J Obstet Gynaecol Can. 2015 Dec;37(12):1098-103.

Vaginally Administered Danazol: An Overlooked Option in the Treatment of Rectovaginal Endometriosis?

Godin R¹, Marcoux V¹

Abstract

Danazol has been used in the treatment of endometriosis and heavy menstrual bleeding for more than 40 years. This medication has both central antigonadotropic actions and direct atrophic effects on endometriotic tissue. Although it demonstrates a high-efficacy profile, the associated side effects have resulted in limited usage. Vaginal administration of the drug may prove favourable specifically in rectovaginal endometriosis. This targeted mode of delivery is associated with a significant reduction in both pain symptoms and nodule size. The relative persistence of these therapeutic benefits is likely related to the direct tissue effects after absorption through the vaginal mucosa. Vaginal administration would also limit systemic propagation of danazol and thus should minimize androgenic side effects. Use of vaginal danazol also improves heavy menstrual bleeding and may even restore fertility in some patients. In this review we provide a critical analysis of the existing literature on the use of vaginal danazol.

 

 

Hum Reprod. 2016 Feb;31(2):324-31.

Timing of human preimplantation embryonic development is confounded by embryo origin.

Kirkegaard K¹, Sundvall L², Erlandsen M³, Hindkjær JJ⁴, Knudsen UB², Ingerslev HJ².

Abstract

STUDY QUESTION:

To what extent do patient- and treatment-related factors explain the variation in morphokinetic parameters proposed as embryo viability markers?

SUMMARY ANSWER:

Up to 31% of the observed variation in timing of embryo development can be explained by embryo origin, but no single factor elicits a systematic influence.

WHAT IS KNOWN ALREADY:

Several studies report that culture conditions, patient characteristics and treatment influence timing of embryo development, which have promoted the perception that each clinic must develop individual models. Most of the studies have, however, treated embryos from one patient as independent observations, and only very few studies that evaluate the influence from patient- and treatment-related factors on timing of development or time-lapse parameters as predictors of viability have controlled for confounding, which implies a high risk of overestimating the statistical significance of potential correlations.

STUDY DESIGN, SIZE, DURATION:

Infertile patients were prospectively recruited to a cohort study at a hospital fertility clinic from February 2011 to May 2013. Patients aged <38 years without endometriosis were eligible if ≥8 oocytes were retrieved. Patients were included only once. All embryos were monitored for 6 days in a time-lapse incubator.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

A total of 1507 embryos from 243 patients were included. The influence of fertilization method, BMI, maternal age, FSH dose and number of previous cycles on timing of t2-t5, duration of the 2- and 3-cell stage, and development of a blastocoel (tEB) and full blastocoel (tFB) was tested in multivariate, multilevel linear regression analysis. Predictive parameters for live birth were tested in a logistic regression analysis for 223 single transferred blastocysts, where time-lapse parameters were investigated along with patient and embryo characteristics.

MAIN RESULTS AND THE ROLE OF CHANCE:

Moderate intra-class correlation coefficients (0.16-0.31) were observed for all parameters except duration of the 3-cell stage, which demonstrates that embryos from one patient elicit clustering at a patient level. No single patient- and treatment-related factor was found to systematically influence the timing from cleavage to blastocyst stage, which indicates that no individual patient-related factor can be identified that separately explains the clustering throughout the entire developmental stages. The blastocyst parameters were more affected by patient-related factors than cleavage stage parameters, as tEB occurred significantly later with older age (0.29 h/year (95% confidence interval: CI 0.03; 0.56)), while both tEB and tFB occurred significantly later with increasing dose of FSH (tEB: 0.12 h/100 IU FSH (95% CI 0.01;0.24); tFB 0.14 h/100 IU FSH (95% CI 0.03;0.27)) and with more previous attempts (tEB: 1.2 h/attempt (95% CI 0.01;2.5); tFB 1.4 h/attempt (0.10;2.7)). Fertilization method affected timing of the first division, with ICSI embryos cleaving significantly faster than IVF embryos (-3.6% (95% CI -6.4; -0.77)), whereas no difference was found in the subsequent divisions. The univariable regression analysis identified female age, cumulative FSH dose, degree of blastocyst expansion, score of the inner cell mass and timing of full blastocyst formation as predictors of live birth. The timing of full blastocyst formation (tFB) did not remain significant when adjusting for age, number of previous cycles and cumulative FSH dose, which were the parameters shown to influence tFB in the mixed regression model.

LIMITATIONS, REASONS FOR CAUTION:

Only good prognosis patients were enrolled, so these results may not be generalized to all infertile women. Not all patient-related factors were investigated.

WIDER IMPLICATIONS OF THE FINDINGS:

Our findings underline the importance of treating embryos as dependent observations and suggest a high risk of patient-based confounding in retrospective studies. The impact of confounders and the embryo origin needs to be addressed in order to apply appropriate statistical models in observational studies. Furthermore, this observation emphasizes the need for RCTs for evaluating use of time-lapse parameters for embryo selection.

STUDY FUNDING/COMPETING INTERESTS:

Funding for the cohort study was provided by the Lippert Foundation, the Toyota Foundation, the Aase og Einar Danielsen foundation and NordicInfu Care research grant. Research at the Fertility Clinic, Aarhus University Hospital is supported by an unrestricted grant from MSD and Ferring. K.K. is funded by a grant from the Danish Council for Independent Research Medical Sciences. The authors declare no competing interest.

 

 

Duodecim. 2015;131(19):1777-84.

Is endometriosis a premalignant condition to ovarian carcinoma?.

Lassus H, Pasanen A, Bützow R.

Abstract

Endometriosis is an estrogen dependent disease, which causes chronic inflammation and may lead to pelvic pain and infertility. Women with endometriosis have a 1.5 to 2-fold risk for ovarian epithelial cancer. The risk is increased especially for the endometrioid and clear cell histological types of ovarian carcinoma. Endometriosisand its atypical form are often found in the proximity of these cancers, and molecular changes similar to those in cancer have been detected in nearby endometriosis. The risk of cancer is associated with ovarian endometriosis, i.e. endometriomas and is increased by prolonged disease and/or older age at diagnosis and infertility. The progression of endometriosis to cancer is usually slow, possibly enabling diagnosis at an early stage of the disease.

 

 

Exp Clin Transplant. 2015 Nov;13 Suppl 3:144-5.

Catamenial Pneumothorax.

Kolos A¹, Dzhieshev Z, Dikolaev V, Amangaliev A

Abstract

The Spanish congress of the European association of pulmonologists and thoracic surgeons, held in 2009, confirmed the international classification of spontaneous pneumothorax in which catamenial (menstrual) pneumothorax was identified. Different from usual pneumothorax, its reason is not because of bleb disease in the lungs, but rather, caused by menstrual cycle in women. The cause was partly studied and explained by several theories. By the first of them, congenital defects (holes, fenestrations) in the diaphragm allow air to get into pleural space because of increased permeability of the fallopian tubes during menstruation. The second hypothesis, the same mechanism is considered, but it has been supposed that a hole in the diaphragm can be caused by endometriosis. The third theory, endometriosis of a pulmonary parenchyma can create leak of air during menstruation. The fourth theory, significance is attached to production of F2 prostaglandin, which is a powerful broncho- and vasoconstriction agent, causing ruptures of alveoli in women in the period of the woman’s menstrual cycle. Two groups of patients were identified: with a defect in the diaphragm and without. Existence of such defects is described in 50% of cases. Having a wide clinical experience in the field of thoracic surgery, we, for the first time in practice, diagnosed catamenial pneumothorax in patients with the recurrence course of the disease.

 

 

Int J Fertil Steril. 2015 Oct-Dec;9(3):329-37.

Evaluation of Tumor Necrosis Factor Alpha Polymorphism Frequencies in Endometriosis.

Abutorabi R¹, Baradaran A², Sadat Mostafavi F³, Zarrin Y⁴, Mardanian F⁵.

Abstract

BACKGROUND:

The pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-α), is a pathogenic element for a number of disorders. Previous studies have reported that the -1031 T/C and -238 G/A polymorphisms in the promoter region of the TNF-α gene are important factors in reproductive-related disorders. One of the most common gynecological diseases of women during the reproductive years is endometriosis. This study aims to assess an association between the -1031 T/C, -238 G/A and -308 G/A polymorphisms of the TNF-α gene promoter region to endometriosis.

MATERIALS AND METHODS:

In this case-control study, we enrolled 65 endometriosis patients and 65 matched healthy control women by simple sampling. Polymerase chain reaction (PCR) analysis was used to analyze -1031 T/C, -238 G/A and -308 G/A polymorphisms in the TNF-α gene promoter region. Statistical analysis was performed using the chi-square test. P values less than 0.05 were considered statistically significant.

RESULTS:

We found a strong association between the -1031 T/C polymorphism in the promoter region of the TNF-α gene with endometriosis (P=0.001). There were no significant associations between the -238 G/A (P=0.243) and -308 G/A (P=1) polymorphisms with endometriosis and again endometriosis stages have no association with these polymorphisms.

CONCLUSION:

The -1031 T/C polymorphism and CC genotype can be used as a relevant marker to identify women at risk of developing endometriosis.

 

 

Expert Rev Clin Pharmacol. 2016;9(2):317-27.

Innovations in classical hormonal targets for endometriosis.

Pluchino N¹, Freschi L², Wenger JM¹, Streuli I¹.

Abstract

Endometriosis is a chronic disease of unknown etiology that affects approximately 10% of women in reproductive age. Several evidences show that endometriosis lesions are associated to hormonal imbalance, including estrogen synthesis, metabolism and responsiveness and progesterone resistance. These hormonal alterations influence the ability of endometrial cells to proliferate, migrate and to infiltrate the mesothelium, causing inflammation, pain and infertility. Hormonal imbalance in endometriosis represents also a target for treatment. We provide an overview on therapeutic strategies based on innovations of classical hormonal mechanisms involved in the development of endometriosis lesions. The development phase of new molecules targeting these pathways is also discussed. Endometriosis is a chronic disease involving young women and additional biological targets of estrogen and progesterone pharmacological manipulation (brain, bone and cardiovascular tissue) need to be carefully considered in order to improve and overcome current limits of long-term medical management of endometriosis.

 

 

Scand J Work Environ Health. 2016 Jan;42(1):52-60.

Occupational risk factors for endometriosis in a cohort of flight attendants.

Johnson CY¹, Grajewski B, Lawson CC, Whelan EA, Bertke SJ, Tseng CY.

Abstract

OBJECTIVES:

This study aimed to (i) compare odds of endometriosis in a cohort of flight attendants against a comparison group of teachers and (ii) investigate occupational risk factors for endometriosis among flight attendants.

METHODS:

We included 1945 flight attendants and 236 teachers aged 18-45 years. Laparoscopically confirmed endometriosis was self-reported via telephone interview, and flight records were retrieved from airlines to obtain work schedules and assess exposures for flight attendants. We used proportional odds regression to estimate adjusted odds ratios (OR adj) and 95% confidence intervals (95% CI) for associations between exposures and endometriosis, adjusting for potential confounders.

RESULTS:

Flight attendants and teachers were equally likely to report endometriosis (OR adj1.0, 95% CI 0.5-2.2). Among flight attendants, there were no clear trends between estimated cosmic radiation, circadian disruption, or ergonomic exposures and endometriosis. Greater number of flight segments (non-stop flights between two cities) per year was associated with endometriosis (OR adj2.2, 1.1-4.2 for highest versus lowest quartile, P trend= 0.02) but block hours (taxi plus flight time) per year was not (OR adj1.2, 95% CI 0.6-2.2 for highest versus lowest quartile, P trend=0.38).

CONCLUSION:

Flight attendants were no more likely than teachers to report endometriosis. Odds of endometriosis increased with number of flight segments flown per year. This suggests that some aspect of work scheduling is associated with increased risk of endometriosis, or endometriosis symptoms might affect how flight attendants schedule their flights.

 

 

 

Obstet Gynecol. 2016 Jan;127(1):67-77.

Association Between Patient Characteristics and Treatment Procedure Among Patients With Uterine Leiomyomas.

Borah BJ¹, Laughlin-Tommaso SK, Myers ER, Yao X, Stewart EA.

Abstract

OBJECTIVE:

To analyze the association between patient characteristics and the probability of undergoing any uterine-sparing procedure (endometrial ablation, myomectomy, and uterine artery embolization) compared with hysterectomy as the first uterine leiomyoma (index) procedure and the probability of undergoing a specific uterine-sparing procedure.

METHODS:

We conducted a retrospective analysis using a commercial insurance claims database containing more than 13 million enrollees annually. Based on the index procedure performed 2004-2009, women were classified into one of the four procedure cohorts. Eligible women were aged 25-54 years on the index date, continuously insured through 1-year baseline and 1-year follow-up, and had a baseline uterine leiomyoma diagnosis. Logistic regression was used to assess the association between patient characteristics and leiomyoma procedure.

RESULTS:

The study sample comprised 96,852 patients (endometrial ablation=12,169; myomectomy=7,039; uterine artery embolization=3,835; and hysterectomy=73,809). Patient characteristics associated with undergoing any uterine-sparing procedure compared with hysterectomy included health maintenance organization health plan enrollment, Northeast region residence, the highest income and education quintiles based on zip code, an age-race interaction, and baseline diagnoses including menstrual disorders, pelvic pain, anemia, endometriosis, genital prolapse, and infertility. Among those who had a uterine-sparing procedure, characteristics associated with undergoing uterine artery embolization or endometrial ablation compared with myomectomy included increasing age, being from the Midwest relative to the Northeast, and certain baseline conditions including menstrual disorder, pelvic pain, endometriosis, and infertility.

CONCLUSION:

Both clinical and nonclinical factors were associated with the receipt of alternatives to hysterectomy for uterine leiomyomas in commercially insured women.

 

 

Reproduction. 2016 Mar;151(3):271-83.

The mare as a model for luteinized unruptured follicle syndrome: intrafollicular endocrine milieu.

Bashir ST, Gastal MO, Tazawa SP¹, Tarso SG, Hales DB¹, Cuervo-Arango J¹, Baerwald AR¹, Gastal EL.

Abstract

Luteinized unruptured follicle (LUF) syndrome is a recurrent anovulatory dysfunction that affects up to 23% of women with normal menstrual cycles and up to 73% with endometriosis. Mechanisms underlying the development of LUF syndrome in mares were studied to provide a potential model for human anovulation. The effect of extended increase in circulating LH achieved by administration of recombinant equine LH (reLH) or a short surge of LH and decrease in progesterone induced by prostaglandin F2α (PGF2α) on LUF formation (Experiment 1), identification of an optimal dose of COX-2 inhibitor (flunixin meglumine, FM; to block the effect of prostaglandins) for inducing LUFs (Experiment 2), and evaluation of intrafollicular endocrine milieu in LUFs (Experiment 3) were investigated. In Experiment 1, mares were treated with reLH from Day 7 to Day 15 (Day 0=ovulation), PGF2α on Day 7, or in combination. In Experiment 2, FM at doses of 2.0 or 3.0 mg/kg every 12 h and human chorionic gonadotropin (hCG) (1500 IU) were administered after a follicle ≥32 mm was detected. In Experiment 3, FM at a dose of 2.0 mg/kg every 12 h plus hCG was used to induce LUFs and investigate the intrafollicular endocrine milieu. No LUFs were induced by reLH or PGF2α treatment; however, LUFs were induced in 100% of mares using FM. Intrafollicular PGF2α metabolite, PGF2α, and PGE2 were lower and the ratio of PGE2:PGF2α was higher in the induced LUF group. Higher levels of intrafollicular E2 and total primary sex steroids were observed in the induced LUF group along with a tendency for higher levels of GH, cortisol, and T; however, LH, PRL, VEGF-A, and NO did not differ between groups. In conclusion, this study reveals part of the intrafollicular endocrine milieu and the association of prostaglandins in LUF formation, and indicates that the mare might be an appropriate model for studying the poorly understood LUF syndrome.

 

 

Mol Med Rep. 2016 Jan;13(1):1040-6.

Association between DNMT3L polymorphic variants and the risk of endometriosis-associated infertility.

Mostowska A¹, Szczepańska M², Wirstlein P², Skrzypczak J², Jagodziński PP¹.

Abstract

Endometriosis is considered to be an epigenetic disease. It has previously been reported that the DNA methyltransferase 3-like (DNMT3L) rs8129776 single nucleotide polymorphism (SNP) contributes to endometrioma. In the present study, high‑resolution melting curve analysis was used to investigate the risks associated with the DNMT3L c.910‑635A/G (rs8129776), c.832C/T (rs7354779), c.812C/T (rs113593938) and c.344+62C/T (rs2276248) SNPs on stage I‑II endometriosis‑associated infertility. Included in the present study were patients presenting with stage I‑II endometriosis‑associated infertility (n=154) and a control cohort of healthy patients with confirmed fertility (n=383). No significant association between the above‑listed DNMT3L SNPs and the development of endometriosis‑associated infertility was identified. The lowest P‑values generated from trend analysis were observed in the DNMT3L c.832C/T (rs7354779) SNP (Ptrend=0.114). Furthermore, haplotype analyses of the DNMT3L SNPs failed to reveal any risk association between the development of endometriosis‑associated infertility and the above‑listed polymorphisms, even when the SNPs were present in combinations. Finally, a meta‑analysis was performed to examine the association between the DNMT3L rs8129776 SNP and the development of endometrioma, from which no association between the two was identified. On the basis of these results, the present study has demonstrated that variations in the DNMT3L gene do not contribute to stage I-II endometriosis-associated infertility.

Inflamm Res. 2016 Mar;65(3):183-92.

Does dienogest influence the inflammatory response of endometriotic cells? A systematic review.

Grandi G^1,2, Mueller M^3,2, Bersinger NA^3,2, Cagnacci A¹, Volpe A¹, McKinnon B^4,5.

Abstract

OBJECTIVE AND DESIGN:

A systematic review of all literature was done to assess the ability of the progestin dienogest (DNG) to influence the inflammatory response of endometriotic cells.

MAIN OUTCOME MEASURES:

In vitro and in vivo studies report an influence of DNG on the inflammatory response in eutopic or ectopic endometrial tissue (animal or human).

RESULTS:

After strict inclusion criteria were satisfied, 15 studies were identified that reported a DNG influence on the inflammatory response in endometrial tissue. These studies identified a modulation of prostaglandin (PG) production and metabolism (PGE2, PGE2 synthase, cyclo-oxygenase-2 and microsomal PGE synthase-1), pro-inflammatory cytokine and chemokine production [interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, monocyte chemoattractant protein-1 and stromal cell-derived factor-1], growth factor biosynthesis (vascular endothelial growth factor and nerve growth factor) and signaling kinases, responsible for the control of inflammation. Evidence supports a progesterone receptor-mediated inhibition of the inflammatory response in PR-expressing epithelial cells. It also indicated that DNG inhibited the inflammatory response in stromal cells, however, whether this was via a PR-mediated mechanism is not clear.

CONCLUSIONS:

DNG has a significant effect on the inflammatory microenvironment of endometriotic lesions that may contribute to its clinical efficacy. A better understanding of the specific anti-inflammatory activity of DNG and whether this contributes to its clinical efficacy can help develop treatments that focus on the inhibition of inflammation while minimizing hormonal modulation.

 

 

Endocrinology. 2016 Feb;157(2):900-12.

Multiple Beneficial Roles of Repressor of Estrogen Receptor Activity (REA) in Suppressing the Progression of Endometriosis.

Zhao Y¹, Chen Y¹, Kuang Y¹, Bagchi MK¹, Taylor RN¹, Katzenellenbogen JA¹, Katzenellenbogen BS¹.

Abstract

Endometriosis is an estrogen-dependent, inflammation-driven gynecologic disorder in which endometrial tissue creates inflammatory lesions at extrauterine sites, leading to pelvic pain and impaired fertility. Although dysregulated estrogen receptor (ER) signaling has been implicated, understanding of this disease is incomplete and current therapies are of limited benefit. Using an immunocompetent syngeneic murine model, we used combinations of donor uterine tissue and/or recipient host mice with partial genetic deletion of the ER coregulator, repressor of ER activity (REA) (also known as prohibitin 2), to investigate roles of REA in the contributions of donor uterine tissue and host cell influences on endometriosis establishment and progression. Ectopic lesions derived from donor tissue with half the wild-type gene dosage of REA (REA(+/-)) grown in REA(+/-) hosts displayed enhanced proliferation, vascularization, and markedly increased neuron innervation and inflammatory responses, including elevated cytokine production, nuclear factor kappa B activation, cyclooxygenase-2 expression, and immune cell infiltration. Although lesion progression was greatest when REA was reduced in both donor tissue and host animals, other donor/host combinations indicated that distinct stimulatory inputs were derived from ectopic tissue (proliferative signals) and host cells (inflammatory signals). Importantly, depletion of REA in primary human endometriotic stromal cells led to elevated proliferation and expression of cell cycle regulators. Notably, REA was significantly lower in human endometriotic tissue versus normal human endometrium. Thus, REA modulates cross talk among multiple cell types in the uterine tissue and host background, serving as a brake on the estradiol-ER axis and restraining multiple aspects that contribute to the pathologic progression of endometriosis.

 

 

J Proteome Res. 2016 Feb 5;15(2):572-84.

Deep Quantitative Proteomics Reveals Extensive Metabolic Reprogramming and Cancer-Like Changes of Ectopic Endometriotic Stromal Cells.

Kasvandik S^1,2,3, Samuel K², Peters M^2,3, Eimre M⁴, Peet N⁴, Roost AM^2,3, Padrik L⁵, Paju K⁴, Peil L¹, Salumets A^2,3.

Abstract

Endometriosis is a prevalent health condition in women of reproductive age characterized by ectopic growth of endometrial-like tissue in the extrauterine environment. Thorough understanding of the molecular mechanisms underlying the disease is still incomplete. We dissected eutopic and ectopic endometrial primary stromal cell proteomes to a depth of nearly 6900 proteins using quantitative mass spectrometry with a spike-in SILAC standard. Acquired data revealed metabolic reprogramming of ectopic stromal cells with extensive upregulation of glycolysis and downregulation of oxidative respiration, a widespread metabolic phenotype known as the Warburg effect and previously described in many cancers. These changes in metabolism are additionally accompanied by attenuated aerobic respiration of ectopic endometrial stromal cells as measured by live-cell oximetry and by altered mRNA levels of respective enzyme complexes. Our results additionally highlight other molecular changes of ectopic endometriotic stromal cells indicating reduced apoptotic potential, increased cellular invasiveness and adhesiveness, and altered immune function. Altogether, these comprehensive proteomics data refine the current understanding of endometriosis pathogenesis and present new avenues for therapies.

 

 

Gynecol Endocrinol. 2016;32(4):323-8.

Effects of the hypoxia-inducible factor-1 inhibitor echinomycin on vascular endothelial growth factor production and apoptosis in human ectopic endometriotic stromal cells.

Tsuzuki T¹, Okada H¹, Shindoh H¹, Shimoi K¹, Nishigaki A¹, Kanzaki H¹.

Abstract

Recent evidence points to a possible role for hypoxia-inducible factor (HIF)-1 in the pathogenesis and development of endometriosis. The objectives of this study were to investigate the critical role of HIF-1 in endometriosis and the effect of the HIF-1 inhibitor echinomycin on human ectopic endometriotic stromal cells (eESCs). Ectopic endometriotic tissues were obtained from 20 patients, who received an operation for ovarian endometriomas. We examined vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) production, HIF-1 expression, cell proliferation and apoptosis of eESCs. Cobalt chloride (CoCl2) significantly induced expression of HIF-1α protein and VEGF production in a time-dependent manner in eESCs, but reduced SDF-1 production. VEGF production was significantly suppressed by treatment of 100 nM echinomycin without causing cell toxicity, but 0.1-10 nM echinomycin or 100 nM progestin had no significant effect. SDF-1 production was not affected by echinomycin treatment at any dose. Echinomycin inhibited cell proliferation and induced apoptotic cell death of the eESCs, and significantly inhibited expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL. Echinomycin inhibits VEGF production and induces apoptosis of eESCs by suppression of Bcl-2 and Bcl-xL. These findings suggest the unique therapeutic potential for echinomycin as an inhibitor of HIF-1 activation for endometriosis treatment.

 

 

 

 

 

Fertil Steril. 2016 Mar;105(3):815-824.

c-Jun NH2-terminal kinase inhibitor bentamapimod reduces induced endometriosis in baboons: an assessor-blind placebo-controlled randomized study.

Hussein M¹, Chai DC², Kyama CM², Mwenda JM², Palmer SS³, Gotteland JP⁴, D’Hooghe TM⁵.

Abstract

OBJECTIVE:

To test the hypothesis that the c-Jun NH2-terminal kinase (JNK) inhibitor (JNKI) bentamapimod (AS602801/PGL5001) can reduce induced endometriosis in baboons.

DESIGN:

Prospective randomized placebo-controlled study.

SETTING:

Nonhuman primate research center.

ANIMAL(S):

Twenty baboons each underwent four laparoscopies. Initial screening laparoscopy (L1) was followed after one rest cycle by an endometriosis-induction laparoscopy (L2). Fifty days after L2, the baboons were randomized just before staging laparoscopy (L3). Treatment lasted for 60 days, followed by a post-treatment staging laparoscopy (L4).

INTERVENTION(S):

Randomization before a 60-day treatment in four groups: daily placebo (n = 5), daily oral administration of 20 mg/kg JNKI (n = 5), concomitant daily oral administration of 20 mg/kg JNKI and 10 mg medroxyprogesterone acetate (MPA; n = 5), or subcutaneous administration of 3 mg cetrorelix every 3 days (n = 5).

MAIN OUTCOME MEASURE(S):

Type, surface area and volume of endometriotic lesions, and revised American Society for Reproductive Medicine score and stage were recorded during L3 and L4. Menstrual cycle length and serum hormonal concentration were recorded before and after treatment.

RESULT(S):

Compared with placebo, treatment with JNKI, JNKI + PMA, or cetrorelix resulted in lower total surface area and volume of endometriotic lesions. Remodeling of red active lesions into white lesions was observed more frequently in baboons treated with JNKI + MPA than in baboons treated with JNKI only. Menstrual cycle length and serum hormonal concentration were similar between placebo and JNKI groups.

CONCLUSION(S):

JNKI alone was as effective as JNKI + MPA or cetrorelix in reducing induced endometriosis in baboons, but without severe side effects or effect on cycle length or serum reproductive hormones.

Eur J Obstet Gynecol Reprod Biol. 2016 Jan;196:26-30.

Overexpression of a steroid receptor-binding protein bearing the regulator of the G-protein signaling domain suppresses migration and invasion of human endometrial stromal cells stimulated by 17β-estradiol.

Xiong YF¹, Xiong ZF².

Abstract

OBJECTIVE:

Endometriosis is an estrogen-dependent disease, a steroid receptor-binding protein bearing the regulator of the G-protein signaling domain (SRB-RGS) can suppress the estrogen receptors-mediated transcriptional activities. We sought to determine whether overexpression of SRB-RGS suppresses the migration and invasion ability of endometrial stromal cells stimulated by 17β-estradiol (E2).

STUDY DESIGN:

Endometrial stromal cells were obtained from endometriosis patients. SRB-RGS was overexpressed in the cells stimulated by E2. The migration and invasion ability of the cells were measured by migration assay and invasion assay, respectively. Western blot analysis was done to test the expression of matrix metalloproteinase-9 (MMP-9), tissue inhibitors of metalloproteinase-1 (TIMP-1) and vascular endothelial growth factor (VEGF).

RESULTS:

Overexpression of SRB-RGS suppressed the migration and invasion ability of the stromal cells stimulated by E2; it also suppressed the expression of MMP-9 and VEGF, while the expression of TIMP-1 was increased.

CONCLUSIONS:

Overexpression of SRB-RGS suppresses the migration and invasion ability of the E2-stimulated endometrial stromal cells. The molecular mechanism is the reduced expression of MMP-9 and VEGF, and the increased expression of TIMP-1. These findings suggest that the coding gene of SRB-RGS is a promising target gene for endometriosis gene therapy.

 

 

Minerva Ginecol. 2016 Jun;68(3):380-7.

Do we need a robot in endometriosis surgery?

Hickman LC¹, Kotlyar A, Luu TH, Falcone T.

Abstract

Since the initial approval of robotic surgery for gynecologic procedures in 2005, its use has been widely adopted, and its application has been expanded beyond hysterectomies and myomectomies. The role of robotics in endometriosis surgery remains controversial, as no randomized control trials have been conducted to evaluate its use over conventional laparoscopy, the current gold standard for diagnosis and treatment. The advantage of robotic surgery in early stage endometriosis remains unclear, whereas several case reports and retrospective studies have suggested a role for robotics in treating advanced stage and deep infiltrating endometriosis. Advantages in advanced stage endometriosis include lower blood loss and possible reduction in length of hospital stay, compared to conventional laparoscopy; however, operative times are consistently longer in robotic surgery with no differences in quality of life and fertility outcomes. Randomized control trials comparing robotic to conventional laparoscopy for endometriosis surgery are needed to more clearly define the role for this promising technology.

 

 

Adv Exp Med Biol. 2016;886:171-189.

Non-coding RNAs in Uterine Development, Function and Disease.

Nothnick WB¹.

Abstract

The major function of the uterus is to accept and provide a suitable environment for an embryo, ultimately leading the birth of offspring and successful propagation of the species. For this occur, there must be precise coordination of hormonal signalling within both the endometrial and myometrial components of this organ. Non-coding RNAs, specifically, microRNAs (miRNAs) have been shown to be essential for normal uterine development and function. Within this organ, miRNAs are proposed to fine-tune the actions of the female steroid hormones estradiol and progesterone. Not surprising, mis-expression of miRNAs has been documented in diseases of the endometrium and myometrium such as endometriosis and leiomyomas, respectively. In this chapter, I will review the current understanding on the role, regulation and function of non-coding RNAs focusing on miRNAs in both the normal physiology of the endometrium and myometrium as well as in pathologies of these tissues, namely endometriosisand leiomyomas.

 

 

Mol Biosyst. 2016 Feb;12(2):362-70.

The differential expression of mRNAs and long noncoding RNAs between ectopic and eutopic endometria provides new insights into adenomyosis.

Zhou C¹, Zhang T², Liu F¹, Zhou J¹, Ni X¹, Huo R¹, Shi Z³.

Abstract

Adenomyosis, defined as ectopic endometrial tissue within the myometrium, can often be misdiagnosed as multiple uterine leiomyomata or endometrial thickening. We therefore performed a combined mRNA and long noncoding (lnc)RNA microarray and bioinformatic analysis of eutopic and ectopic endometria in women with adenomyosis to better understand its pathogenesis and help in the development of a semi-invasive diagnostic test. A total of 586 mRNAs were increased and 305 mRNAs decreased in the ectopic endometrium of adenomyosis compared with the eutopic endometrium, while 388 lncRNA transcripts were up-regulated and 188 down-regulated in ectopic compared with paired eutopic endometrial tissue. Bioinformatic analysis suggested a series of metabolic and molecular abnormalities in adenomyosis, which have many similarities with endometriosis. Furthermore, our study constitutes the first known report of lncRNA expression patterns in human adenomyosis ectopic and eutopic endometrial tissue.

 

 

Lung India. 2015 Nov-Dec;32(6):648-50

A case of young woman with recurrent right pleural effusion.

Mehta AA¹, Gupta A¹, Venkitakrishnan R¹.

Abstract

Endomterisois is usually found in women of child-bearing age. A case is presented of massive right-sided pleural effusion caused by endometriosis. The final diagnosis was made by thoracoscopic pleural biopsy. Physicians should be aware of this potentially treatable cause of pleural effusion having excluded other possibilities such as malignancy and tuberculosis.

 

 

J Res Med Sci. 2015 Aug;20(8):727-32.

Comparison of clinicopathologic variables in coexistence cancers of the endometrium and ovary: A review of 55 cases in an academic center in Iran.

Sadidi H¹, Izadi-Mood N², Sarmadi S², Yarandi F³, Amini-Moghaddam S⁴, Esfahani F⁵, Sadidi M¹.

Abstract

BACKGROUND:

The coexistence primary cancers of the endometrium and ovary are relatively uncommon. The purpose of this study was to characterize patients diagnosed primary synchronous endometrial and ovarian cancer (SEOC), endometrial cancer (EC) with ovarian metastasis, and ovarian cancer (OC) with endometrial metastasis and compare clinicopathologic variables and prognosis.

MATERIALS AND METHODS:

All the patients with diagnosis of both endometrium and OC, who hospitalized between 2002 and 2012 in an academic center affiliated to Tehran University of Medical Sciences, were evaluated with respect to different clinicopathologic variables, follow-up times, and outcomes.

RESULTS:

Fifty-five patients had been diagnosed with both endometrium and OC. 17, 26, and 12 patients were diagnosed as SEOC, EC, and OC, respectively. The frequency of abnormal uterine bleeding was significantly lower in OC (16.7%) compared to others (58.8% in SEOC and 53.8% in EC). However, the abdominal/pelvic pain was significantly higher in OC (50%) compared to others (35.3% in SEOC and 34.6% in EC) (P < 0.05). Complex atypical hyperplasia (87.5%), endometriosis (88.8%), and endometrioid carcinoma (54.5%) was observed most in SEOC group. The duration of follow-up time was between 3 and 171 months with a mean of 16 months. There was no death in SEOC who followed. Survivals of patients between three group were statistically significant (P = 0.032).

CONCLUSION:

Our results showed that overall survival (OS) and progression-free survival (PFS) of SEOC patients is better than those with EC and OC (P = 0.032).

 

 

J Zoo Wildl Med. 2015 Dec;46(4):913-7.

MEDICAL MANAGEMENT OF LEIOMYOMATA AND SUSPECTED ENDOMETRIOSIS IN AN ALLEN’S SWAMP MONKEY (ALLENOPITHECUS NIGROVIRIDUS).

Jafarey YS, Hanley CS, Berlinski RA, Warner C, Armstrong A.

Abstract

A 13-yr-old female nulliparous Allen’s swamp monkey (Allenopitchecus nigroviridis) presented with intermittent excessive vaginal bleeding, cyclical lethargy, and a history of irregular menstrual cycles. Abdominal ultrasonography revealed a subjectively thickened, irregular endometrium, multiple leiomyomata (uterine fibroids), and bilateral anechoic foci on the ovaries. Treatment was initiated with leuprolide acetate i.m. monthly for 6 mo. Recheck ultrasound at 3 mo showed a decrease in leiomyoma diameter and no evidence of active follicles on the ovaries. Eleven months following completion of treatment, clinical signs recurred and the animal was treated with a deslorelin implant. Since implant placement, no vaginal bleeding has been noted.

 

 

Ulus Cerrahi Derg. 2015 Jul 10;31(4):250-2.

Endometriosis within the sigmoid colon/extragenital endometriosis.

Acar T¹, Acar N¹, Çelik SC¹, Ekinci N², Tarcan E¹, Çapkınoğlu E¹.

Abstract

Endometriosis is the presence of endometrial glands and stroma outside the uterine cavity. Although it is common in women in the reproductive age, intestinal endometriosis is extremely rare and may lead to serious clinical problems. In this article, we present two rare cases of endometriosis localized in the sigmoid colon lumen. The first case is a 45 year-old female complaining of rectal bleeding for 6 months. A polypoid lesion with suspicion of malignancy, 3-4 cm in size was identified at colonoscopy. Laparoscopic anterior resection was performed since it was not suitable for colonoscopic polypectomy. The pathology examination revealed extragenital endometriosis. The second case is a 36 year-old female admitted for lower abdominal pain and rectal bleeding for the last 3 months. She was diagnosed with sigmoid diverticulitis. The patient’s symptoms regressed with medical treatment, but due to early and multiple recurrent episodes it was decided to perform an elective laparoscopic anterior resection. The pathology report stated diverticulosis coli and intraluminal endometriosis. Intestinal endometriosisshould be considered as part of the differential diagnosis in female patients of the reproductive age who present with constipation, gastrointestinal bleeding, nausea, vomiting, cramp-like abdominal pain, diarrhea and pelvic pain. In these patients, resection and anastomosis of the effected bowel segment is accepted as the choice of treatment.

 

 

J Fam Plann Reprod Health Care. 2015 Oct;41(4):278-83.

Sexual function in women undergoing surgery for deep infiltrating endometriosis: a comparison with healthy women.

Di Donato N, Montanari G, Benfenati A, Monti G, Leonardi D, Bertoldo V, Facchini C, Raimondo D, Villa G, Seracchioli R.

Abstract

BACKGROUND:

Endometriosis is a chronic and progressive condition of women of reproductive age. It is strongly associated with significant impairment of sexual function.

AIM:

To objectively evaluate the impact of laparoscopic excision of endometriosis on sexual function in patients with deep infiltrating endometriosis (DIE) compared to healthy women.

SETTING AND DESIGN:

Prospective study, including 250 patients with a diagnosis of DIE scheduled for laparoscopic surgery and 250 healthy women.

METHODS:

A sexual activity questionnaire, SHOW-Q (Sexual Health Outcomes in Women Questionnaire), was used to collect data pertaining to women’s satisfaction, orgasm, desire and pelvic problem interference with sexual function. Women with DIE underwent complete excision of endometriotic lesions. All participants were asked to complete the SHOW-Q questionnaire before and after surgery.

RESULTS:

SHOW-Q scores in the endometriosis group before and 6 months after surgery were compared with the healthy group scores. A significant improvement was found between pre- and post-treatment in the scores of the satisfaction scale, desire scale and pelvic problem interference scale of SHOW-Q. The distribution of post-surgery SHOW-Q scores was comparable to healthy women’s scores apart from the orgasm scale score, which was unchanged in the post-surgery group.

CONCLUSIONS:

The surgical approach to treatment has a positive impact not only on organ impairment but also on sexual function in women affected by DIE.

 

 

Acta Obstet Gynecol Scand. 2016 Mar;95(3):285-90.

Ovarian damage due to cyst removal: a comparison of endometriomas and dermoid cysts.

Perlman S¹, Kjer JJ¹.

Abstract

INTRODUCTION:

Surgical treatment of endometriomas and potential damage to the ovary have been debated. Studies have described the inconsistent risk of unintended removal of ovarian tissue when a cystectomy of an endometrioma is performed. We evaluated the risk of inadvertently removed ovarian tissue during surgery by comparing specimens of endometriomas and dermoid cysts removed laparoscopically.

MATERIAL AND METHODS:

The material included 326 women in a retrospective cohort study at Rigshospitalet, University hospital in Copenhagen, Denmark from 2011 to 2013. Surgery was performed laparoscopically for 393 benign cysts with a diagnosis of either endometrioma (n = 294) or dermoid cyst (n = 99). The microscopic existence of ovarian tissue in the cystectomy specimens were compared and correlation between CA 125 and size of cysts was examined.

RESULTS:

In total, 80.3% endometrioma cystectomies disclosed ovarian stroma compared with 17.2% of the resected dermoid cysts (p < 0.001). The difference was found despite skilled laparoscopic surgeons performing the procedure in the endometriosis cohort. A significant positive correlation between the size of endometriomas and the value of CA 125 was found (p < 0.009).

CONCLUSION:

The risk of removal of ovarian tissue during laparoscopic surgery is significantly higher for endometriomas than for dermoid cysts.

 

 

Eur J Pediatr. 2016 May;175(5):623-30.

Characteristics of the menstrual cycle in 13-year-old Flemish girls and the impact of menstrual symptoms on social life.

Hoppenbrouwers K¹, Roelants M², Meuleman C³, Rijkers A³, Van Leeuwen K⁴, Desoete A⁵, D’Hooghe T³.

Abstract

This study aimed to investigate the characteristics of symptoms related to the menstrual cycle and their impact on social activities in young teenage girls. Between March and June 2009, all girls born in 1996 who were residents of eight regions in Flanders (Belgium) received a semi-structured questionnaire, including questions about the age of menarche, characteristics of the menstrual cycle, and its impact on social activities. Participants were 792 13-year-old girls (15.7 % of the target population). Out of 363 (47.2 % of participants) postmenarcheal girls, 41.6 % (95 % confidence interval (CI) 36.4-47.0 %) reported painful menstruations. The proportion of girls with painful menstrual periods decreased approximately 16 % with each year the age at menarche increased (relative risk (RR) = 0.84; 0.73-0.98; p < 0.05) and was positively correlated with the amount of blood loss (RR = 0.33; 0.16-0.67; p < 0.05 when little and 1.85; 1.49-2.31; p < 0.001 when abundant, compared to average). One in four (25.4 %) postmenarcheal girls indicated a negative impact of menstruation on social activities, but this proportion was significantly higher in girls who experienced menstruation as painful (41.3 %) compared to those who did not (14.2 %).

CONCLUSION:

Early menstrual complaints are common in young adolescent girls and the likelihood of pain increased significantly with lower menarcheal age. What is Known? • Menstrual cycle-related symptoms may negatively interfere with school absence and social activities. • Early menarche and severe dysmenorrhea are correlated with endometriosis. What is New? • In this large population-based study on the characteristics of the menstrual cycle in young teenage girls at or shortly after menarche, painful menstruation was highly prevalent (41.7 %), but related school absenteeism was low (3.2 %). The likelihood of pain increased significantly with lower menarcheal age. • The findings support the need for a systematic evaluation of the characteristics of the menstrual cycle shortly after menarche.

 

 

Rev Esp Enferm Dig. 2015 Dec;107(12):761-3.

Malignant degeneration of rectal endometriosis.

García-Marín JA¹, Pellicer-Franco EM², Soria-Aledo V³, Mengual-Ballester M³, Valero-Navarro G³, Aguayo-Albasini JL³.

Abstract

BACKGROUND:

Endometriosis is a relatively common disease among women with child-bearing potential, and rare before puberty or following menopause. It consists of the presence of hormone-responsive endometrium outside the endometrial cavity.

CASE REPORT:

We report the case of a patient with a rectal lesion, initially approached as a primary rectal malignancy, where histopathology eventually revealed an adenocarcinoma arising from endometrial tissue in the colonic wall.

DISCUSSION:

Endometriosis has an estimated rated of 10-20%. Sites may be split up into two larger categories – gonadal and extragonadal. The frequency of extragonadal endometriosis in the bowel is estimated to involve 3%-37% of women with pelvic endometriosis, and most lesions are found in the sigmoid colon and rectum. The malignant transformation of endometriotic lesions is estimated between 0.3% and 1% of cases. The gold standard in the diagnosis of intestinal endometriosis is exploratory laparotomy and the pathological study of specimens. Adjuvant radiotherapy and chemotherapy, although used for some patients, have not proven effective.

 

 

 

Postepy Hig Med Dosw (Online). 2015 Dec 2;69:1275-90.

Ovarian cancer–from biology to clinic.

Kujawa KA¹, Lisowska KM¹.

Abstract

Ovarian cancer is the most frequent cause of deaths from among gynecologic malignancies. Due to its asymptomatic development the disease is frequently diagnosed at an advanced, incurable stages. Although ovarian cancers usually respond well to the first line chemotherapy based on platinum compounds and taxanes, majority of patients develop recurrence and chemo-resistance. Despite many years of studies there is still lack of reliable diagnostic markers as well as other diagnostic methods enabling early detection and suitable for screening. Thus, current studies are aimed on finding new biomarkers with diagnostic, prognostic and predictive potential as well as on the search for the new therapeutic targets. Interestingly, an understanding of ovarian cancer etiology has changed fundamentally within recent years. The classical theory, claiming that ovarian cancers originate from ovarian surface epithelial cells, was undermined. Currently, there is a lot of evidence that majority of serous ovarian cancers have its origin in malignant tubal epithelium, while endometrioid and clear cell ovarian cancers develop most likely from endometriosis. These new findings will have an impact on diagnostic approaches as well as on the prevention options for women with genetic predisposition to ovarian cancer. The new knowledge about an origin of different histological types of ovarian cancer may open new pathways in basic research and clinical studies. In this paper we report current knowledge about ovarian cancer risk factors, we also present the arguments for extraovarian origin of the majority of ovarian cancers and stress the mechanisms of action of new drugs for targeted therapies that show most promising results in the current clinical trials.

 

 

Reprod Sci. 2016 Jul;23(7):847-57

rhTNFR: Fc Suppresses the Development of Endometriosis in a Mouse Model by Downregulating Cell Proliferation and Invasiveness.

Liu Y¹, Sun L², Hou Z³, Mao Y³, Cui Y³, Liu J³.

Abstract

Tumor necrosis factor α (TNF-α), a proinflammatory cytokine, may play an important role in the pathogenesis of endometriosis; therefore, TNF-α inhibitors potentially have an effect on endometriosis. To investigate the effect of anti-TNF-α treatment on endometriosis, 2 TNF-α inhibitors: recombinant human TNF receptor: Fc fusion protein (rhTNFR: Fc) and TNF-α monoclonal antibody (TNF-α mAb) were used to treat human eutopic endometrial stromal cells (hESCs), and the effects on cell survival, cell cycle, and invasiveness were compared. It was found that rhTNFR: Fc suppressed the TNF-α-induced hESC survival and invasiveness but not TNF-α mAb. Recombinant human TNF receptor: Fc fusion protein decreased the S phase of hESC compared with the TNF-α-treated group. Then, we used a surgically induced mouse model of endometriosis to study the effect of rhTNFR: Fc treatment in vivo. The fluorescence intensity and the size of implanted endometriotic lesions in the mouse model were decreased by rhTNFR: Fc. In conclusion, rhTNFR: Fc suppresses hESC survival and invasiveness and decreases the fluorescence intensity and implant size in the mouse model of endometriosis.

J Med Case Rep. 2015 Dec 17;9:280.

Prolapse of fallopian tube through abdominal wound after caesarean section mimicking scar endometriosis: a case report.

Goyal LD¹, Maheshwari S², Kaur S³, Kaur H⁴.

Abstract

INTRODUCTION:

Prolapse of the fallopian tube after hysterectomy is a rare but known complication. Cases of prolapse of the fallopian tube through the vaginal vault have been reported after abdominal, vaginal or laparoscopic hysterectomies. This is the first case report to the best of our knowledge on the prolapse of a fallopian tube through an abdominal wound after caesarean section.

CASE PRESENTATION:

We report a case of the prolapse of the fimbrial end of a fallopian tube through an abdominal scar after caesarean section mimicking scar endometriosis. A 24-year-old primipara South Asian woman of Punjabi ethnicity presented to our institute with a fleshy mass protruding through her abdominal scar and bleeding from the mass during menstruation for the past 5 months. She underwent a caesarean section 6 months earlier for breech presentation. Her history revealed she had wound dehiscence on the sixth postoperative day. The major portion of her wound healed in 1 month leaving a 2 cm area in the middle of her vertical scar. An abdominal examination revealed a 2×2 cm fleshy mass protruding through the middle part of her infraumbilical abdominal scar. At the time of the surgery we found that the fimbrial end of her left fallopian tube was protruding through her abdominal scar.

CONCLUSION:

Awareness of this complication may prevent improper management of wound dehiscence and such complication causing prolonged agony to the patient.

 

 

Zhonghua Fu Chan Ke Za Zhi. 2015 Aug;50(8):591-5.

Change tendency during 30 years of infertility and endometriosis in Peking Union Medical College Hospital.

Zheng T¹, Sun A¹, Lang J², Deng Y¹, Chen R¹, Tian Q¹, Deng S¹

Abstract

OBJECTIVE:

To analyze the incidence of endometriosis in inpatients with infertility in Peking Union Medical College Hospital in 30 years.

METHODS:

The inpatients of Peking Union Medical College Hospital admitted between May 1983 and November 2013 was searched. The infertile patients receiving laparoscopy or laparotomy were included. The discharge diagnosis and the operation were summarized. The incidence of gynecologic diseases were demonstrated, such as endometriosis, pelvic adhesions, uterine fibroid, hydrosalpinx, ovarian benign tumor, and adenomyosis. The age was collected, and the change of age and the incidence of endometriosis was analyzed.

RESULTS:

The incidence of endometriosis in infertile female inpatients was 35.50% (95% CI: 34.50%-36.49%). The incidence showed relatively stable increasing tendency after 2004 (with P < 0.01). The age had increased significantly since 1996 (with P < 0.01); the average age was (29.76 ± 3.74) years old in 1996, and (32.85 ± 4.49) years old in 2013 (P < 0.01). The inpatients diagnosed with endometriosis had greater age, (32.67 ± 4.06) versus (32.04 ± 4.55) years old (P < 0.01); the incidence of endometriosis differed in different age group, the older group had higher incidence (χ² = 85.807, P < 0.01).

CONCLUSIONS:

Infertile female inpatients showed increasing incidence of endometriosis in recent years. Older infertile patients maybe have higher risk of endometriosis.

 

 

PLoS One. 2015 Dec 16;10(12)

TGF-βI Regulates Cell Migration through Pluripotent Transcription Factor OCT4 in Endometriosis.

Au HK^1,2,3, Chang JH⁴, Wu YC^4,5, Kuo YC⁴, Chen YH⁴, Lee WC^4,6, Chang TS^4,7, Lan PC^4,5, Kuo HC⁸, Lee KL^4,6, Lee MT⁴, Tzeng CR^1,2,3, Huang YH^4,6,5,2,9,10.

Abstract

Transforming growth factor (TGF-β)/TGF-β receptor signal is known to promote cell migration. Up-regulation of TGF-β in serum/peritoneal fluid and increased levels of pluripotent transcription factor OCT4 in endometriotic tissues are frequently observed in patients with endometriosis. However, the mechanisms underlying how TGF-β/TGF-β receptor and OCT4 affect endometriotic cell migration still remain largely unknown. Therefore, endometriotic tissue with high cell migratory capacity were collected from patients with adenomyotic myometrium (n = 23) and chocolate cyst (n = 24); and endometrial tissue with low cell migratory capacity in normal endometrium or hyperplastic endometrium (n = 8) were collected as the controls. We found the mRNA levels of TGF-β receptor I (TGF-β RI) and OCT4 were significantly higher in the high-migratory ectopic endometriotic tissues than those of the low-migratory normal or hyperplastic endometrium. Positive correlations between TGF-β RI and OCT4, and either TGF-β RI or OCT4 with migration-related genes (SNAIL, SLUG and TWIST) regarding the mRNA levels were observed in human endometriotic tissues. TGF-βI dose-dependently increased the gene and protein levels of OCT4, SNAIL and N-Cadherin (N-CAD) and silencing of endogenous OCT4 significantly suppressed the TGF-βI-induced expressions of N-CAD and SNAIL in primary human endometriotic stromal cells and human endometrial carcinoma cell lines RL95-2 and HEC1A. Furthermore, TGF-βI significantly increased the migration ability of endometriotic cells and silencing of OCT4 dramatically suppressed the TGF-βI-induced cell migration activity evidenced by wound-closure assay, transwell assay, and confocal image of F-actin cellular distribution. In conclusion, the present findings demonstrate that the niche TGF-β plays a critical role in initiating expressions of pluripotent transcription factor OCT4 which may contribute to the ectopic endometrial growth by stimulating endometrial cell migration. These findings would be useful for developing therapeutic strategies targeting TGF-β-OCT4 signaling to prevent endometriosis in the future.

 

 

Zhonghua Fu Chan Ke Za Zhi. 2015 Oct;50(10):770-6.

Targeted interruption of COX-2 gene by siRNA inhibits the expression of VEGF, MMP-9, the activity of COX-2 and stimulates the apoptosis in eutopic, ectopic endometrial stromal cells of women with endometriosis.

Ma Y¹, Shen A², Li C¹, Xu S¹, Guo H¹, Zou S¹.

Abstract

OBJECTIVE:

To investigate the effect of targeted interruption of cyclooxygenase-2 (COX-2) gene by small interference RNA (siRNA) on the expression of COX-2, vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) in eutopic and ectopic endometrial stromal cells (ESC) with endometriosis, and the effect on the content of 6-keto-prostaglandin-F1α (6-keto-PGF1α, metabolites of COX) and the apoptosis of eutopic and ectopic ESC with endometriosis.

METHODS:

Ectopic and eutopic ESC from 30 women with endometriosis were isolated and cultured respectively. Then, ESC were classified into three groups: interference group, negative control group and blank control group. ESC in interference group were injected into siRNA transfection complex while ESC in negative control group were injected into negative control transfection complex. ESC from 10 participants without endometriosis were the normal control group. The mRNA and protein expression of COX-2, VEGF, MMP-9 in pre-transfected and post-transfected eutopic and ectopic ESC were detected through real time reverse transcription PCR and western blot. The content of 6-keto-PGF1α was determined by ELISA, the apoptotic cells were detected by flow cytometry.

RESULTS:

After interruption of COX-2 gene, there were no significant difference in the mRNA and protein expression of COX-2, VEGF and MMP-9 between the negative control group and blank control group (P > 0.05); the mRNA and protein expression of the three genes in interference group were significantly lower than those in negative control group and blank control group (P < 0.05); the mRNA expression of the three genes in interference group of eutopic ESC were 0.87 ± 0.06, 1.76 ± 0.59, 1.04 ± 0.32, in interference group of ectopic ESC were 0.75 ± 0.12, 1.62 ± 0.47, 0.88 ± 0.25, the protein expression of the three genes in interference group of eutopic ESC were 0.457 ± 0.019, 0.500 ± 0.012, 0.361 ± 0.008, in interference group of ectopic ESC were 0.323 ± 0.018, 0.474 ± 0.016, 0.339 ± 0.009; the mRNA and protein expression of the three genes in ectopic ESC had a more reduction than those in eutopic ESC (P < 0.05). The results from ELISA revealed that the content of 6-keto-PGF1α in the normal control group [(17.7 ± 1.9) pg/ml] were significantly lower than those in the blank control group (P < 0.05), the content of 6-keto-PGF1α in ectopic ESC were significantly higher than that in eutopic ESC (P < 0.05), the content of 6-keto-PGF1α in the blank control group of eutopic and ectopic ESC were (32.4 ± 2.6) pg/ml, (38.2 ± 3.7) pg/ml; there was no significant difference in the content of 6-keto-PGF1α between the negative control group and blank control group (P > 0.05); compared with those of negative control group and blank control group, the content of 6-keto-PGF1α in interference group decreased significantly (P < 0.05), the content of 6-keto-PGF1α in interference group of eutopic and ectopic ESC were (17.1 ± 2.4) pg/ml, (20.9 ± 2.7) pg/ml; the content of 6-keto-PGF1α in eutopic ESC had a slightly more reduction than that in ectopic ESC (P > 0.05). The results from flow cytometry displayed that, there was no significant difference in apoptotic cells between the negative control group and blank control group (P > 0.05); compared with those of negative control group and blank control group, more apoptotic cells were detected in interference group and the difference was significant (P < 0.01); the apoptotic cells in ectopic ESC were significantly more than that in eutopic ESC (P < 0.05); the apoptosis rate in interference group of eutopic and ectopic ESC were (33.76 ± 0.06)%, (47.18 ± 0.12)%.

CONCLUSIONS:

Our results suggested the targeted interruption of COX-2 gene by siRNA effectively inhibited the mRNA and protein expression of COX-2, VEGF and MMP-9 in both eutopic ESC and ectopic ESC with endometriosis, greatly increased the apoptotic rate of cells and obviously reduced the content of 6-keto-PGF1α by inhibiting the activity of COX-2. And the changes in ectopic endometrium were more evident than those in eutopic endometrium.

 

 

Ginekol Pol. 2015 Oct;86(10):726-30.

Inhibin A and B levels in serum and follicular fluids of women with various reproductive failures undergoing in vitro fertilization.

Babćová K, Ulčová-Gallová Z, Rumpík D, Mičanová Z, Bibková K.

Abstract

OBJECTIVE:

Ovarian inhibins (INH) are hormones participating in the regulation of gametogenesis. We monitored inhibin A and B levels in serum (S) and follicular fluids (FF), depending on the type of fertility failure and treatment outcome.

MATERIAL AND METHODS:

We examined INHA and B levels in S and FF of 72 women undergoing ovarian stimulation for in vitro fertilization, including embryo transfer We took serum samples at the time of egg collection (S1), embryo transfer (S2), and diagnostics of early pregnancy (S3). FF samples were obtained during egg collection. INH A and B levels were measured by ELISA set kit in all media.

RESULTS:

Healthy women had median of INHA S1 592.02pg/ml INHA S2 593.58pg/ml, INHA S3 15.17pg/ml and INH B S1 242.46pg/ml, INH B S2 and INH B S3 zero levels. Women with ovarian disorders had significantly lower levels of INH A S1 and INH A S2 (p<0.05). Women with polycystic ovaries had significant higher INH B S2 levels (p<0. 05). No statistically significant differences were found in women with endometriosis. Presence of oocyte in the dominant follicle positively correlated with INH B FF levels (p<0.05).

CONCLUSIONS:

WE confirmed differences in the levels of inhibins in sera depending on type of fertility failure. Inhibin B better reflected the presence of an oocyte. The potential paracrine role of inhibins needs to be examined to improve preparation for the in vitro fertilization treatment (IVF).

 

 

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2015 Oct;35(10):1210-7.

Effects of Bushen Wenyang Huayu Recipe on Expressions of HIF-1α, PHD2, and VHL in Endometriosis Rats with Shen Yang Deficiency Blood Stasis Syndrome.

Jia YB, Du HL, Gao X, Bian WH, Lin XH, Ban GG, Tian QH.

Abstract

OBJECTIVE:

To observe the effect of Bushen Wenyang Huayu Recipe (BWHR) on hypoxia inducible factor-1α (HIF-1α), proline hydroxylase2 (PHD2), von Hippel Lindau disease (VHL) suppressor gene expressions in endometriosis (EM) rats with Shen yang deficiency blood stasis syndrome (SYDBSS), and to explore the pathogenesis of EM and the mechanism of BWHR for treating EM.

METHODS:

Totally 50 SD rats were randomly divided into five groups, i.e., the blank control group, the sham-operation group, the model group, the Chinese medicine (CM) group, and the Western medicine (WM) group, 10 in each group. Rats in the blank control group and the sham-operation group were fed routinely. Rats in the rest 3 groups received 30-day “extended refrigerator freezing and ice water immersion” and combined with ” autotransplantation” to establish EM rat model with SYDBSS. One Milliliter BWHR at 3.33 g/mL was administered to rats in the CM group by gastrogavage. Gestrinone at the daily dose of 0. 5 mg/kg was administered to rats in the WM group by gastrogavage. Equal volume of normal saline was administered to rats in the model group, the blank control group, and the sham-operation group. The size and morphology of ectopic foci in rats were observed after 4 weeks of medication. Expressions of serum CA125, plasma cyclic adenosine monophosphate (cAMP), and plasma cyclic guanosine monophosphate (cGMP) were detected by radioimmunoassay. Morphological changes of eutopic endometrium and ectopic tissue were observed under the optical microscope by HE staining. Protein expressions and contents of HIF-lα, PHD2, and VHL were detected by immunohistochemical SABC method and Western blot. mRNA expressions of HIF-1α, PHD2, and VHL were detected by RT-PCR.

RESULTS:

The ectopic foci grew significantly in the model group. Their volumes were obviously contracted after treated by CM and WM. Compared with the blank control group and the sham-operation group, serum CA125 and plasma cGMP obviously increased, cAMP obviously decreased (P < 0.05); expressions and contents of HIF-1α mRNA and protein all decreased (P < 0.05); mRNA and protein expressions and contents of PHD2 and VHL all decreased in the model group (P < 0.05). Compared with model group, levels of CA125 and cGMP obviously decreased; cAMP levels obviously increased, expressions and contents of HIF-1α mRNA and protein all increased, mRNA and protein expressions and contents of PHD2 and VHL all increased in the WM group and the CM group (P < 0.05). Compared with the CM group, PHD2 protein contents were higher in the WM group (P < 0.05). HIF-1α was negatively correlated with PHD2 (r = -0.799, P = 0.00). HIF-1α was negatively correlated with VHL (r = -0. 625, P = 0.003).

CONCLUSIONS:

BWHR could effectively treat EM. Its mechanism might be associated with reducing contents of HIF-1α, serum CA125, and plasma cGMP, and up-regulating expressions of PHD2, VHL, and cAMP.

 

Fertil Steril. 2016 Mar;105(3):734-743.

Norethindrone acetate or dienogest for the treatment of symptomatic endometriosis: a before and after study.

Vercellini P¹, Bracco B², Mosconi P³, Roberto A³, Alberico D⁴, Dhouha D², Somigliana E⁴.

Abstract

OBJECTIVE:

To assess the proportion of patients satisfied with their treatment before and after a systematic change from norethindrone acetate to dienogest as the first-line progestin for symptomatic endometriosis.

DESIGN:

Before and after study.

SETTING:

Academic department.

PATIENT(S):

The last 90 new consecutive endometriosis patients in whom norethindrone acetate was used, and the first 90 new consecutive endometriosis patients in whom dienogest was used.

INTERVENTION(S):

Norethindrone acetate at the oral dose of 2.5 mg once a day until June 6, 2013, then dienogest at the oral dose of 2 mg once a day thereafter.

MAIN OUTCOME MEASURE(S):

Degree of satisfaction with treatment after 6 months of progestin therapy and assessment of any variations in pain symptoms, psychological status, sexual function, or health-related quality of life associated with the introduction of dienogest.

RESULT(S):

The proportion of satisfied plus very satisfied women after 6 months of treatment was 71% in the “before” period (norethindrone acetate) and 72% in the “after” period (dienogest). The implementation of dienogest was not associated with statistically significant ameliorations in overall pain relief, psychological status, sexual functioning, or health-related quality of life. Treatment was well tolerated by 58% of norethindrone acetate users compared with 80% of dienogest users. After dienogest implementation, the absolute risk reduction in the occurrence of any side effect was 13.9% (95% confidence interval, 0.8%-28.6%).

CONCLUSION(S):

Considering the large difference in the cost of the two drugs, dienogest should be suggested selectively in women who do not tolerate norethindrone acetate.

 

 

PLoS One. 2015 Dec 17;10(12)

Aquaporin 5 Plays a Role in Estrogen-Induced Ectopic Implantation of Endometrial Stromal Cells in Endometriosis.

Jiang XX¹, Fei XW², Zhao L¹, Ye XL³, Xin LB⁴, Qu Y², Xu KH¹, Wu RJ¹, Lin J¹.

Abstract

Aquaporin 5 (AQP5) participates in the migration of endometrial cells. Elucidation of the molecular mechanisms associated with AQP5-mediated, migration of endometrial cells may contribute to a better understanding of endometriosis. Our objectives included identifying the estrogen-response element (ERE) in the promoter region of the AQP5 gene, and, investigating the effects of AQP5 on ectopic implantation of endometrial cells. Luciferase reporter assays and electrophoretic mobility shift assay (EMSA) identified the ERE-like motif in the promoter region of the AQP5 gene. After blocking and up-regulating estradiol (E2) levels, we analysed the expression of AQP5 in endometrial stromal (ES) cells. After blocking E2 /or phosphatidylinositol 3 kinase(PI3K), we analysed the role of AQP5 in signaling pathways. We constructed an AQP5, shRNA, lentiviral vector to knock out the AQP5 gene in ES cells. After knock-out of the AQP5 gene, we studied the role of AQP5 in cell invasion, proliferation, and the formation of ectopic endometrial implants in female mice. We identified an estrogen-response element in the promoter region of the AQP5 gene. Estradiol (E2) increased AQP5 expression in a dose-dependent fashion, that was blocked by ICI182,780(an estrogen receptor inhibitor). E2 activated PI3K /protein kinase B(AKT) pathway (PI3K/AKT), that, in turn, increased AQP5 expression. LY294002(PI3K inhibitor) attenuated estrogen-enhanced, AQP5 expression. Knock-out of the AQP5 gene with AQP5 shRNA lentiviral vector significantly inhibited E2-enhanced invasion, proliferation of ES cells and formation of ectopic implants. Estrogen induces AQP5 expression by activating ERE in the promoter region of the AQP5gene, activates the PI3K/AKT pathway, and, promotes endometrial cell invasion and proliferation. These results provide new insights into some of the mechanisms that may underpin the development of deposits of ectopic endometrium.

 

 

Sociol Health Illn. 2016 Jun;38(5):721-35.

‘We needed to change the mission statement of the marriage’: biographical disruptions, appraisals and revisions among couples living with endometriosis.

Hudson N¹, Culley L¹, Law C¹, Mitchell H¹, Denny E², Raine-Fenning N^3,4.

Abstract

The concept of biographical disruption has been widely applied in sociological explorations of chronic illness and has been subject to much theoretical scrutiny, reflection and development. However, little attention has been given to the impact of biographical disruption beyond the individual level. This article explores the concept from a dyadic perspective, utilising data from an exploratory, qualitative study (ENDOPART) that investigated the impact of endometriosis on women and their male partners. In total, 22 couples participated in in-depth, semi-structured, face-to-face interviews. The women and their partners were interviewed separately and, in most cases, simultaneously, by different interviewers. Data analysis was informed by an interpretivist relational approach, foregrounding the meanings participants applied to their experiences, treating interviews as accounts, and exploring partners’ accounts in relation to one another. Two analytic approaches generated several themes for exploration in the context of the concept of biographical disruption: sex and intimacy; planning for and having children; working lives and social lives. The article argues that biographical disruptions are social and inter-relational processes and discusses how couples living with endometriosis negotiated these disruptions, how they were appraised and how lives and expectations were revised as a result.

 

 

Surg Technol Int. 2015 Nov;27:163-8.

Laparascopic Neurolysis of Deep Endometriosis Infiltrating Left Femoral Nerve: Case Report.

Andrade C¹, Barata S², António F³, Alho C⁴, Calhaz-Jorge C⁵, Osório F⁶.

Abstract

Pelvic endometriosis may infiltrate somatic nerves causing severe neuropathic symptoms with a high impact on quality of life. It is a medical condition poorly known, and few published data about involvement of femoral nerve are available. We report an isolated unilateral endometriosis lesion of the left lumbar region infiltrating the femoral nerve in a 38-year-old woman. She described severe dysmenorrhea, dyspareunia, dischezia, and chronic pelvic pain with irradiation to the anterior part of the left thigh. After investigation, it was identified as a 5-centimeter endometriotic nodule involving the femoral nerve and the psoas muscle. The patient was treated by two laparoscopic surgeries with neurolysis of the involved somatic nerve by a multidisciplinary team, with improvement of the symptoms. Laparoscopic neurolysis is the first approach advocated in these cases, leading to relief of neurological symptoms resulting from nerve infiltration by endometriosis.

 

 

Gynecol Endocrinol. 2016;32(5):403-7.

Development of a mouse model for testing therapeutic agents: the anticancer effect of dienogest on endometrial neoplasms.

Saito F¹, Tashiro H¹, Yamaguchi M¹, Honda R¹, Ohba T¹, Suzuki A², Katabuchi H¹.

Abstract

OBJECTIVE:

As the number of younger women with endometrial carcinoma has increased, fertility-sparing treatments have received more attention. Although there have been several reports on conservative treatments with progestins for endometrial carcinoma, only medroxyprogesterone acetate (MPA) is available in Japan. Dienogest has been developed as a fourth-generation progestin for treating endometriosis. Because of its high progesterone activity, its antitumor activity has attracted attention. In this study, we investigated the anticancer effect of dienogest on endometrial neoplasms using mouse model of endometrial carcinoma.

METHODS/MATERIALS:

Pten(loxP/loxP) mice were injected with MPA or dienogest subcutaneously to evaluate the anticancer effect against endometrial neoplasms that developed in the mice. One week after injections, histopathological analyzes were performed.

RESULTS:

Endometrial neoplasms were found in one of the eight (12.5%) mice from each group treated with either dienogest or MPA. In contrast, they were found in seven of eight (87.5%) mice not treated with progestins. Each progestin treatment showed anticancer activity against endometrial neoplasms that developed in the mice compared to those without treatment.

CONCLUSIONS:

Dienogest and MPA showed potent anticancer activity against endometrial neoplasms in our mouse model. The present study demonstrated that dienogest might be a useful therapeutic agent for human endometrial neoplasms.

 

 

Genet Mol Res. 2015 Dec 11;14(4)

Effect of human umbilical cord mesenchymal stem cells on endometriotic cell proliferation and apoptosis.

Xu LN¹, Lin N², Xu BN³, Li JB¹, Chen SQ¹.

Abstract

The objective of this study was to observe the effects of human umbilical cord mesenchymal stem cells (UCMSCs) on the proliferation and apoptosis of endometriotic cells. Endometriotic cells and UCMSCs were primarily cultured in vitro. In the experimental group, a UCMSC and endometriotic cell non-contact co-culture system was established. The control group consisted of 1 x 10(5) endometriotic cells cultured alone. The proliferation and apoptosis of endometriotic cells were respectively detected using the MTT method and flow cytometry. The mRNA expression level of the tensin homologue gene (PTEN) in endometriotic cells was detected by reverse transcription-polymerase chain reaction amplification. Compared with the control group, the proliferation of endometriotic cells in the experimental group was clearly inhibited (P < 0.05) and time-dependent (P < 0.05). In addition, the number of apoptotic cells were significantly increased (P < 0.05), and the amount of cells, which entered S phase from G1 phase, decreased significantly. Furthermore, the mRNA expression level of the PTEN gene in the experimental group was significantly higher than in the control group (P < 0.05). These results suggest that UCMSCs might inhibit the proliferation of human endometriotic cells in vitro and promote their apoptosis by upregulating the expression of PTEN.

 

 

Hum Reprod. 2016 Feb;31(2):339-44.

Comparison between the stripping technique and the combined excisional/ablative technique for the treatment of bilateral ovarian endometriomas: a multicentre RCT.

Muzii L¹, Achilli C², Bergamini V³, Candiani M⁴, Garavaglia E⁴, Lazzeri L⁵, Lecce F², Maiorana A⁶, Maneschi F⁷, Marana R⁸, Perandini A³, Porpora MG², Seracchioli R⁹, Spagnolo E⁹, Vignali M¹⁰, Benedetti Panici P².

Abstract

STUDY QUESTION:

Is the combined excisional/ablative technique for the treatment of ovarian endometriomas better than the traditional stripping technique in terms of recurrence rate?

SUMMARY ANSWER:

There is no evidence that the combined excisional/ablative technique is better than the traditional stripping technique, as similar recurrence rates were observed for the two techniques.

WHAT IS KNOWN ALREADY:

The stripping technique is associated with better results compared with ablative, non-excisional techniques for the treatment of ovarian endometriomas. Excisional techniques, such as stripping, have, however, been associated with reduced ovarian reserve as evaluated with anti-Mullerian hormone, and surgical techniques that better preserve the ovarian reserve are needed.

STUDY DESIGN, SIZE, DURATION:

A prospective, multicentre, randomized blinded clinical trial was carried out on 51 patients with bilateral endometriomas larger than 3 cm. For each patient, serving as her own control, one ovary was randomized to the stripping technique and the contralateral to the combined excisional/ablative technique. Patients were enrolled between January 2013 and April 2014.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

Patients of reproductive age with pelvic pain and/or infertility affected by bilateral endometriomas larger than 3 cm were included (n = 51). The patients underwent laparoscopic removal of endometriomas with two different surgical techniques performed at either side after random assignment: complete removal by stripping on one side versus the combined technique, consisting of partial excisional cystectomy followed by completion with ablative surgery using bipolar coagulation, on the other side. Post-operative follow-up was performed at 1, 3 and 6 months after surgery for the evaluation of endometrioma recurrence (primary outcome) and of antral follicle count (AFC) and ovarian volumes (OVs) to assess ovarian reserve (secondary outcome).

MAIN RESULTS AND THE ROLE OF CHANCE:

Recurrence rates were 5.9% for the stripping technique versus 2.0% for the combined technique (odds ratio 3.00; 95% confidence interval: 0.24-157.5; P = 0.62). AFC in the ovaries treated with the stripping technique did not differ significantly from AFC in ovaries treated with the combined technique at all follow-up visits, whereas OV was significantly lower after the combined technique at the 6-month follow-up visit (P = 0.04).

LIMITATIONS, REASONS FOR CAUTION:

A major limitation of this study is the small sample size and particularly for ovarian reserve, the secondary outcome, for which no formal sample size calculation was performed. The lower-than-expected recurrence rates in the present series may be related to the shorter follow-up in our study compared with most studies in the literature. Further studies with larger sample sizes and longer follow-up are needed to confirm the findings of this study. The combined technique using CO2 laser energy instead of bipolar coagulation should also be evaluated.

WIDER IMPLICATIONS OF THE FINDINGS:

The traditional excisional technique, i.e. the stripping technique, should still be considered the gold standard approach for the surgical treatment of endometriomas.

STUDY FUNDING/COMPETING INTERESTS:

No commercial funding was received. The authors report no relevant conflict of interest.

 

 

Endocr Dev. 2016;30:106-29.

Therapeutic Neuroendocrine Agonist and Antagonist Analogs of Hypothalamic Neuropeptides as Modulators of the Hypothalamic-Pituitary-Gonadal Axis.

Newton CL, Anderson RC, Millar RP.

Abstract

Reproductive hormones play a role at all stages of life and affect most tissues of the body. Gonadotropin-releasing hormone (GnRH) synthesized in the hypothalamus stimulates the secretion of gonadotropins which in turn stimulate gonadal sex hormone production and gamete formation. This hypothalamic-pituitary-gonadal (HPG) axis has, therefore, been the target for the development of numerous drugs which regulate it at various points. These include sex steroid agonists and antagonists, inhibitors of sex steroid biosynthesis, and GnRH agonists and antagonists, which have found extensive applications in treating numerous conditions such as precocious puberty, delayed puberty, prostate cancer, benign prostatic hyperplasia, endometriosis, uterine fibroids and also in in vitro fertilization protocols. The novel neuroendocrine peptides, kisspeptin (KP) and neurokinin B (NKB), were recently discovered as upstream regulators of GnRH, and inactivating mutations of KP and NKB ligands or receptors result in a failure to progress through puberty. Agonists and antagonists of KP and NKB are being developed as more subtle modulators of the HPG axis. These new drugs offer additional and alternative therapeutic options in pediatric and adult hormone-dependent diseases.

 

 

Eur J Pain. 2016 May;20(5):742-52.

Dynamic weight bearing as a non-reflexive method for the measurement of abdominal pain in mice.

Laux-Biehlmann A¹, Boyken J¹, Dahllöf H¹, Schmidt N¹, Zollner TM¹, Nagel J¹.

Abstract

BACKGROUND:

Chronic pelvic pain (CPP) is a high burden for patients and society. It affects 15-24% of women in reproductive age and is an area of high unmet medical need. CPP can be caused by a wide range of visceral diseases such as abdominal infections, gastrointestinal or gynaecological diseases like endometriosis. Despite the high medical need for this condition, pharmacological approaches are hampered by the limited number of available methods for the behavioural evaluation of pain in inflammation-driven animal models of pelvic pain.

METHODS:

The dynamic weight bearing (DWB) system was used for the evaluation of spontaneous behaviour changes in the zymosan-induced peritonitis mouse model. Inflammatory mediator levels were evaluated in peritoneal lavage and their correlation with the behavioural endpoints was assessed. We evaluated the effect on behavioural endpoints of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib and the Nav 1.8 blocker A-803467.

RESULTS:

The presence of a relief posture, characterized by a significantly increased weight distribution towards the front paws, was observed following intraperitoneal injection of zymosan. A positive correlation was detected between PGE2 levels in the peritoneal lavage and DWB endpoints. In addition, zymosan-induced weight bearing changes were reverted by celecoxib and A-803467.

CONCLUSIONS:

This study described for the first time the use of DWB as a non-subjective and non-reflexive method for the evaluation of inflammatory-driven abdominal pain in a mouse model.

 

 

Fertil Res Pract. 2015 Dec 21;1:19.

Robotic single-site excision of ovarian endometrioma.

Gargiulo AR^1,2, Feltmate C^3,2, Srouji SS^1,2.

Abstract

BACKGROUND:

Conventional single-incision laparoscopic surgery has been successfully employed for treatment of ovarian endometriomas. However, this technique presents surgeons with formidable ergonomic challenges, that make its widespread adoption unlikely. Robotic assistance in single-incision laparoscopic surgery provides adequate instrument triangulation through a single fulcrum, while eliminating ergonomic challenges to the surgeon. The objective of this video is to describe a novel technique of laparoscopic excision and ablation of ovarian endometriomas with single-site robotic assistance. Footage from a single surgical case is shown in our video. The da Vinci Si surgical system with da Vinci Single-Site platform was utilized. A flexible CO2 laser fiber was employed as the main energy tool. To describe a technique of single-incision laparoscopic excision and ablation of endometriomas with robotic assistance. Footage from a single surgical case is shown in this video. The da Vinci Si surgical system with da Vinci Single-Site platform was utilized. A flexible CO2 laser fiber was employed as the main energy tool.

RESULTS:

Our technique achieved excellent surgical, clinical and cosmetic results, with complete excision and ablation of the endometriomas and no complications. The procedure was completed in day-surgery setting.

CONCLUSION:

Our step-by-step video tutorial shows how the dedicated single incision laparoscopy technology for the da Vinci Si surgical system can be safely and effectively applied to the excision and ablation of ovarian endometriomas.

 

 

Eur J Obstet Gynecol Reprod Biol. 2016 Jan;196:57-9.

Clinical significance of neonatal menstruation.

Brosens I¹, Benagiano G².

Abstract

Past studies have clearly shown the existence of a spectrum of endometrial progesterone responses in neonatal endometrium, varying from proliferation to full decidualization with menstrual-like shedding. The bleedings represent, similar to what occurs in adult menstruation, a progesterone withdrawal bleeding. Today, the bleeding is completely neglected and considered an uneventful episode of no clinical significance. Yet clinical studies have linked the risk of bleeding to a series of events indicating fetal distress. The potential link between the progesterone response and major adolescent disorders requires to be investigated by prospective studies.

 

 

Cell Tissue Res. 2016 Apr;364(1):1-7.

Oxidative stress and oocyte quality: ethiopathogenic mechanisms of minimal/mild endometriosis-related infertility.

Da Broi MG¹, Navarro PA².

Abstract

Endometriosis, a highly prevalent gynecological disease, is often associated with infertility, even in its milder forms (minimal and mild endometriosis). However, no consensus has been established with regard to this relationship and the possible mechanisms involved have not been completely elucidated. The oocyte is believed to have an important role in the infertility presented by these patients. Hence, oxidative stress events associated with alterations in the peritoneal, serum and/or follicular microenvironments might result in poor oocyte quality and compromise the reproductive potential of these women. Here, we review possible mechanisms involved in oocyte quality impairment that might lead to infertility in patients with early endometriosis.

 

 

Int J Colorectal Dis. 2016 Mar;31(3):643-52.

Robot-assisted surgery for the radical treatment of deep infiltrating endometriosis with colorectal involvement: short- and mid-term surgical and functional outcomes.

Morelli L^1,2, Perutelli A³, Palmeri M⁴, Guadagni S¹, Mariniello MD¹, Di Franco G¹, Cela V⁵, Brundu B⁶, Salerno MG³, Di Candio G¹, Mosca F².

Abstract

PURPOSE:

Sexual and urinary dysfunctions are complications in radical treatment of deep infiltrating endometriosis (DIE) with colorectal involvement. The aim of this article is to report the preliminary results of our single-institution experience with robotic treatment of DIE, evaluating intraoperative and postoperative surgical outcomes and focusing on the impact of this surgical approach on autonomic functions such as urogenital preservation and sexual well-being.

METHODS:

From January 2011 through December 2013, a case series of 10 patients underwent robotic radical treatment of DIE with colorectal resection using the da Vinci System. Surgical data were evaluated, together with perioperative urinary and sexual function as assessed by means of self-administered validated questionnaires.

RESULTS:

None of the patients reported significant postoperative complications. Questionnaires concerning sexual well-being, urinary function, and impact of symptoms on quality of life demonstrated a slight worsening of all parameters 1 month after surgery, while data were comparable to the preoperative period 1 year after surgery. Dyspareunia was the only exception, as it was significantly improved 12 months after surgery.

CONCLUSIONS:

Robot-assisted surgery seems to be advantageous in highly complicated procedures where extensive dissection and proper anatomy re-establishment is required, as in DIE with colorectal involvement. Our preliminary results show that robot-assisted surgery could be associated with a low risk of complications and provide good preservation of urinary function and sexual well-being.

 

 

Eur J Obstet Gynecol Reprod Biol. 2017 Feb;209:55-60.

Markers of deep infiltrating endometriosis in patients with ovarian endometrioma: a predictive model.

Perelló M¹, Martínez-Zamora MA¹, Torres X¹, Munrós J¹, Llecha S¹, De Lazzari E², Balasch J¹, Carmona F³.

Abstract

OBJECTIVE:

The purpose of the study was to develop an easily applicable predictive model to predict deep infiltrating endometriosis in patients with ovarian endometrioma.

STUDY DESIGN:

We performed a retrospective analysis of 178 consecutive women with ovarian endometrioma who underwent surgery, with histological confirmation and complete removal of endometriosis in the Hospital Clinic of Barcelona. Several markers were prospectively obtained and compared between the group of patients presenting deep infiltrating endometriosis associated with ovarian endometrioma and women with only ovarian endometrioma. Multiple logistic regression analysis was performed to create a model to predict the presence of deep infiltrating endometriosis and internal validation was later performed.

RESULTS:

Of the 178 patients studied, 80 (45%) were classified in the ovarian endometrioma group and 98 (55%) in the group of patients presenting deep infiltrating endometriosis associated with ovarian endometrioma. The independent variables to predict deep infiltrating endometriosis were: at least one previous pregnancy, a past history of surgery for endometriosis and the mean endometriosis-associated pelvic pain score. The area under the ROC curve was 0.91 (95% confidence interval: 0.86-0.94), with an optimal cut-off of the predicted probability of 0.54. The sensitivity of the model was 80% and the specificity 84%.

CONCLUSIONS:

This model predicts the development of deep infiltrating endometriosis in patients with ovarian endometriomas allowing prioritization of women for referral to specialized centers.