Gynecol Endocrinol. 2010 Jun 29. [Epub ahead of print]Polymorphisms in ESR1, ESR2 and HSD17B1 genes are associated with fertility status in endometriosis.Lamp M, Peters M, Reinmaa E, Haller-Kikkatalo K, Kaart T, Kadastik U, Karro H, Metspalu A, Salumets A.Department of Obstetrics and Gynaecology, University of Tartu, Tartu, Estonia.Objective. To investigate ...
Reprod Biomed Online. 2018 Feb;36(2):239-244.
Do endometriomas grow during ovarian stimulation for assisted reproduction? A three-dimensional volume analysis before and after ovarian stimulation.
Whether endometriomas grow because of supraphysiological oestradiol levels attained during ovarian stimulation for assisted reproduction techniques is a concern. In this prospective study, 25 women with 28 endometriomas underwent three-dimensional ultrasound using sono-automated volume calculation software. Endometrioma volume was measured on the first day of gonadotrophin injection (V1) and the day of ovulation trigger (V2). Nine (36%) women were stimulated in a gonadotrophin releasing hormone antagonist protocol (GnRH), 13 (52%) in a long, and three (12%) in an ultra-long GnRH agonist protocol. Mean duration of stimulation was 10.3 days with median total gonadotrophin dose of 4500 IU/day. Median number of cumulus oocyte complexes was five, and metaphase-two oocytes was four. None of the endometriomas were punctured during oocyte retrieval. Median V1 was 22.2 ml (12-30 ml) and median V2 was 24.99 ml (11.2-37.4 ml) with P = 0.001. Twenty-three out of 28 endometriomas (82%) grew to some extent during ovarian stimulation. Endometrioma growth was positively correlated with prestimulation cyst volume (Correlation coefficient 0.664; P < 0.01). Although the 3-ml average growth was statistically significant, it could be regarded as clinically insignificant.
Dysmenorrhea in teenagers.
Dysmenorrhea affects quality of life, but is often inadequately treated in teenagers. The mainstay of treatment is NSAID, which must be started pre-emptively and in adequate dose. If NSAID provides insufficient pain relief, or when contraception is required, combined oral contraceptives can be prescribed concomitantly. Hormonal IUD can also be used in teenagers. If dysmenorrhea persists despite appropriate treatment, the patient must be referred to a gynecologist. Endometriosis, the most common cause of severe dysmenorrhea, can manifest already during adolescence.
Int J Gynaecol Obstet. 2017 Dec 4.
Effect of disease-modifying anti-rheumatic drugs on therapeutic outcomes among women with endometriosis.
To determine whether disease-modifying anti-rheumatic drugs (DMARDs) affect the use of hormonal treatments, subsequent ablative surgery, and need for pain management, including opioids, non-steroidal anti-inflammatory drugs and anti-depressants, among women with endometriosis.
In a retrospective study, data were reviewed from women with surgically confirmed endometriosis who were not treated (n=234) or treated with DMARDs for 6 weeks or more (n=25) before surgical diagnosis at a single healthcare system in the USA between 2003 and 2013. The postoperative use of hormonal treatments, proportion of women undergoing subsequent ablative surgery, and use of adjunct therapies such as antidepressants, steroids, and opioids after surgery were compared between the two groups.
The two groups showed differences in age (P=0.007) and follow-up time (P<0.001). Univariate analysis showed more frequent use of hormonal treatments (P=0.045) and antidepressants (P=0.006) among women treated with DMARDs. The frequency of post-diagnostic use of opioids was lower among treated women (P=0.001); this association remained significant in multivariate analysis controlling for potential confounders (P=0.003).
The findings suggest that administration of DMARDs for at least 6 weeks is associated with decreased opioid usage among women with endometriosis.
Hum Reprod. 2017 Dec 1:1-6.
Time to redefine endometriosis including its pro-fibrotic nature.
Endometriosis is currently defined as presence of endometrial epithelial and stromal cells at ectopic sites. This simple and straightforward definition has served us well since its original introduction. However, with advances in disease knowledge, endometrial stromal and glands have been shown to represent only a minor component of endometriotic lesions and they are often absent in some disease forms. In rectovaginal nodules, the glandular epithelium is often not surrounded by stroma and frequently no epithelium can be identified in the wall of ovarian endometriomas. On the other hand, a smooth muscle component and fibrosis represent consistent features of all disease forms. Based on these observations, we believe that the definition of endometriosis should be reconsidered and reworded as ‘A fibrotic condition in which endometrial stroma and epithelium can be identified’. The main reasons for this change are: (1) to foster the evaluation of fibrosis in studies on endometriosis pathogenesis using animal models; (2) to limit potential false negative diagnoses if pathologists stick stringently to the current definition of endometriosis requiring the demonstration of endometrial stromal and glands; (3) to consider fibrosis as a potential target for treatment in endometriosis. This opinion article is aimed at boosting the attention paid to a largely neglected aspect of the disease. We hope that targeting the fibrotic process might increase success in developing new therapeutic approaches.
Mymensingh Med J. 2017 Oct;26(4):840-845.
Correlation between Seropositivity of Chlamydia Trachomatis and Tubal and/or Pelvic Pathology Detected by Diagnostic Laparoscopy in Subfertile Women.
This prospective observational study was carried out in the Infertility Unit, Department of Obstetrics and Gynaecology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, from February 2011 to December 2013. Sixty-nine (69) subfertile women who were seropositive for Chlamydia Trachomatis were included in this study. Inclusion criteria was patients with sub-fertility having age between 22 and 40 years, seeking infertility treatment, normal ovarian function, all normozoospermic male partner, duration of infertility ranged from 1.5 to 14 years. Exclusion criteria were patients having sub-fertility with extensive pelvic and/or ovarian surgery, endometriosis, ablation of endometriotic spots, pelvic tuberculosis and history of ectopic pregnancy. Before laparoscopic evaluation, all study women were screened for Chlamydia Trachomatis Specific IgG & IgM antibodies using ELISA in the Microbiology Department of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. All the study women had positive results for IgG antibodies. All study women underwent diagnostic laparoscopy. During laparoscopy, we observed the condition of pelvic cavity, uterus, fallopian tubes, ovaries, peritubal adhesions, tubo-ovarian relationship, status of Pouch of Douglas (POD), fimbriae etc. During dye test procedure, dilute methylene blue dye was injected through the cervical canal and the dye spill out was observed to confirm the tubal patency or blockage or pattern of flow of dye. The results of laparoscopic findings demonstrated that mobility of uterus was restricted in 20(29%) cases, adhesion of uterus with peritoneum was in 8(11.6%) cases, uterine fibroid was present in 11(15.9%) cases, hydrosalpinx in right fallopian tubes were in 27(39.1%) cases, in left fallopian tubes were in 32(46.4%) cases and in both fallopian tubes in 16(23.2%) cases, inflamed right fallopian tubes in 32(46.4%) cases, inflamed left fallopian tubes in 36(52.2%) cases and inflamed both fallopian tubes in 26(37.7%) cases, adhesions in pouch of Douglas was in 4(5.8%) cases, collections in pouch of Douglas was in 7(10.1%) cases and obliterations in pouch of Douglas was in 5(7.2%) cases. Results of Dye test during laparoscopy were that right fallopian tube was blocked in 32(46.4%) cases, left fallopian tube was blocked in 32(46.4%) cases and both fallopian tubes were blocked in 21(30.4%) cases. This study shows that by laparoscopy, significant number of cases of tubal and pelvic pathology was diagnosed in the chlamydia trachomatis seropositive subfertile female. This indicates strong correlation between seropositivity of chlamydia trachomatis and/or pelvic pathology detected by diagnostic laparoscopy.
Facts Views Vis Obgyn. 2017 Jun;9(2):115-119.
Primary umbilical endometriosis: a case report.
Primary umbilical endometriosis is a rare phenomenon accounting for 0,4-1,0% of extragenital endometriosis. Despite the fact that it mostly presents as a typical cyclic umbilical discharge coincidental with a palpable mass, the diagnosis is often delayed due to its low prevalence, as was seen in the presented case. The exact pathogenesis is still unclear. The golden standard for diagnosis is histopathological examination, but diagnostic tools like ultrasound, MRI or CT scan can be helpful. The differential diagnosis includes a wide range of disorders. Surgical management is the preferred treatment.
Aust N Z J Obstet Gynaecol. 2017 Dec;57(6):676-678.
Surgery or in vitro fertilization: The simplicity of this question belies its complexity.
Unlike surgery, assisted reproduction, particularly in vitro fertilisation (IVF), requires a low skill base, is largely practitioner independent, is highly effective, quality controlled, reproducible and consistent in the management of endometriosis-associated infertility. Ultimately, however, the decision to proceed to IVF or surgery is dependent on the woman, her reproductive expectations, her specific disease pattern, her support and family network and the resources available in a given health care setting.
MSMR. 2017 Nov;24(11):30-38.
Incidence and burden of gynecologic disorders, active component service women, U.S. Armed Forces, 2012-2016.
This report describes the incidence, burden, and co-occurrence of four common gynecologic disorders among active component service women during 2012-2016. Overall incidence rates were highest for menorrhagia (100.9 per 10,000 person-years [p-yrs]), followed by uterine fibroids (63.2 per 10,000 p-yrs), endometriosis (30.8 per 10,000 p-yrs), and polycystic ovary syndrome (PCOS, 25.3 per 10,000 p-yrs). Annual incidence rates and medical encounters for menorrhagia decreased by roughly 50% from 2012 through 2015, and then increased slightly in 2016. Annual incidence rates of PCOS decreased modestly between 2012 and 2016, whereas rates for endometriosis and uterine fibroids remained relatively stable. Service women in the Army, older service women, and non-Hispanic black service women had overall higher rates of menorrhagia, uterine fibroids, and endometriosis. Incidence of PCOS was highest among women aged 25-29 years, non-Hispanic black service women, and service women in the Air Force. Approximately one-quarter (25.6%) of women with incident endometriosis, one-third (33.6%) of women with incident uterine fibroids, and 7% of women with PCOS had a co-occurring incident diagnosis for menorrhagia during the surveillance period. Additional research focused on the severity of these conditions would allow for a fuller examination of the impact of these disorders on the readiness of the force and on healthcare utilization.
Hum Reprod. 2018 Feb 1;33(2):238-247.
Reduced live-birth rates after IVF/ICSI in women with previous unilateral oophorectomy: results of a multicentre cohort study.
Is there a reduced live-birth rate (LBR) after IVF/ICSI treatment in women with a previous unilateral oophorectomy (UO)?
A significantly reduced LBR after IVF/ICSI was found in women with previous UO when compared with women with intact ovaries in this large multicentre cohort, both crudely and after adjustment for age, BMI, fertility centre and calendar period and regardless of whether the analysis was based on transfer of embryos in the fresh cycle only or on cumulative results including transfers using frozen-thawed embryos.
WHAT IS KNOWN ALREADY:
Similar pregnancy rates after IVF/ICSI have been previously reported in case-control studies and small cohort studies of women with previous UO versus women without ovarian surgery. In all previous studies multiple embryos were transferred. No study has previously evaluated LBR in a large cohort of women with a history of UO.
STUDY DESIGN, SIZE, DURATION:
This research was a multicentre cohort study, including five reproductive medicine centres in Sweden: Carl von Linné Clinic (A), Karolinska University Hospital (B), Uppsala University Hospital (C), Linköping University Hospital (D) and Örebro University Hospital (E). The women underwent IVF/ICSI between January 1999 and November 2015. Single embryo transfer (SET) was performed in approximately 70% of all treatments, without any significant difference between UO exposed women versus controls (68% versus 71%), respectively (P = 0.32), and a maximum of two embryos were transferred in the remaining cases. The dataset included all consecutive treatments and fresh and frozen-thawed cycles.
PARTICIPANTS/MATERIALS, SETTING, METHODS:
The exposed cohort included 154 women with UO who underwent 301 IVF/ICSI cycles and the unexposed control cohort consisted of 22 693 women who underwent 41 545 IVF/ICSI cycles. Overall, at the five centres (A-E), the exposed cohort underwent 151, 34, 35, 41 and 40 treatments, respectively, and they were compared with controls of the same centre (18 484, 8371, 5575, 4670 and 4445, respectively). The primary outcome was LBR, which was analysed per started cycle, per ovum pick-up (OPU) and per embryo transfer (ET). Secondary outcomes included the numbers of oocytes retrieved and supernumerary embryos obtained, the Ovarian Sensitivity Index (OSI), embryo quality scores and cumulative pregnancy rates. We used a Generalized Estimating Equation (GEE) model for statistical analysis in order to account for repeated treatments.
MAIN RESULTS AND THE ROLE OF CHANCE:
The exposed (UO) and control women’s groups were comparable with regard to age and performance of IVF or ICSI. Significant differences in LBR, both crude and age-adjusted, were observed between the UO and control groups: LBR per started cycle (18.6% versus 25.4%, P = 0.007 and P = 0.014, respectively), LBR/OPU (20.3% versus 27.1%, P = 0.012 and P = 0.015, respectively) and LBR/ET (23.0% versus 29.7%, P = 0.022 and P = 0.025, respectively). The differences in LBR remained significant after inclusion of both fresh and frozen-thawed transfers (both crude and age-adjusted data): LBR/OPU (26.1% versus 34.4%, P = 0.005 and P = 0.006, respectively) and LBR/ET (28.3% versus 37.1%, P = 0.006 and P = 0.006, respectively). The crude cancellation rate was significantly higher among women with a history of UO than in controls (18.9% versus 14.5%, P = 0.034 and age-adjusted, P = 0.178). In a multivariate GEE model, the cumulative odds ratios for LBR (fresh and frozen-thawed)/OPU (OR 0.70, 95% CI 0.52-0.94, P = 0.016) and LBR (fresh and frozen-thawed)/ET (OR 0.68, 95% CI 0.51-0.92, P = 0.012) were approximately 30% lower in the group of women with UO when adjusted for age, BMI, reproductive centre, calendar period and number of embryos transferred when appropriate. The OSI was significantly lower in women with a history of UO than in controls (3.6 versus 6.0) and the difference was significant for both crude and age-adjusted data (P = <0.001 for both). Significantly fewer oocytes were retrieved in treatments of women with UO than in controls (7.2 versus 9.9, P = <0.001, respectively).
LIMITATIONS, REASONS FOR CAUTION:
Due to the nature of the topic, this is a retrospective analysis, with all its inherent limitations. Furthermore, the cause for UO was not possible to obtain in all cases. A diagnosis of endometriosis was also more common in the UO group, i.e. a selection bias in terms of poorer patient characteristics in the UO group cannot be completely ruled out. However, adjustment for all known confounders did not affect the general results.
WIDER IMPLICATIONS OF THE FINDINGS:
To date, this is the largest cohort investigated and the first study indicating an association of achieving reduced live birth after IVF/ICSI in women with previous UO. These findings are novel and contradict the earlier notion that IVF/ICSI treatment is not affected, or is only marginally affected by previous UO.
Int J Epidemiol. 2017 Dec 2.
Racial/ethnic differences in the epidemiology of ovarian cancer: a pooled analysis of 12 case-control studies.
Peres LC1, Risch H2, Terry KL3,4, Webb PM5, Goodman MT6,7, Wu AH8, Alberg AJ9, Bandera EV10, Barnholtz-Sloan J11, Bondy ML12, Cote ML13, Funkhouser E14, Moorman PG15, Peters ES16, Schwartz AG13, Terry PD17, Manichaikul A1,18, Abbott SE1, Camacho F1, Jordan SJ5, Nagle CM5; Australian Ovarian Cancer Study Group, Rossing MA19,20, Doherty JA21, Modugno F22,23,24, Moysich K25, Ness R26, Berchuck A27, Cook L28, Le N29, Brooks-Wilson A30,31, Sieh W32, Whittemore A33, McGuire V33, Rothstein J32, Anton-Culver H34,35, Ziogas A34, Pearce CL8,36, Tseng C8, Pike M8,37, Schildkraut JM; African American Cancer Epidemiology Study and the Ovarian Cancer Association Consortium.
Ovarian cancer incidence differs substantially by race/ethnicity, but the reasons for this are not well understood. Data were pooled from the African American Cancer Epidemiology Study (AACES) and 11 case-control studies in the Ovarian Cancer Association Consortium (OCAC) to examine racial/ethnic differences in epidemiological characteristics with suspected involvement in epithelial ovarian cancer (EOC) aetiology.
We used multivariable logistic regression to estimate associations for 17 reproductive, hormonal and lifestyle characteristics and EOC risk by race/ethnicity among 10 924 women with invasive EOC (8918 Non-Hispanic Whites, 433 Hispanics, 911 Blacks, 662 Asian/Pacific Islanders) and 16 150 controls (13 619 Non-Hispanic Whites, 533 Hispanics, 1233 Blacks, 765 Asian/Pacific Islanders). Likelihood ratio tests were used to evaluate heterogeneity in the risk factor associations by race/ethnicity.
We observed statistically significant racial/ethnic heterogeneity for hysterectomy and EOC risk (P = 0.008), where the largest odds ratio (OR) was observed in Black women [OR = 1.64, 95% confidence interval (CI) = 1.34-2.02] compared with other racial/ethnic groups. Although not statistically significant, the associations for parity, first-degree family history of ovarian or breast cancer, and endometriosis varied by race/ethnicity. Asian/Pacific Islanders had the greatest magnitude of association for parity (≥3 births: OR = 0.38, 95% CI = 0.28-0.54), and Black women had the largest ORs for family history (OR = 1.77, 95% CI = 1.42-2.21) and endometriosis (OR = 2.42, 95% CI = 1.65-3.55).
Although racial/ethnic heterogeneity was observed for hysterectomy, our findings support the validity of EOC risk factors across all racial/ethnic groups, and further suggest that any racial/ethnic population with a higher prevalence of a modifiable risk factor should be targeted to disseminate information about prevention.
Arch Gynecol Obstet. 2018 Feb;297(2):521-528.
Effect of laser-assisted zona thinning, during assisted reproduction, on pregnancy outcome in women with endometriosis: randomized controlled trial.
To compare the ICSI-ET outcomes in patients with endometriosis with or without laser-assisted zona pellucida thinning.
Randomized controlled trial.
The study was conducted in the Obstetrics & Gynecology Department, Cairo University hospital, and two private IVF centers in Cairo & Beni-Suif from July 2015 to January 2017 upon infertile and known endometriosis patients who planned to do ICSI-ET.
Before randomization, all patients received the same ovarian stimulation preparation, oocyte retrieval procedures, and the same intracytoplasmic sperm injection procedures. After randomization, laser-assisted hatching was performed only for embryos of 158 patients, while the other group (n = 150) no laser-assisted hatching was made. The verification of pregnancy was achieved by the serum hCG concentration 14 days after the embryo transfer, and the clinical pregnancy was confirmed 2 weeks later by the presence of gestational sac with pulsating fetal pole on vaginal ultrasonography.
The main outcome measures were the clinical pregnancy rate and the clinical implantation rate.
Both groups were comparable with regard their baseline characteristics, baseline hormonal profile, the ovarian stimulation characteristics, and the ovulation characteristics. The mean number of embryos developed per patient and the mean transferred number of embryos per patient were comparable between groups (p value > 0.05). The implantation rate was significantly higher (p value 0.002) in the study group than the control group with an odds ratio of 1.86 (CI 95% 1.24-2.80) and NNT 13.81 (CI 95% 8.35-39.94). The clinical pregnancy rate, was significantly (p value 0.022) higher in the study group than in the control group with an odds ratio of 1.79 (CI 95% 1.05-3.06) and NNT 9.57 (CI 95% 5.03-98.99).
That laser-assisted hatching by thinning of the zona pellucida may be a suitable method to improve the ICSI-ET outcomes, in term of the implantation and the pregnancy rates, in cases of endometriosis.
Obstet Gynecol. 2018 Jan;131(1):150-157..
Opioid Knowledge and Prescribing Practices Among Obstetrician-Gynecologists.
To describe obstetrician-gynecologists’ (ob-gyns) knowledge and prescribing practices regarding opioid analgesics.
We conducted a cross-sectional survey of a national sample of American College of Obstetricians and Gynecologists Fellows and Junior Fellows who are part of the Collaborative Ambulatory Research Network. We used a sequential mixed-method approach. We collected data on opioid knowledge and typical prescribing practices, including number, type, and indication for prescriptions. We determined adherence to four recommended practices: 1) screening for dependence, 2) prescribing the smallest amount required, 3) tailoring prescriptions, and 4) counseling on proper disposal. We also explored variables associated with prescribing practices.
Sixty percent (179/300) of sampled members responded. Respondents reported prescribing a median of 26 (5-80) pills per patient across all indications combined. Ninety-eight percent prescribed opioids after surgery and a smaller proportion for nonsurgical indications: vaginal birth (22%), ovarian cysts (30%), endometriosis (24%), and chronic pelvic pain of unknown cause (18%). The number prescribed varied only by indication for the prescription. Nineteen percent reported adherence to three or more (of four) recommended practices. There was no significant difference in the median number of pills prescribed between those who reported adherence to at least one compared with those who did not adhere to any recommended practices (25 [interquartile range 25-30] vs 28 [interquartile range 20-30], P=.58). Regarding knowledge, 81% incorrectly identified the main source of misused opioids, which is through diversion from a friend or family member, and 44% did not know how to properly dispose of unused prescription opioids.
Obstetrician-gynecologists reported prescribing a median of 26 opioid pills across all indications combined. Amount prescribed varied widely by indication but not by reported adherence to recommended prescribing practices. This study highlights an urgent need for increased efforts to improve ob-gyns’ knowledge of opioid use, misuse, disposal, and best prescribing practices.
Patol Fiziol Eksp Ter. 2017 Apr-Jun;61(2):56-60.
Histamine metabolism disorder in pathogenesis of chronic pelvic pain in patients with external genital endometriosis.
To study features of histamine metabolism in patients with chronic pelvic pain associated with external genital endometriosis.
For quantitative assessment of histamine level in peripheral blood was taken from 100 patients which than was centrifuged. In blood serum histamine concentration was determined by enzyme-linked immunosorbent assay method with reagents «Histamine ЕLISA» on the machine BAE-1000 Histamine (Labor Diagnostika Nord – LDN, Hermany). A pain syndrome was assessed by Visual Analog Scale (VAS), quality of life assessment – by Endometriosis Health Profile Questionnaire (EHR-30), level of anxiety was determined by Spielberger-Khanin questionnaire.
Showed statistically higher histamine level in patients with severe pain according to VAS. After assessment of results obtained from Spielberger-Khanin questionnaire 100% experimental group’s women with external genital endometriosis (n = 60) were noted to be have high level of state and trait anxiety, then 40% women of control group (n = 16) have moderate level of anxiety. The incidence of depression in women with chronic pelvic pain was 58.3% (n = 35) and the main part (n = 20) were women with severe stage of pelvic pain according to VAS.
Psycho emotional condition of women with external genital endometriosis associated pelvic pain characterized by higher depression and anxiety levels, with significant decrease quality of life. Direct relationship also was found between pain syndrome intensity and histamine level in peripheral blood in patients with external genital endometriosis.
Environ Res. 2018 Feb;161:439-445.
Phthalate esters on urban airborne particles: Levels in PM10 and PM2.5 from Mexico City and theoretical assessment of lung exposure.
Endocrine disrupting chemicals (EDCs) from the environment are associated with reproductive abnormalities (i.e. decreased sperm concentration; increased endometriosis) and alterations of the cardiovascular system (i.e. increased blood pressure and risk of coronary disease). Some phthalates esters have been identified as EDCs, for which inhalation is considered as one of the routes of exposure. However, only little is known regarding inhalational exposure to EDCs via urban airborne particles. In the present study, we report the monthly concentration of 8 phthalate esters measured in PM10 and PM2.5collected and recovered during 7 months in a highly populated area of Mexico City. Using the levels of PM10 and PM2.5 reported by the automatized network of environmental monitoring of Mexico City for the sampling site, we estimated exposure levels for people of different ages and gender. Two endocrine disrupting compounds, the phthalate esters DEHP and DnBP, were found on the particles in higher concentrations during the warmer months of the year. The highest concentration was reported for DEHP (229.7μg/g of particles) in PM2.5 collected in May 2013. After calculations of the DEHP concentration in the atmosphere, and using the respiratory flow rate, we determined males were potentially exposed to larger quantities of DEHP, reaching up to 18ng/8h in April 2013. Despite the concentrations of phthalates seem to be rather small, a comprehensive characterization of its presence is necessary in order to evaluate the overall exposure to these compounds, providing a clear view of exposure on children, adolescents and pregnant women.
Eur J Obstet Gynecol Reprod Biol. 2017 Dec 4;221:1-4.
p27kip1 as a key regulator of endometriosis.
p27kip1 as a key regulator of endometriosis Gonçalves GA p27kip1 is a cyclin-dependent kinase (CDK) inhibitor whose specific late G1 destruction allows progression of the cell across the G1/S boundary. There is a direct relationship between low level of p27 and rapid proliferation occurring in several benign states and in many malignances. In the glandular cells of the normal endometrium, the level of p27kip1 is exceedingly low during the proliferative phase, whereas it is markedly increased during the secretory phase. The expression of p27kip1 in endometriosis is very low but has been found to increase following treatment with progesterone. However, estrogen exposure is considered as a major risk factor in developing endometrial cancer. Endometriosis endometrial cells cultures have also lower levels of p27kip1compared to heath endometrial cells cultures and restore the cell cycle balance when transduced with an adenoviral vector carring the p27kip1 coding gene (Adp27EGFP). More uniform and rigorous studies are required to confirm these and additional markers utility in a diagnostic and possible treatment panel. As a major clinical priority is to determine which lesions can be treated medically and which require surgical intervention, focusing future studies on markers that distinguish response to hormone therapy or are involved in hormone regulation, will be important future considerations. The goal of this highlight review is to provide a broad overview of the advancements in studies about endometriosis mainly correlating the cytokine p27kip1 expression with the diagnostic and disease treatment.
Am J Transl Res. 2017 Nov 15;9(11):4707-4725.
Autophagy in endometriosis.
Endometriosis (EMS) is a common gynecologic disease that causes chronic pelvic pain, dysmenorrhea, and infertility in women. The doctrine of menstruation back flow planting and defects in the immune system are well known and widely accepted. In recent years, increasing studies have been focused on the role of autophagy in EMS, and have shown that autophagy plays a vital role in EMS. Autophagy, which is known as the non-apoptotic form of programmed cell death induced by a large number of intracellular/extracellular stimuli, is the major cellular pathway for the degradation of long-lived proteins and cytoplasmic organelles in eukaryotic cells. Autophagy commonly refers to macroautophagy, which is characterized by autophagosomes (double-membrane vesicles). In normal endometrial tissues, autophagy is induced in glandular epithelial and stromal cells throughout the menstrual cycle. However, aberrant autophagy occurs in the eutopic endometrium and ectopic endometriotic foci, which contributes to the pathogenesis of EMS by promoting the hyperplasia of endometriotic tissues and stromal cells, restricting apoptosis, and inducing abnormal immune responses. Consistent with changes in autophagy levels between normal endometria, eutopic and ectopic endometria from patients with EMS, the altered expression of autophagy-related genes (ATGs) is also observed. Currently, many factors are involved in the aberrant autophagy of endometriotic tissues, including female hormones, certain drugs, hypoxia, and oxidative stress. Therefore, studies focusing on autophagy may uncover a new potential treatment for EMS. The aim of this review is to discuss the role of aberrant autophagy in EMS and to explore the potential value of autophagy as a target for EMS therapy.
J Surg Case Rep. 2017 Nov 29;2017(11):rjx238.
Primary low-grade endometrial stromal sarcoma arising in the vagina: report of an unusual case and literature review.
Endometrial stromal sarcoma rarely occurs as an extrauterine neoplasm and it is even more unlikely to be found in the vagina. To the best of our knowledge, only six cases of primary vaginal endometrial stromal sarcoma without association with endometriosis have been published to this day. We describe a case of a 58-year-old female with a history of vaginal heaviness caused by a mass lesion. After a biopsy was taken, the histopathological findings and immunohistochemical stains were consistent with low-grade endometrial stromal sarcoma. The patient underwent total hysterectomy and bilateral salpingo-oophorectomy with lymph node dissection followed by hormonal therapy. This line of management was heavily based on the treatment guidelines for endometrial stromal sarcoma.
Arch Gynecol Obstet. 2018 Feb;297(2):409-414.
Bipolar vessel-sealing devices in laparoscopic hysterectomies: a multicenter randomized controlled clinical trial.
To compare operating time and blood loss in patients undergoing total laparoscopic hysterectomies (TLH) for benign conditions with either the Marseal™ IQ 5 mm (MS) or the Ligasure™ 5 mm (LS) vessel-sealing device.
DESIGN AND SETTING:
A randomized controlled clinical trial (RCT) in two German gynecology departments.
74 patients scheduled to undergo TLH for a symptomatic fibroid uterus, adenomyosis or severe meno-metrorrhagia.
Patients were randomized to receive a TLH with either the MS or the LS device. 27 variables were prospectively collected to address potential confounding issues.
MEASUREMENT AND MAIN RESULTS:
Operating time, defined as the time period between the first (round ligament dissection) and the last (uterine vessels sealing) use of the device, estimated and calculated intraoperative blood loss. The mean operating time (95% confidence interval, CI) was 22.7 min (95% CI 17.6-27.7) for LS and 26.4 min (95% CI 20-32.8) for the MS device (p = .89). The estimated intraoperative blood loss was 164 ml (95% CI 110-217) for LS and 160 ml (95% CI 116-203) for the MS device (p = .36). The multivariate analyses accounting for BMI, endometriosis, uterine weight and appearance of fibroids did not reveal any significant effect of the type of device used on operating time and estimated blood loss.
In this RCT, both devices provided reliable and effective sealing and dissection. The reusable MS showed non-inferiority against the disposable LS device with regard to operating time and estimated intraoperative blood loss.
Acta Obstet Gynecol Scand. 2017 Dec 8.
Outcome of sonography-based minimally invasive surgery for deep infiltrating endometriosis of the ureter and urinary bladder – a retrospective cohort study.
To evaluate the accuracy of transvaginal sonography for preoperative detection of bladder endometriosis and surgical outcomes regarding fertility and pain symptoms of women with urinary tract endometriosis.
MATERIAL AND METHODS:
Retrospective cohort study of consecutive patients with urinary tract endometriosis undergoing laparoscopic partial cystectomy and/or ureterolysis/decompression, ureteric resection and end-to-end anastomosis or ureteroneocystostomy for ureteral stenosis and hydronephrosis.
Of 207 patients with deep infiltrating endometriosis, 50 exhibited urinary tract endometriosis, comprising 30 patients with bladder endometriosis and 23 women with solitary or additional hydronephrosis. Sensitivity, specificity, positive and negative predictive value, positive/negative likelihood ratios and test accuracy for transvaginal sonography detecting bladder endometriosis were 93%, 99%, 97%, 99%, 155.5, 0.07 and 98.6% respectively. All women with bladder endometriosis underwent partial cystectomy. In cases of hydronephrosis, 14 conservative ureterolysis/decompressions, six ureteral resection anastomoses and three ureteroneocystostomies were performed. Duration of surgery was 205 min (range 89-365 min), average blood loss was 1.6 g/dL (range 0.3-4.6 g/dL) and hospital stay on average 8 days (range 2-16 days). The conversion rate was 4%. We observed five grade III complications. After a median follow up of 23 months, there was a decrease in dysmenorrhea (7.6-1.6; p < 0.001), dyspareunia (3.0-0.9, p < 0.001) and dysuria (3.3-0.2; p < 0.003), and an increase in quality of life (3.3-8.1; p < 0.001). The overall clinical pregnancy rate was 46% and life birth rate 18%.
Laparoscopic surgery for urinary tract endometriosis is effective for treatment of hydronephrosis, reduction of pain symptoms and may improve fertility. Transvaginal sonography is highly accurate for presurgical detection of bladder involvement.
Eur J Obstet Gynecol Reprod Biol. 2017 Dec 5. pii: S0301-2115(17)30538-9.
Familial deep endometriosis: A rare monogenic disease?
Endometriosis is a frequent cause of pelvic pain and subfertility in women of reproductive age. Presence of extra-uterine endometrial-like tissue is responsible for non-specific symptoms such as chronic pelvic pain, dysmenorrhea, dyspareunia, dyschesia and sometimes infertility. Three different phenotypes according to the location of the lesions are described, namely peritoneal, ovarian and deep infiltrating endometriosis. Deep endometriosis is considered as a distinct homogeneous disease. Heritability of endometriosis has been previously demonstrated. Despite extensive efforts to characterize candidate alleles contributing to genetic basis of endometriosis, these factors relevant to endometriosis pathophysiology remain unclear. No high penetrance pathogenic variant could be identified. We report herein two families with familial aggregation of severe deep infiltrating endometriosis, providing further evidence for monogenic mendelian inheritance of this form of endometriosis.
J Immunol Res. 2017;2017:3175394.
Fas-Related Apoptosis of Peritoneal Fluid Macrophages in EndometriosisPatients: Understanding the Disease.
Recent studies of the peritoneal cavity environment in endometriosis demonstrate quantitative and qualitative changes in the cells responsible for cell-mediated immunity. Such changes may have led to disturbances in the surveillance, recognition, and destruction of misplaced endometrial cells and might have, in fact, brought about the disease. The aim of the study was to assess CD95 (Fas) expression on (activated) peritoneal fluid (PF) macrophages, as well as to ascertain soluble Fas (sFas) concentration in the PF of endometriosis patients, as compared to the nonendometriotic group. The concentration of leukocytes in the PF, the percentage of cells expressing CD45+/CD14+, and the percentage of PF macrophages expressing the HLA-DR antigen were significantly higher in patients with stages I and II endometriosis. The percentage of Fas- (CD95+-) expressing macrophages was significantly higher in all stages of the disease, in comparison with controls. Moreover, the concentration of sFas in the PF of patients with moderate and severe endometriosis was significantly higher, as compared to the reference group. The high number of immune cells in PF in early stage endometriosis and their increased susceptibility to apoptosis confirm the role of the impaired peritoneal environment and immune defects in the development and progression of the disease.
Cancer Biomark. 2017 Nov 30.
The clinical significance of the combined detection of serum Smac, HE4 and CA125 in endometriosis-associated ovarian cancer.
This study aims to investigate the clinical significance of serum Smac, HE4 and CA125 alone or combined for detecting endometriosis-associated ovarian cancer (EAOC).
The level of serum Smac, HE4 and CA125 in 40 healthy controls, 40 cases of benign endometriosis ovarian tumor, and 60 cases of EAOC were detected by ELISA and electrochemical immune method.
Serum Smac expression level was significantly lower in the EAOC group than in the control group and benign ovarian tumor group (P< 0.05), while HE4 and CA125 expression levels were significantly higher in the EAOC group than the other two groups. The sensitivity of Smac single detection was up to 91.67%, and the specificity of HE4 was up to 98.75%. Furthermore, the sensitivity of Smac + HE4 + CA125 combined was the highest, which reached up to 98.33%; but the specificity was low, which reached up to 75%. The serum expression level differences before and after surgery were statistically significant. As the number of chemotherapies increases, the Smac level increased, and HE4 and CA125 levels gradually decreased. Furthermore, Smac increased to normal at the end of the 2nd period of chemotherapy, while HE4 and CA125 decreased to normal in 2nd and 3rd period of chemotherapy, respectively.
Serum Smac, HE4 and CA125 may play an important role in predicting EAOC and in monitoring the prognosis of postoperative EAOC.
Georgian Med News. 2017 Nov;(272):33-37.
PERSPECTIVE MANAGEMENT IN THE TREATMENT OF GENITAL ENDOMETRIOSIS IN WOMEN WITH POLYMORPHISM OF GENS GSTT1 AND GSTM1.
The article covers the management of patients with internal genital endometriosis, in which the polymorphism of the glutathione-S-transferase genes has been diagnosed. The aim of our study was to select the optimal conservative method for treatment of internal genital endometriosis in women of reproductive age by developing complex therapy taking into account the polymorphism of the genes of the detoxification system. 102 patients with combined gynecological pathology were examined. All patients were subject to a dynamic clinical and laboratory examination. According to the presence of GSTT1 genes deletion, GSTM1 has established research groups and treatment. Analyzing the performed research, it was discovered that the clinical efficacy of complex treatment depended on the genotypes of patients. The presence of pathologically burdened alleles of genes GSTM1 and GSTT1 somewhat reduced the response to standard treatment in the second group of patients. However, when comparing the levels achieved in the group I of patients, it was determined that in general, the clinical effect of our proposed therapy was more pronounced than in the II and III clinical groups. Clinical research has proved the effectiveness of hormone therapy combined with immunomodulatory and target drug in the form of reducing recurrence and restoring fertility.
Hum Reprod. 2018 Feb 1;33(2):202-211.
Medical treatment or surgery for colorectal endometriosis? Results of a shared decision-making approach.
What is the degree of patient satisfaction in women with symptomatic colorectal endometriosis who choose medical or surgical treatment after a shared decision-making (SDM) process?
The degree of satisfaction with treatment was high both in women who chose medical treatment with a low-dose oral contraceptive (OCP) or a progestin, and in those who chose to undergo surgical resection of bowel endometriosis.
WHAT IS KNOWN ALREADY:
Hormonal therapies and surgery for colorectal endometriosis have been investigated in non-comparative studies with inconsistent results.
STUDY DESIGN, SIZE, DURATION:
Parallel cohort study conducted on 87 women referring to our centre with an indication to surgery for colorectal endometriosis. A standardised SDM process was adopted, allowing women to choose their preferred treatment. Median follow-up was 40 [18-60] months in the medical therapy group and 45 [30-67] in the surgery group.
PARTICIPANTS/MATERIALS, SETTING, METHODS:
Patients with endometriosis infiltrating the proximal rectum, the rectosigmoid junction, and the sigmoid, not causing severe sub-occlusive symptoms were enroled. A total of 50 patients chose treatment with an OCP (n = 12) or a progestin (n = 38), whereas 37 women confirmed their previous indication to surgery. Patient satisfaction was graded according to a 5-category scale. Variations in bowel and pain symptoms were measured by means of a 0-10 numeric rating scale. Constipation was assessed with the Knowles-Eccersley-Scott Symptom Questionnaire (KESS), health-related quality of life with the Short Form-12 questionnaire (SF-12), psychological status with the Hospital Anxiety and Depression scale (HADS) and sexual functioning with the Female Sexual Function Index (FSFI).
MAIN RESULTS AND THE ROLE OF CHANCE:
Six women in the medical therapy group requested surgery because of drug inefficacy (n = 3) or intolerance (n = 3). Seven major complications were observed in the surgery group (19%). At 12-month follow-up, 39 (78%) women in the medical therapy group were satisfied with their treatment, compared with 28 (76%) in the surgery group (adjusted odds ratio (OR), 1.37; 95% confidence interval (CI), 0.45-4.15; intention-to-treat analysis). Corresponding figures at final follow-up assessment were 72% in the former group and 65% in the latter one (adjusted OR, 1.74; 95% CI, 0.62-4.85). The 60-month cumulative proportion of dissatisfaction-free participants was 71% in the medical therapy group compared with 61% in the surgery group (P = 0.61); the Hazard incidence rate ratio was 1.21 (95% CI, 0.57-2.62). Intestinal complaints were ameliorated by both treatments. Significant between-group differences in favour of medical treatment were observed at 12-month follow-up in diarrhoea, dysmenorrhoea, non-menstrual pelvic pain and SF-12 physical component scores. The total HADS score improved significantly in both groups, whereas the total FSFI score improved only in women who chose medical therapy.
LIMITATIONS REASONS FOR CAUTION:
As treatments were not randomly assigned, selection bias and confounding are likely. The small sample size exposes to the risk of type II errors.
WIDER IMPLICATIONS OF THE FINDINGS:
When adequately informed and empowered through a SDM process, most patients with non-occlusive colorectal endometriosis who had already received a surgical indication, preferred medical therapy. The possibility of choosing the preferred treatment may allow maximisation of the potential effect of the interventions.
STUDY FUNDING/COMPETING INTEREST(S):
This study was financed by Italian fiscal contribution ‘5 × 1000′-Ministero dell’Istruzione, dell’Università e della Ricerca-devolved to Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy. P.V., M.P.F., R.R., D.D., A.R., P.M., O.D.G. and M.C. declare that they have no conflicts of interest. E.S. received grants from Ferring and Serono.
Respir Med. 2017 Nov;132:112-116.
Asthma is associated with endometriosis: A retrospective population-based cohort study.
Evidence regarding the association between asthma and endometriosis is limited and inconsistent. The goal of the study was to investigate whether women diagnosed as having asthma were at a greater risk of endometriosis than age-matched unaffected women.
We conducted a nationwide population-based retrospective study by using data retrieved from the Taiwan National Health Insurance Research Database during the period of 2000-2005 with follow-up through 2013. The current analysis included 7337 women aged 12-50 years with newly diagnosed asthma and using asthma-related medications and 29,348 age-matched women without asthma. A Cox proportional hazards regression model was used to estimate the risks of endometriosis in women with asthma as compared with those without asthma.
The overall risk of endometriosis in the asthma group was 1.50-fold higher (95% confidence interval = 1.33-1.70) than that in the nonasthma group. A stratified analysis by age further revealed that patients with asthma were associated with a higher risk of endometriosis in age groups of 21-50 years.
Compared with women without asthma, women with asthma of reproductive age are at a higher risk of endometriosis. Additional studies are warranted to elucidate the mechanism(s) underlying the association between asthma and a higher risk of endometriosis.
J Steroid Biochem Mol Biol. 2017 Dec 9.
Expression and shedding of CD44 in the endometrium of women with endometriosis and modulating effects of vitamin D: A randomized exploratory trial.
Endometriosis is an estrogen-dependent disease. The impaired estrogen and progesterone signaling over-activates the Wnt/β-catenin pathway in endometriosis patients, which can explain the increased invasion potency of endometrial cells derived from the endometrium of women with endometriosis. The regulatory effects of vitamin D on Wnt/β-catenin pathway were demonstrated by previous studies. According to gene prioritization method, among Wnt target genes, CD44 was in high ranking in relation to endometriosis. The aim of this study is to investigate the expression of CD44 in the endometrium of women with endometriosisand to study the effects of vitamin D on its expression. This prospective study was performed, during a 12 months period from December 2015 to November 2016, on healthy women as the control group (n = 14) and endometriosis patients (n = 34). The endometriosis patients randomly divided into two groups: One group treated according to the routine protocol and the other group, alongside the routine protocol, took 50,000 IU vitamin D weekly for 12-14 weeks. Blood, endometrial fluid, and endometrial tissue samples were obtained from the control group and endometriosis groups before and after the intervention. We used in silico gene prioritization to study the relevance of CD44. The expression of CD44 was evaluated using the techniques of Western blot, real-time polymerase chain reaction, and ELISA. The eutopic endometrium of women with endometriosis in mid-secretory phase expressed significantly higher levels of CD44s, CD44V, and CD44v6. The concentration of soluble CD44 in the serum and endometrial fluid of endometriosispatients was higher than of healthy women. The expression level of CD44s, CD44V, and CD44v6 in the eutopic endometrium as well as the concentration of soluble CD44 in the endometrial fluid was decreased after modification of the circulating levels of 25(OH)D. It seems that the increased expression and extensive shedding of CD44 in eutopic endometrium play a role in the pathogenesis of endometriosis. Vitamin D can control and modify this process at least in part. We suggest more in vivo investigations on the therapeutic potency of vitamin D in endometriosis.
Stem Cells Int. 2017;2017:3215962.
Mesenchymal Stromal Cells Are More Immunosuppressive In Vitro If They Are Derived from Endometriotic Lesions than from Eutopic Endometrium.
Endometriosis is an inflammatory disease with predominance of immunosuppressive M2 macrophages in the pelvic cavity that could be involved in the pathology through support and immune escape of ectopic lesions. Mesenchymal stromal cells (MSC) are found in ectopic lesions, and MSC from nonendometriosis sources are known to induce M2 macrophages. Therefore, MSC were hypothesized to play a role in the pathology of endometriosis. The aim was to characterize the functional phenotype of MSC in ectopic and eutopic endometrium from women with endometriosis. Stromal cells from endometriotic ovarian cysts (ESCcyst) and endometrium (ESCendo) were examined if they exhibited a MSC phenotype. Then, ESC were phenotypically examined for protein and gene expression of immunosuppressive and immunostimulatory molecules. Finally, ESC were functionally examined for their effects on monocyte differentiation into macrophages. ESCcyst and ESCendo expressed MSC markers, formed colonies, and differentiated into osteoblasts and adipocytes. Phenotypically, ESCcyst were more immunosuppressive, with significantly higher expression of immunosuppressive molecules. Functionally, ESCcyst induced more spindle-shaped macrophages, with significantly higher expression of CD14 and CD163, both features of M2 macrophages. The results suggest that ESCcyst may be more immunosuppressive than ESCendo and may promote immunosuppressive M2 macrophages that may support growth and reduce immunosurveillance of ectopic lesions.
J Med Case Rep. 2017 Dec 13;11(1):346.
Deep infiltrating ureteral endometriosis with catamenial hydroureteronephrosis: a case report.
This aim of this case report is to raise awareness of ureteral endometriosis in women of reproductive age with hydronephrosis in the absence of urolithiasis to enable early diagnosis and prevent loss of renal function.
A 44-year-old Asian woman presented with a 4-year history of cyclic right flank pain and right hydronephrosis during menstruation. Despite several evaluations by physicians, including gynecologists, the cause of her symptoms was not diagnosed. On transvaginal ultrasonography, the uterus was observed deviated to the right, with a nodular lesion at the right uterosacral ligament, and the right ovary was attached to the uterus with no apparent cystic lesion. Magnetic resonance imaging showed a mass in the right uterine wall and mild wall thickening with delayed enhancement of the right distal ureter. Right ureteral endometriosis was suspected. Diagnostic laparoscopy revealed narrowing of the distal right ureter between the right uterosacral ligament and the right ovary with adhesions caused by deep infiltrating endometriosis. The adhesion bands and infiltrating endometriosis around the right ureter were dissected.
The nonspecific symptoms of ureteral endometriosis can result in incorrect diagnosis, with renal damage as a result of prolonged hydronephrosis. A high index of suspicion and use of imaging modalities enable earlier diagnosis and preservation of renal function.
Reprod Biomed Online. 2018 Feb;36(2):181-187.
Decreased expression of FOXA2 promotes eutopic endometrial cell proliferation and migration in patients with endometriosis.
Endometriosis is characterized by eutopic endometrial cell ‘metastasis’ to ectopic foci. FOXA2 is a member of the forkhead transcription factor family, which may participate in transcriptional regulation in endometrial cells and contribute to the aetiology of endometriosis. This study investigated the roles played by FOXA2 in eutopic endometrium using endometriosis samples. Western blotting showed that the relative expression of FOXA2 was significantly reduced in eutopic endometrium from patients with endometriosis (n = 14) compared with endometriosis-free controls (n = 16) (0.69 ± 0.07 versus 1.24 ± 0.06, P < 0.05). To mimic eutopic endometrium of endometriosis, primary eutopic endometrial stromal cells (ESC) of controls were harvested and transfected with FOXA2 siRNA. MTT assay showed that cell viability of ESC with transfected FOXA2 siRNA increased significantly, whereas the apoptosis rate decreased as indicated by flow cytometry experiments (both P < 0.05). Wound healing assays revealed that transfection of FOXA2 siRNA promoted ESC migration. Moreover, real-time PCR analysis showed progesterone-induced FOXA2 expression in ESC under physiological conditions. In conclusion, these findings indicate that FOXA2 might be a progesterone-induced gene, which may participate in the ‘metastatic’ process of eutopic endometrium to ectopic loci in patients with endometriosis.
Gynecol Oncol. 2017 Dec 9. pii: S0090-8258(17)31552-4.
Genomic landscape of ovarian clear cell carcinoma via whole exome sequencing.
To analyze whole exome sequencing (WES) data on ovarian clear cell carcinoma (OCCC) in Korean patients via the technique of next generation sequencing (NGS). Genomic profiles were compared between endometriosis-associated OCCC (EMS-OCCC) and Non-EMS-OCCC.
We used serum samples and cancer tissues, stored at the Seoul National University Hospital Human Biobank, that were initially collected from women diagnosed with OCCC between 2012 and 2016. In total, 15 patients were enrolled: 5 with pathologically confirmed EMS-OCCC and 10 with Non-EMS-OCCC. We performed NGS WES on 15 fresh frozen OCCC tissues and matched serum samples, enabling comprehensive genomic characterization of OCCC.
OCCC was characterized by complex genomic alterations, with a median of 178 exonic mutations (range, 111-25,798) and a median of 343 somatic copy number variations (range, 43-1,820) per tumor sample. In all, 54 somatic mutations were discovered across 14 genes, including PIK3CA (40%), ARID1A (40%), and KRAS (20%) in the 15 Korean OCCCs. Copy number gains in NTRK1 (33%), MYC (40%), and GNAS (47%) and copy number losses in TET2 (73%), TSC1 (67%), BRCA2 (60%), and SMAD4 (47%) were frequent. The significantly altered pathways were associated with proliferation and survival (including the PI3K/AKT, TP53, and ERBB2 pathways) in 87% of OCCCs and with chromatin remodeling in 47% of OCCCs. No significant differences in frequencies of genetic alterations were detected between EMS-OCCC and Non-EMS-OCCC groups.
We successfully characterized the genomic landscape of 15 Korean patients with OCCC. We identified potential therapeutic targets for the treatment of this malignancy.
Gynecol Oncol Rep. 2017 Oct 31;22:105-107..
Polypoid endometriosis mimicking invasive cancer in an obese, postmenopausal tamoxifen user.
Tamoxifen is a medication often used for the treatment and prevention of breast cancer. It is classically associated with several gynecological side effects to include a thickened endometrial stripe, increased uterine polyp formation, and an increased risk of uterine cancer. Rarely tamoxifen use has been associated with proliferation of endometriosis often severe enough to mimic a late-stage gynecologic malignancy.
A 62-year-old Gravida 0 postmenopausal female with a medical history of severe obesity, infertility, and preventative tamoxifen use presented for evaluation of gross hematuria. A CT urogram was performed and demonstrated findings concerning for carcinomatosis, likely gynecologic in origin. Cervical cancer screening was up-to-date and she had a negative colonoscopy within the prior 2 years. Serum tumor markers were remarkable only for a mildly elevated CA125 of 37.6. Diagnostic laparoscopy demonstrated apparent operable carcinomatosis limited to the pelvis. The procedure was converted to an exploratory laparotomy, where radical tumor cytoreduction was performed to no gross residual disease. Frozen sections performed intraoperatively were unclear of origin but suggestive of low malignant potential. Final pathology resulted for endometriosis.
This case illustrates a presentation of endometriosis in a postmenopausal woman mimicking advanced mullerian malignancy. The patient’s estrogenic state from obesity in combination with the agonist action of the tamoxifen likely contributed to her rare presentation. While findings such as a thickened endometrial stripe are typical of tamoxifen use, such widespread proliferation of endometriosisresulting in a pelvic mass, genito-urinary obstruction, and plaque-like pelvic spread are not.
Endometriosis is a benign estrogen dependent condition rarely problematic in a postmenopausal patient. Tamoxifen use in the setting of an obese patient may contribute to a proliferation of pre-existing endometriosis which resembles an aggressive late-stage gynecological malignancy.
Mol Genet Genomics. 2017 Dec 12.
The impact of HLA-G, LILRB1 and LILRB2 gene polymorphisms on susceptibility to and severity of endometriosis.
Bylińska A1, Wilczyńska K1, Malejczyk J2, Milewski Ł2, Wagner M1, Jasek M1, Niepiekło-Miniewska W1, Wiśniewski A1, Płoski R3, Barcz E4, Roszkowski P5, Kamiński P6, Malinowski A7, Wilczyński JR8, Radwan P9,10, Radwan M9,11, Kuśnierczyk P12, Nowak I13.
Endometriosis is a disease in which endometriotic tissue occurs outside the uterus. Its pathogenesis is still unknown. The most widespread hypothesis claims that ectopic endometrium appears as a result of retrograde menstruation and its insufficient elimination by immunocytes. Some reports have shown expression of non-classical HLA-G molecules on ectopic endometrium. HLA-G is recognized by KIR2DL4, LILRB1 and LILRB2 receptors on natural killer (NK) and other cells. These receptors are polymorphic, which may affect their activity. In this study we investigated whether HLA-G, KIR2DL4, LILRB1 and LILRB2 polymorphisms may influence susceptibility to endometriosis and disease progression. We used polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism (PCR-RFLP) and allelic discrimination methods with TaqMan SNP Genotyping Assays for typing of 276 patients with endometriosisand 314 healthy fertile women. The HLA-G rs1632947:GG genotype was associated with protection against the disease and its severe stages; HLA-G rs1233334:CT protected against progression; LILRB1 rs41308748:AA and LILRB2 rs383369:AG predisposed to the disease and its progression. No effect of KIR2DL4 polymorphism was observed. These results support the role of polymorphisms of HLA-G and its receptors LILRB1 and LILRB2 in susceptibility to endometriosis and its progression.
SAGE Open Med Case Rep. 2017 Dec 5;5:2050313X17745204.
Endometrioid adenocarcinoma arising from colon endometriosis.
Endometriosis-associated intestinal tumors represent the malignant transformation of gastrointestinal endometriosis. Approximately 50 cases have been reported in the literature. They are most commonly found among women aged 30-60 years, whereas exogenous hormone therapy and obesity are primary risk factors for the malignant transformation of endometriotic lesions. Clinical features simulate a primary colonic carcinoma. A high index of suspicion in conjunction with careful histological and immunohistochemical examination (CK7, CK20, CDX2, CD10, ER, and PR) is important for establishing a correct diagnosis. In this article, a rare case of a postmenopausal woman with no risk factors and conflicting clinical presentation, diagnosed with endometriosis-associated intestinal tumor, is described.
Pathology. 2017 Dec 11. pii: S0031-3025(17)30384-7.
Endometriosis-associated ovarian neoplasia.
This article reviews the most relevant pathological and molecular features of ovarian tumours that are associated with endometriosis. Endometriosis is a common condition, affecting 5-15% of all women, and it has been estimated that 0.5-1% of cases are complicated by neoplasia. The most common malignant tumours in this setting are endometrioid adenocarcinoma and clear cell adenocarcinoma, each accounting for approximately 10% of ovarian carcinomas in Western countries. A minority of cases are associated with Lynch syndrome. These carcinomas are often confined to the ovaries at presentation in which case they have relatively favourable outcomes. However, high-stage tumours, particularly clear cell carcinomas, generally have a poor prognosis and this partly reflects relative resistance to current treatment. Histological diagnosis is straightforward in the majority of cases but some variants, for example endometrioid carcinomas with sex cord-like appearances or oxyphil cells, may create diagnostic difficulty. Similarly, clear cell carcinomas can show a range of architectural and cytological patterns that overlap with other tumours, both primary and metastatic, involving the ovaries. Endometriosis-associated borderline tumours are less common, and they often show mixed patterns of differentiation (seromucinous tumours). Atypical endometriosis may represent an intermediate step in neoplastic progression and some of these lesions demonstrate immunohistological and molecular alterations similar to those observed in endometriosis-related tumours. ARID1A mutations are relatively common in all of these tumours, but each has additional characteristic molecular alterations which are likely to be of increasing clinical relevance as targeted therapies are developed. Less is known of the pathogenesis of rarer endometriosis-associated ovarian tumours including endometrioid stromal sarcoma, mesodermal (Müllerian) adenosarcoma, and carcinosarcoma. This article also briefly reviews the issue of synchronous endometrioid carcinomas of the endometrium and the ovary, including the most recent developments on pathogenesis.
J Cell Physiol. 2017 Dec 15.
NOVEL DIETARY SUPPLEMENT ASSOCIATIONREDUCES SYMPTOMS IN ENDOMETRIOSIS PATIENTS.
Endometriosis is characterized by disabling symptoms that afflict young women with severe physical discomfort, difficulty in relationship life, and infertility; however, the currently available therapeutic strategies are unsatisfactory. Goal of this research was to identify a new combination of natural active ingredients that, administered as dietary supplements, could have the effect of reducing inflammatory response in endometriosis patients, decreasing the symptoms the disease produces and its harmful effects on affected organs. A cohort of endometriosis patient was treated for three months with a composition including quercitin, curcumin, parthenium, nicotinamide, 5-methyltetrahydrofolate and omega 3/6. Using a VAS scale, we demonstrated a significant reduction of the symptoms in endometriosis patients treated with the dietary composition respect to the controls. Moreover, we demonstrated also a significant reduction in the serum levels of PGE2 and CA-125. Further study are required to compare the effect of this combination of molecules with standard therapies and to evaluate if the use of these dietary supplements in combination with standard therapies may lead to the improvement of the regular medical treatment for endometriosis. This article is protected by copyright. All rights reserved.
Medicine (Baltimore). 2017 Dec;96(49):e9136.
Endometriosis-associated malignant transformation in abdominal surgical scar: A PRISMA-compliant systematic review.
Endometriosis-associated malignant transformation in abdominal surgical scar (EAMTAS) is a very rare and aggressive phenomenon. Our current article aims to provide a clinical overview, focusing on risk factors affecting survival.
We performed a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review based on prior reviews and case reports regarding the phenomenon published as abstracts in English, from January 1980 to November 2016. Overall, we identified 47 cases, and we included another case from our institution. We further contacted previous investigators to receive updated follow-up regarding their patients. We analyzed the data, focusing on risk factors that might affect overall survival.
All the patients reported in the literature had a uterine surgery, mainly caesarean section. The median time-lag from first surgery to the diagnosis of cancer was about 19 years. Clear-cell carcinoma (CCC) was the most prevalent histology (67%), followed by endometrioid adenocarcinoma (15%). Most of the patients were treated by extensive surgery and chemotherapy and/or radiation. Overall 5 years survival was about 40%. Median overall survival was 42 months (95% confidence interval of [18.7, 65.3]). Although our review is currently the largest in the literature, we cannot draw any statistical significant results due to the limited number of patients reported. According to univariate Cox-regression models, a tendency toward worse prognosis was shown for 3-year disease-free survival clear cell histologic-type (P = .169), and tumor diameter ≥8 cm in nonclear-cell histology, 18 months postdiagnosis (P = .06).
EAMTAS is a rare and aggressive disease. It is mostly related to cesarean section scars and is diagnosed many years postsurgery. Clear-cell histology tends to endure from the worse prognosis. The treatment is mainly extensive surgery and adjuvant chemotherapy and/or radiotherapy.
Sci Rep. 2017 Dec 15;7(1):17670.
Ginsenoside Rg3 Decreases Fibrotic and Invasive Nature of Endometriosis by Modulating miRNA-27b: In Vitro and In Vivo Studies.
This research aimed to evaluate the potential therapeutic effects of Rg3 on endometriosis and identify target miRNAs. We designed an in vitro study using human endometrial stromal cells (HESCs) obtained from patients with endometriosis and an in vivo study using mouse models. HESCs were treated with Rg3-enhanced red ginseng extract (Rg3E); real-time PCR and microarray profiling, transfection, and western blot were performed. Mouse endometriosis models were developed and supplemented with Rg3E for 8 weeks. Gross lesion size and fibrotic character were analyzed in the mouse models. RNA levels of Ki-67, col-1, CTGF, fibronectin, TGF-β1, MMP2 and MMP9 significantly decreased in HESCs after Rg3E treatment. Microarray analysis revealed downregulation of miR-27b-3p, which is related to fibrosis modulation. Expression of miR-27b-3p was significantly higher in HESCs from patients with endometriosisthan that of controls, and Rg3E treatment significantly decreased its expression; the contraction and migration assay revealed significant reductions in both fibrosis and migration potential in Rg3E-treated HESCs from endometriosis patients. A decrease in size and fibrotic character of endometrial lesions from the Rg3E groups was observed in vivo. In conclusion, Rg3 effectively altered fibrotic properties of HESCs from patients with endometriosis, which is likely associated with miR-27b-3p modulation.
Mol Reprod Dev. 2017 Dec 16.
Oocyte oxidative DNA damage may be involved in minimal/mild endometriosis-related infertility.
Early endometriosis is associated with infertility, and oxidative stress may play a role in the pathogenesis of disease-related infertility. This prospective case-control study aimed to compare the presence of oxidative stress markers in the follicular microenvironment and systemic circulation of infertile women with minimal/mild endometriosis (EI/II) versus individuals undergoing controlled ovarian stimulation for intracytoplasmic sperm injection (ICSI). Seventy-one blood samples (27 from infertile women with EI/II and 44 controls with tubal and/or male infertility factor) and 51 follicular fluid samples (19 EI/II and 32 controls) were obtained on the day of oocyte retrieval. Total hydroperoxides (FOX1 ), reduced glutathione, vitamin E, Superoxide dismutase, total antioxidant capacity, malondialdehyde, advanced oxidation protein products, and 8-hydroxy-2′-deoxyguanosine (8OHdG) concentrations were measured in both fluids. Women with EI/II showed higher FOX1 (8.48 ± 1.72 vs. 7.69 ± 1.71 μmol/g protein) and lower total antioxidant capacity (0.38 ± 0.18 vs. 0.46 ± 0.15 mEq Trolox/L) concentrations in serum, and higher 8OHdG concentrations (24.21 ± 8.56 vs. 17.22 ± 5.6 ng/ml) in follicular fluid compared with controls. These data implicate both systemic and follicular oxidative stress may in infertile women with EI/II undergoing controlled ovarian stimulation for ICSI. Furthermore, the elevated 8OHdG concentrations in follicular fluid of women with EI/II may be related to compromised oocyte quality.
Am J Obstet Gynecol. 2017 Dec 13.
Spectrum Of Symptoms In Women Diagnosed With Endometriosis During Adolescence Versus Adulthood.
Endometriosis symptoms often start at a young age, and the time between symptom onset and endometriosis diagnosis can be several years. It is not clear if symptoms experienced by adolescents differ from adults. Better understanding may shorten the often lengthy delay in diagnosis.
To further elucidate the symptom presentation of adolescents as compared to adults to determine if differences existed based upon age at surgical diagnosis that could impact time to diagnosis.
This investigation was a cross-sectional study at enrollment within a longitudinal cohort of adolescents and women with endometriosis. The population-based cohort was recruited from two tertiary care centers and the surrounding communities. Participants included adolescents (diagnosed ≤18y, n=295) and adults (diagnosed >18y, n=107) with surgically-confirmed endometriosis who were enrolled into The Women’s Health Study: From Adolescence to Adulthood. Participants completed an expanded version of the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project (WERF EPHect) standard clinical questionnaire including items regarding menstrual history, associated symptoms, and pain. Chi-square or Fisher’s exact tests were applied to categorical data, and Wilcoxon rank sum tests to continuous data.
Most participants (90%) experienced moderate-severe menstrual pain. On average, 3 doctors were seen before diagnosis, regardless of age at presentation (range 0-25). Time from symptoms to diagnosis averaged 2y for adolescents and 5y for adults (p<0.001). More adolescents (50%) than adults (33%) reported pain starting at menarche (p=0.002) and nausea accompanying pain (69% vs. 53%, p=0.01). Non-cyclic, general pelvic pain was prevalent. Half of participants reported relief of their general pelvic pain after a bowel movement. Pain interfered with work/school, daily activities, exercise, and sleep to a moderate-extreme degree; difficulties were similar by age at diagnosis.
Pelvic pain was severe, non-cyclical, and negatively impacted quality of life. At our tertiary care centers, symptoms of endometriosis did not differ between women surgically diagnosed during adolescence compared to those diagnosed as adults. Adolescents had more nausea and symptom onset at menarche. Multi-year delays in diagnosis were common. Clinicians should be aware of these alternate symptom patterns, and include endometriosis in their differential diagnosis for both adolescent and young adult women experiencing non-cyclic pelvic pain and nausea.
J Steroid Biochem Mol Biol. 2017 Dec 14.
Pharmacokinetic profile of PBRM in rodents, a first selective covalent inhibitor of 17β-HSD1 for breast cancer and endometriosis treatments.
The development of a covalent inhibitor of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a promising approach for the treatment of hormone-dependent breast cancer and endometriosis. After reporting the steroid derivative PBRM as a first potent covalent inhibitor of 17β-HSD1 without estrogenic activity, we are now interested in studying its pharmaceutical behavior. The metabolism study in a human liver microsomal preparation showed a gradual transformation of PBRM into PBRM-O, an oxidized ketonic form of PBRM at position C17. Interestingly, PBRM-O also inhibits 17β-HSD1 and is not estrogenic in estrogen-sensitive T-47D cells. However, when PBRM was injected subcutaneously (sc) in mice, a very small proportion of PBRM-O was measured in a 24 h-time course experiment. A pharmacokinetic study in mice revealed suitable values for half-life (T1/2 = 3.4 h), clearance (CL = 2088 mL/h kg), distribution volume (Vz = 10.3 L/kg) and absolute bioavailability (F = 65%) when PBRM was injected sc at 14.7 mg/kg. A good F value of 33% was also obtained when PBRM was given orally. A tritiated version of PBRM, 3H-PBRM, was synthesized and used for an in vivo biodistribution study that showed its gradual accumulation in various mouse tissues (peak at 6 h) followed by elimination until complete disappearance after 72 h. Elimination was found to occur in feces (93%) and urine (7%) as revealed by a mass balance experiment. PBRM was also evaluated for its toxicity in mice and it was found to be very well tolerated after weekly sc administration (30-405 mg/kg for 8 weeks) or by po administration (300-900 mg/kg for 4 weeks). Overall, these experiments represent important steps in the preclinical characterization of the pharmaceutical behavior of PBRM, as well as for its translation to clinical trials.
World J Surg Oncol. 2017 Dec 19;15(1):226.
Low-grade appendiceal mucinous neoplasm and endometriosis of the appendix.
A distended, mucous-filled appendix is known as an appendiceal mucocele. They are a rare form of an appendiceal mass and develop from both benign and malignant processes. Mucoceles can develop secondarily to an obstruction, such as from a fecalith, scarring or, rarely, endometriosis. Only 12 cases of non-neoplastic appendiceal mucoceles caused by endometriosis have been previously described. The association between neoplastic appendiceal mucoceles in the presence of endometriosis is described for the first time in this report.
A 57-year-old woman presented with a chief complaint of worsening abdominal pain over the past 3 months. Imaging studies revealed an appendiceal mass. Laparoscopic evaluation confirmed an appendiceal mucocele, and the patient underwent complete appendectomy. No evidence of mucinous or endometrial deposits were present within the abdominal cavity. Pathological diagnosis revealed low-grade appendiceal mucinous neoplasm (LAMN) with evidence of endometriosis within the muscularis propria of the appendix. The patient recovered without complications and her abdominal pain completely resolved.
Endometriosis of the appendix is a rare manifestation and is most often identified as an incidental finding. Endometriosis leading to an obstructive mucocele of the appendix is an exceedingly rare finding, having only been described 12 times in the medical literature. LAMN in the presence of endometriosis of the appendix is described for the first time in this report. The association between appendiceal neoplasms in the presence of endometriosis requires further research in order to optimize operative treatment.