoms of endometriosis early on in disease development. A thorough understanding of the etiopathogenesis of endometriosis is essential toward the development of novel diagnostic assays and effective treatments of the disease.
J Clin Endocrinol Metab. 2015 Nov;100(11):E1404-14.
C-Jun NH2-Terminal Kinase and p38 Inhibition Suppresses Prostaglandin E2-Stimulated Aromatase and Estrogen Receptor Levels in Human Endometriosis.
Endometriosis is an estrogen-dependent disease. P38 and C-jun NH2-terminal kinase (JNK) inhibitors may have a therapeutic effect on endometriosis through regulation of prostaglandin E2 (PGE2)-induced estrogen metabolism.
The objective of this study was to determine whether the activated MAPKs signaling pathway observed in human ectopic endometrial stromal cells (ESCs) from ovarian endometriomas influences levels of aromatase and estrogen receptor β (ERβ) protein regulated by PGE2. In turn, the effects of inhibiting MAPKs in the presence of PGE2 on estrogen production were investigated in vitro and in vivo.
Expression of aromatase and ERβ regulated by PGE2 were much higher in ESCs than eutopic ESCs from the same person. Activation of p38, JNK, ERK 1/2 and ERK 5 MAPKs by PGE2 were observed in ESCs, where PGE2-stimulated aromatase and ERβ expression mainly through p38 and JNK pathway. P38 and JNK inhibition or small interfering RNA knockdown blocked PGE2-induced aromatase and ERβ expression. PGE2 enhanced binding of downstream p38 and JNK transcription factors activating transcription factor-2 and c-Jun to aromatase and ERB promoter regions in ESCs. Moreover, treatment of endometriosis xenografts with inhibitors of p38 and JNK abrogated PGE2-amplified estradiol synthesis and xenograft growth.
PGE2 activates p38 and JNK signaling pathways, further stimulating c-Jun and activating transcription factor-2 binding to aromatase and ERB promoter regions with elevated estradiol production. Inhibition of JNK and P38 may be a potential method of treating human endometriosis.