Risk Of Endometrial Hyperplasia Research Articles

A Novel Intrauterine Device for the Spatio-Temporal Release of Norethindrone Acetate as a Counter-Estrogenic Intervention in the Genitourinary Syndrome of Menopause.

The genitourinary syndrome of menopause (GSM) is a widely occurring condition affecting millions of women worldwide. The current treatment of GSM involves the use of orally or vaginally administered estrogens, often with the risk of endometrial hyperplasia. The utilization of progestogens offers a means to counteract the effects of estrogen on the endometrial tissue, decreasing unwanted side effects and improving therapeutic outcomes. In this study, a norethindrone acetate (NETA)-loaded, hollow, cylindrical, and sustained release platform has been designed, fabricated, and optimized for implantation in the uterine cavity as a counter-estrogenic intervention in the treatment of GSM. The developed system, which comprises ethyl cellulose (EC) and polycaprolactone (PCL), has been statistically optimized using a two-factor, two-level factorial design, with the mechanical properties, degradation, swelling, and in vitro drug release of NETA from the device evaluated. The morphological characteristics of the platform were further investigated through scanning electron microscopy in addition to cytocompatibility studies using NIH/3T3 cells. Results from the statistical design highlighted the platform with the highest NETA load and the EC-to-PCL ratio that exhibited favorable release and weight loss profiles. The drug release data for the optimal formulation were best fitted with the Peppas-Sahlin model, implicating both diffusion and polymer relaxation in the release mechanism, with cell viability results noting that the prepared platform demonstrated favorable cytocompatibility. The significant findings of this study firmly establish the developed platform as a promising candidate for the sustained release of NETA within the uterine cavity. This functionality serves as a counter-estrogenic intervention in the treatment of GSM, with the platform holding potential for further advanced biomedical applications.

Trend changes and factor analysis of endometrial hyperplasia in patients with polycystic ovarian syndrome based on the Korean National Health Insurance Database

BackgroundPolycystic ovary syndrome (PCOS) is a common endocrine disorder associated with an increased risk of other gynecological disorders, such as endometrial hyperplasia (EH). However, substantial factors in the comorbidity of EH and PCOS remain to be investigated. We analyzed trend changes in PCOS and factors related to the comorbidity of PCOS and EH using data from the Korea National Health Insurance (KNHI) claims database.MethodsThe data for this population-based study of people diagnosed with PCOS or EH in Korea from 2009 to 2016 were collected from the KNHI claims database between 2007 and 2017. We conducted a trend analysis of the prevalence and incidence of PCOS and EH. In addition, we performed a logistic regression analysis to identify risk factors associated with EH incidence in people with PCOS using the matched case-control methodology.ResultsThe average annual growth rate of the incidence of PCOS was 14.1% from 2009 to 2016, whereas the EH rate increased by only 3.4% annually. Comorbidities, type 2 diabetes, obesity, hypertension, hyperlipidemia, and infertility, increased the risk of EH in PCOS patients. Additionally, the cumulative duration of oral contraceptive & progestin treatment for PCOS correlated highly with the comorbidity of EH and PCOS.ConclusionsWe confirmed the relationship between PCOS and EH using big data suitable for time series analyses of the diagnosis and treatment of diseases. Endometrial evaluation should be done with more caution if oral contraceptives & progestins have been used for a long time.

P-696 Serum androgen levels and risk of endometrial hyperplasia and malignancy in patients with polycystic ovarian syndrome: a cross-sectional analysis

Abstract Study question In patients with polycystic ovarian syndrome (PCOS), are serum androgen levels (total and free testosterone) associated with the risk of endometrial hyperplasia or cancer? Summary answer Patients with PCOS diagnosed with endometrial hyperplasia or cancer had statistically significantly lower serum levels of androgens compared to PCOS patients with a normal endometrium. What is known already PCOS affects as many as 12% of women of reproductive age. Women with PCOS are almost three times as likely to develop endometrial cancer as women without PCOS, and endometrial hyperplasia precedes cancer in 36% of cases. Known risk factors of endometrial hyperplasia include anovulation, obesity, and resultant unopposed estrogen stimulation of the endometrium. A hallmark of PCOS is hyperandrogenism, however the effect of androgens on the endometrium is unclear. Study design, size, duration This was a cross-sectional, retrospective study of patients aged 18-40, being evaluated for oligomenorrhea and/or PCOS in the Reproductive Endocrinology Clinic at Los Angeles County Hospital, California, USA. All patients underwent an endometrial biopsy and serum measurement of free and total testosterone, estradiol, and hemoglobin A1c. Patients diagnosed with PCOS and with an endometrial biopsy diagnosis were included in the study. Patients on any hormonal therapy were excluded. Participants/materials, setting, methods In all patients included in the study, serum androgen levels (free and total testosterone) were measured by mass spectrometry. All endometrial biopsies were analyzed by an experienced histopathology, and all diagnoses of endometrial hyperplasia or cancer were confirmed by histologic studies. Main results and the role of chance Using the Rotterdam criteria, a total of 232 patients were diagnosed with PCOS during the study period. Of these patients, 161 patients (70%) had a normal endometrium, 19 (8%) were diagnosed with endometrial hyperplasia (EH) without atypia, 38 (16%) were diagnosed with EH with atypia, and 14 (6%) were diagnosed with endometrial cancer. Patients with a normal endometrium had a mean total testosterone of 60.9 ng/dL and mean free testosterone of 9.3 ng/dL. Relatively, patients with EH without atypia, EH with atypia, and endometrial cancer had lower mean total testosterone levels of 50.1 ng/dL, 45.5 ng/dL, and 30.1 ng/dL, respectively (p-values 0.04, 0.02, 0.001, respectively), as well as lower mean free testosterone levels of 8.2 pg/mL, 6.7 pg/mL, and 5.5 pg/mL, respectively (p-values 0.04, 0.03, and 0.01, respectively). There was no significant difference in age, parity, BMI, estradiol levels, or hemoglobin A1c between the four groups. Limitations, reasons for caution Limitations of our study include its retrospective nature. Furthermore, hormone levels were only measured in the serum, and not in the endometrial tissue directly, which would give the most insight into their actions on the endometrium. Wider implications of the findings Our findings suggest that androgens have a protective effect on the endometrium against endometrial hyperplasia and cancer. Further studies are needed to evaluate the therapeutic potential role of androgens in the prevention or treatment of these conditions. Trial registration number not applicable

P-695 Anti-muellerian Hormone (AMH) and Plasminogen Activator Inhibitor (PAI-1) are robust follicular-fluid (FF) biomarkers predictive of follicle maturity and oocyte quality in women undergoing IVF cycles

Abstract Study question Is AMH the in-vivo trigger that correlates with PAI-1 in the follicular-fluid micro-milieu to influence maturity and quality of oocytes derived in vitro during IVF? Summary answer Lower FF-AMH levels correlate with top quality oocytes whereas Lower FF-PAI-1 levels correlate with follicle-maturity as reflected in mature MII oocytes retrieved in IVF cycles What is known already Ovulation is a time-coordinated tightly regulated proteolytic event. PAI-1, primarily produced by granulosa cells, is a major form of PAI in FF of human preovulatory follicles, allowing localized degradation and regulating ovulation.While ovulation process is rendered redundant in IVF cycles; nevertheless FF PAI-1 concentration may influence maturity of oocyte within the follicle. AMH is exclusively produced by granulosa cells of pre-antral & early-antral ovarian follicles in the adult female and secreted into FF. Although AMH is widely accepted as an ovarian-reserve marker, very few studies have explored direct putative correlation of FF-AMH with oocyte quality in stimulated IVF cycles. Study design, size, duration Prospective study of n = 1150 (Power of study >85%) women (mean age 30.22±4.25 years, BMI 23.97±4.53, W/H ratio 0.88±0.06) undergoing antagonist stimulation protocol with r-FSH (September 2015-December 2018). On day of ovum pick-up, original aspirate per follicle was pooled per patient. AMH and PAI-1 were evaluated in pooled FF by ELISA method using diagnostic kits. These protein-biomolecules were expressed as ratio of total protein content. SerumE2, LH, P on d/hCG trigger were also estimated by RadioImmunoAssay. Participants/materials, setting, methods Elderly women (age>35 years), women with polycystic-ovaries, endometriosis were excluded. Embryo-transfer (ET) was done either on Day3 or day5. Luteal-phase was supported with micronized progesterone. All cycles were divided into Low FF-AMH (≤1.72 ng/mg protein), High FF-AMH (>1.72ng/mg protein) and Low FFPAI-1 (≤592.1 ng/mg protein), High FFAI-1 (>592.1 ng/mg protein) groups. Oocyte quality was graded as poor, average and top based on morphological assessment of COC-complex, zona-pellucida (thickness, regularity) and cytoplasm (granularity, vacuolation, refractile bodies). Main results and the role of chance Mean Age, Baseline D3-Serum AMH, E2 d/hCG and number of eggs retrieved did not differ significantly between low vs. High FF AMH groups as well as Low vs. High FF-PAI-1 groups. Low FF AMH group displayed significantly higher percent of top-quality oocytes (70.38±11.5 vs. 52.16±8.3;p<0.0001) and higher fertilization rates (88.68±10.7 vs. 72.5±9.2%; p = 0.004) compared to High FF AMH group. Incidences of total fertilization failure were significantly higher in high FF AMH (3.25% vs. 1.1%, p = 0.0002) compared to Low-FFAMH group. FF-AMH correlated with oocyte-quality (Pearsonr=0.48); lower-levels increased the odds of top-quality oocytes. Thresholds of FF-AMH for top quality oocytes was <1.8 ng/mg protein;ROCAUC:85%) Low FF PAI-1 group had significantly higher Percentage of MII oocytes (93.55 vs. 74.8%; p < 0.0001), Rates of Fertilization (86.35 vs. 71.04, p = 0.008) and cleavage (79.19 vs. 69.85;p=0.03) compared to High FF-PAI-1 group. FF-PAI-1 correlated with oocyte-maturity (Pearsonr=0.51), lower-levels increased the odds of obtaining MII-oocytes. Cutoff of FF PAI-1 for mature MII oocytes was <504.4 ng/mg protein;ROCAUC:76%). FF-AMH showed strong positive correlation with FF-PAI-1 (Pearsonr=0.66) Limitations, reasons for caution Several other molecules in the follicular-fluid milieu may be responsible for maturity status and quality of oocytes. Although these are apparently the most plausible of markers; role of other factors cannot be ruled out. Also, it may be better to study mono-follicular aspirates rather than pooled FF for each patient. Wider implications of the findings FF-levels of AMH and PAI-1 as non-invasive endogenous biomarkers of oocyte maturity and quality in-vitro may facilitate better understanding of the physiological pathway governing in-vivo ovulation process. This study reiterates ‘Follicle-maturation’ is the rate-determining step that sets off a cascade mechanism triggering oocyte-maturation and quality further influencing fertilization, embryo development. Trial registration number In patients with polycystic ovarian syndrome (PCOS), are serum androgen levels (total and free testosterone) associated with the risk of endometrial hyperplasia or cancer?

Prognostic risk predictors of hyperplastic endometrial processes in women with reduced reproductive potential

In the structure of female infertility, the uterine factor occupies one of the leading places and ranges from 25.20% to 42.30%, and in women with repeated unsuccessful attempts at in vitro fertilization, intrauterine pathology is detected in 45% of cases. In the structure of gynecological diseases, hyperplastic processes of the endometrium are 15–40%, and in women of reproductive age – 24.0–62.0%. The objective: to examine the risk predictors of the developing benign hyperproliferative pathology of the endometrium in women of reproductive age to improve preventive approaches of management of this group of patients. Materials and methods. The results of analytical processing of medical documentation of 860 patients with uterine factor of subfertility (pregnant woman’s card (form 111 / y), ambulatory card (form 025 / y-04)), witch were selected by the method of continuous sampling, were presented. This allowed to establish the structure and frequency of endometrial hyperplastic processes in women of reproductive age, to assess the features of reproductive health parameters in this category of patients and to determine prognostic predictors of endometrial hyperplastic processes. For comparison, we analyzed 100 forms of medical records of patients who were routinely preventively examined in these medical institutions. Results. Dominating influences are such clinical nosologies: endometrial polyposis and hyperplastic processes (44.19%), adenomyosis (22.33%), multiple uterine fibroids (10.47%), including submucous myomas (7.79%), uterine synechia (14.19%), uterine retinas and anomalies in the development of the uterus were rarely inserted (2.09% and 1.28% respectively). The uterine factor was the main factor in terms of reproductive losses and subfertility (38.68%), the incidence of the primary form of infertility was 17.63%, the secondary form (43.68%), the incidence in IVF programs was 119 cases (31.32%), including one in five failed IVF attempts (21.85%). Patients ranged in age from 20 to 45 years, and endometrial hyperplasia and polyposis were more pronounced in late reproductive age (60.00%) versus (40.00%) in early reproductive age, respectively (p<0.05). The performed statistical calculations allowed to present the risks of developing hyperplastic processes of the endometrium in relation to such factors as chronic pelvic inflammatory disease (OR = 6.16; 95% CI: 3.52–10.78), adenomyosis and external genital endometriosis (OR=10,59; 95%: 4.21–26.67), uterine fibroids (OR=3.07; 95%: 1.19–7.92), benign tumors and retention of ovaries (OR=4.98; 95%: 1.96–1.67). It should be noted that the share of somatic disorders and their comorbidity increased with age by 1.7 times in cases of hypertension, metabolic disorders, thyroid pathology and diseases of the urinary system (p<0.05). Assessing the reproductive function in women with endometrial hyperplastic processes, it should be noted the low reproductive potential in this category of patients. Conclusions. The results show an increase in the risk of endometrial hyperplasia and polyps with age by 2.3 times. There is a high proportion of long-term use of intrauterine systems, as well as a low use of hormonal and barrier methods of contraception, which, no doubt, can contribute to the chronicity of inflammatory diseases of the reproductive system. The statistical calculations allowed to present the risks of developing hyperplastic endometrial processes for such factors as chronic pelvic inflammatory disease, adenomyosis and external genital endometriosis, uterine fibroids, benign tumors and retention of ovaries. In the analysis of the structure of somatic morbidity, the share of cardiovascular diseases, thyroid disease and disorders of fat metabolism is high. In the group of patients with endometrial hyperplastic processes, a low proportion of pregnancies was noted, along with a high percentage of miscarriages, missed abortions and recurrent miscarriages. The obtained results allow to supplement the pathogenetic concept of the development of endometrial hyperplastic processes.

Implementation of international guidelines for polycystic ovary syndrome: barriers and facilitators among gynecologists and primary care providers

ObjectiveTo identify barriers and facilitators to the implementation of evidence-based guidelines among gynecologists and primary care physicians (PCPs) caring for women with polycystic ovary syndrome (PCOS).DesignQualitative semi-structured interview study.SettingAcademic medical center.PatientsNone.InterventionsNone.Main Outcome MeasuresBarriers and facilitators in the diagnosis and management of PCOS.ResultsWe interviewed 10 gynecologists and 8 PCPs to reach thematic saturation using a thematic analysis approach. Four themes were identified: diagnostic considerations, treatment of symptoms of PCOS, screening for long-term complications of PCOS, and counseling on long-term complications. Many gynecologists did not perform the recommended metabolic screening and were uncomfortable managing metabolic complications of PCOS. They uniformly counseled patients on the risk of endometrial hyperplasia and infertility. PCPs expressed the lack of familiarity with diagnostic criteria and often did not complete a comprehensive workup before making a diagnosis of PCOS. However, they routinely counseled patients on cardiometabolic risk and were familiar with managing the related long-term complications. Common barriers to comprehensive care delivery included the lack of knowledge and inadequate time and resources. Important facilitators included the overlap between the management of PCOS and other conditions such as obesity and abnormal uterine bleeding.ConclusionsOur study highlights the need for interventions that target the barriers identified among gynecologists and PCPs in implementing guidelines for diagnosing and managing PCOS. In conjunction with prior studies, our findings support a multidisciplinary care model for women with PCOS. Future studies should focus on implementation strategies to facilitate evidence-based care.

British Menopause Society tools for clinicians: Progestogens and endometrial protection.

Progestogen administration is required to oppose naturally produced or administered estrogens to provide endometrial protection. Within HRT regimens, this should be delivered for at least the same duration as that produced during the luteal phase of the monthly cycle and in the recommended doses to protect against the risk of endometrial hyperplasia and endometrial cancer. This includes progestogens administered for 12-14days a month in sequential regimens and continuous daily intake in continuous combined HRT regimens. Shorter durations and lower doses of progestogen intake are likely to be associated with an increased risk of breakthrough bleeding, endometrial hyperplasia, and endometrial cancer.

The Risk of Endometrial Hyperplasia and Malignancy May be Increased in Patients with Endometriosis

<h3>Study Objective</h3> The objective of our study is to further investigate the role of endometriosis on subsequent diagnosis of endometrial hyperplasia and malignancy (EHM). <h3>Design</h3> Retrospective cohort study <h3>Setting</h3> Single academic institution <h3>Patients or Participants</h3> All cases of histologically diagnosed endometriosis were evaluated between 2005 and 2020. Women over 18 years of age were included. All endometrial malignancies were included for analysis. Patients with a history of hysterectomy were excluded. <h3>Interventions</h3> No interventions were performed <h3>Measurements and Main Results</h3> Demographic information and past medical and surgical history were assessed. For the EHM cohort, oncologic data, endometriosis stage, patient age and body mass index (BMI) at time of diagnosis were collected. A total of 2,122 women with endometriosis were included. Of these, 198 (9.3%) were found to have co-existing eutopic endometrial hyperplasia (n=56) or malignancy (n=142). At the time of oncologic diagnosis, the mean age was 55.6 years and mean BMI was 33.1. Within the EHM group, 82.3% of endometriosis diagnoses were made at the time of their surgical management and the majority were stage 1 by ASRM criteria (70.0%). When comparing characteristics between those with and without a diagnosis of EHM, there was no significant difference in race, ethnicity, tobacco use, prior diagnosis of PCOS or diagnosis of breast or colon cancer. Significant differences were seen in type 2 diabetes (p<0.0001), hypertension (p<0.0001), prior use of tamoxifen (p=0.0021), gravidity (p=0.0331) and parity (p<0.0001). Statistical analysis was performed using chi-square and Mann-Whitney tests. A p-value of <0.05 was considered significant. <h3>Conclusion</h3> Compared to the population prevalence of less than 1% of both endometrial hyperplasia and malignancy, our study suggests that endometriosis may be a predictor of subsequent diagnosis of endometrial cancer and malignancy. Further research is needed to control for known confounders of endometrial hyperplasia and malignancy.

Does 2’-hydroxygenistein inhibit the endometrial proliferation? A preliminary study

Isoflavones, due to their claimed or demonstrated beneficial biological activities, have attracted great interest and gained popularity among the public. On the risk of endometrial hyperplasia, conflicting findings for such compounds have been reported and genistein has been intensively studied. Studies also indicated that 2’-hydroxylation of isoflavones can lead to beneficial components with superior bioactivity compared to isoflavones lacking this substituent. Till now there is no study evaluating the effect of 2’-hydroxygenistein on endometrial hyperplasia in vivo. In line with this, a 3-day uterotrophic assay was carried out to evaluate the effect of 2’-hydroxygenistein on the uterus as its endometrial hyperplasia is of significant clinical concern. Daily subcutaneous administration of 2’-hydroxygenistein significantly (p ≤ 0.05) increased uterine wet weight at 2 and 8 mg/kg/day, while it reduced (p ≤ 0.05) uterine epithelial height at all tested doses. In contrast, no significant variation was observed on vaginal epithelial height. As global result, it appears that 2’-hydroxygenistein might exhibit anti-proliferative effects in the uterus, while having no effect on the vagina. However, this aspect needs to be further investigated.

Postmenopausal Bleeding: An Update

The clinical approach to postmenopausal bleeding requires prompt and efficient evaluation to exclude or diagnose endometrial carcinoma and endometrial intraepithelial neoplasia and to find out the real source. Postmenopausal bleeding is ‘endometrial cancer until proven otherwise’, although only 1-14% of such patients will actually have cancer. Clinical risk factors of endometrial carcinoma such as obesity, unopposed estrogen use, polycystic ovary syndrome, diabetes mellitus and family history of gynaecologic malignancy also should be considered during evaluation. Postmenopausal bleeding usually attributed to an intrauterine source, but it may arise from the cervix, vagina, vulva or fallopian tubes &amp; ovaries. The origin of bleeding can also involve non-gynaecologic sites, such as the urethra, bladder, anus/rectum/bowel, or perineum.&#x0D; Meticulous history and thorough physical examination are must. Initial evaluation is by TVS, if endometrial thickness (ET) is &lt;4mm no further evaluation is required but follow up consultation must. If ET is&gt; 4mm, hysteroscopic evaluation and endometrial sampling is recommended&#x0D; Blind endometrial sampling is not accurate as only reveals when endometrial cancer exceeds more than 50% of the endometrial surface area so may be done if hysteroscopic evaluation is not possible. Higher dose of progesterone may be required for endometrial protection when higher doses of estradiol as hormone replacement therapy are used, or in women with high BMI. Unopposed estrogen therapy is associated with a duration and dose-related increase in risk of endometrial hyperplasia and cancer. Endometrial protection requires an adequate dose and duration of progestogen. Endometrial hyperplasia with atypia has much malignant potential but endometrial hyperplasia without atypia may be managed medically with 3 monthly endometrial sampling, if no regression or further progression hysterectomy is the choice of treatment. Finally, patient counseling with discussion of risks /benefits of different options of treatment modalities is the cornerstone of success of addressing postmenopausal bleeding.

RELATION OF ENDOMETRIAL PATHOLOGICAL CHANGES WITH ENDOCRINE DISORDERS AND METABOLIC SYNDROME

Endometrial hyperplasia (EH) is an abnormal proliferation of endometrial glands and stroma and is associated with an increased risk of endometrial cancer (EC). Risk factors such as obesity, chronic anovulation, late menopause, hypertension, and diabetes lead to an increased risk of EH and EC. Aim: to determine the association of pathological changes in the endometrium with endocrine disorders and metabolic syndrome in women in peri and postmenopause. This study including a total of 139 patients in peri and postmenopause. &nbsp;The examined group consisted of 104 women with fractional explorative curettage due to a medical indication and was divided into two subgroups: peri and postmenopausal. The control group included 35 healthy women. Anamnestic data, body weight, height, blood pressure measurement, were taken from all patients, and the following laboratory parameters were determined: glucose, TSH, thyroxine, glycosylated hemoglobin (HbA1c), and Vitamin D . The presence of metabolic syndrome (MetS) according to its diagnostic criteria was also determined. In our study, significance was found in the comparison of the examined and the control group (p = 0.0001) in addition to the significantly higher BMI in the examined group. The comparison also &nbsp;indicated the existence of a significant difference in the level of glycemia in addition to a significantly higher level in the examined group (p = 0.0001). The statistical analysis did not indicate a significant difference between the two subgroups of the examined group, nor between the examined and the control group in terms of TSH, thyroxine and HbA1c levels. The value of vit. D was significantly higher in the control than &nbsp;in the study group (p = 0.0001). The analysis showed that patients with fractional explorative curettage had 4.982 times [OR = 4.982 (2.06–12.02) 99% CI] significantly more often MetS compared to women in the control group. Patients in the examined group had a significantly higher BMI, glycemia, and more frequent presence of MetS than those in the control group. Keywords: endometrium, risk factors, fractional explorative curettage, metabolic syndrome

Candidate genes for age at menarche are associated with endometrial hyperplasia.

To study associations candidate genes for age at menarche with a risk of endometrial hyperplasia (EH). 52 candidate loci for age at menarche were analyzed for possible association with EH in a sample of 520 patients and 981 controls. Association of the polymorphisms was analyzed using the method of logistic regression. The gene-gene and gene-environment interactions were analyzed using MB-MDR. 21 polymorphisms, which were associated with EH, and 397 polymorphisms linked to them (r2≥0.8) were analyzed in silico for their functional significance. 21 out of the 52 studied polymorphisms had association with EH. Locus rs11031010 FSHB was individually associated with the disease according to the dominant (OR=0.62, pperm=0.001) and additive (OR=0.67, pperm=0.002) models. Haplotype GAA of loci rs555621-rs11031010-rs1782507 FSHB were associated with the EH (OR=0.66, pperm=0.007). Seventeen loci were associated with EH within 12 most significant models of intergenic interactions (pperm≤0.001). Locus rs4374421 of the LHCGR gene appeared in the largest number of models (four models). Nine loci involved in 14 most significant models of interactions between SNP, induced abortions, and chronic endometritis were associated with EH. The polymorphisms of genes FTO (rs12324955) and FSHB (rs11031010) appeared in the largest number of the models (9 and 6, respectively). Among the 21 loci associated with EH, 16 manifested association also with either age at menarche (7 SNPs) or height and/or BMI (13 SNPs). The above 21 SNPs and 397 SNPs linked to them have non-synonymous, regulatory and eQTL significance for 25 genes, which play roles in the pathways related to development of the female reproductive organs and hormone-mediated signaling (FDR≤0.05). Candidate genes for age at menarche are associated with endometrial hyperplasia.

Endometrial hyperplasia in infertile women undergoing IVF/ICSI: A retrospective cross-sectional study

ObjectiveTo describe the frequency and risk factors of endometrial hyperplasia (EH) in infertile women undergoing their first IVF/ICSI treatment. MethodsA total of 3198 infertile women undergoing their first IVF/ICSI cycle were recruited retrospectively from a fertility treatment center. Endometrial scratching and biopsy were conducted before IVF/ICSI treatment. The relationship between EH and clinical characteristics were analyzed. ResultsEH without atypia, atypical hyperplasia, and endometrial cancer (EC) were diagnosed in 94 (2.94%), three (0.093%), and two (0.063%) women, respectively. The frequencies of EH were higher in patients with abnormal uterine bleeding (i.e. menstrual cycle irregularity in terms of frequency, volume, or length; 6.8% vs. 1.6%, P < 0.001, OR = 4.42), obesity (4.1% vs. 2.7%, P = 0.044, OR = 1.55), and elevated fasting glucose (4.6% vs. 2.5%, P = 0.017, OR = 1.85). In the multivariate analyses, all the three factors (abnormal uterine bleeding, obesity, elevated fasting glucose) were independently associated with risk of EH. In the subgroup analysis, among women with abnormal uterine bleeding, the frequency of EH in the elevated fasting glucose group was 10.7%, which was higher than that of the normal fasting glucose group (5.6%), even after adjustment for BMI (P = 0.014, OR = 1.53). ConclusionThe frequency of EH in infertile women undergoing their first IVF/ICSI treatment was approximately 3%. Elevated fasting glucose was an independent risk factor for EH in infertile women undergoing IVF/ICSI.

11. 12-month Continuation of the Etonogestrel Implant in Adolescents with Polycystic Ovary Syndrome

Polycystic Ovary Syndrome (PCOS) is characterized by chronic anovulation and risk of endometrial hyperplasia. The etonogestrel (ENG) implant is a long-acting option for the prevention of endometrial hyperplasia in adolescents with PCOS. Current studies report adolescent ENG 12-month discontinuation rates at 10%, but there are no data for adolescents with PCOS. We sought to describe why adolescents with PCOS chose ENG, determine the 12-month continuation rate and characterize factors for discontinuation.

Long-term outcome of postmenopausal women with non-atypical endometrial hyperplasia on endometrial sampling.

To assess the long-term outcome of postmenopausal women diagnosed with non-atypical endometrial hyperplasia (NEH). This was a retrospective study of women aged 55 or older who underwent endometrial sampling in our academic medical center between 1997 and 2008. Women who had a current or recent (< 2 years) histological diagnosis of NEH were included in the study group and were compared with those diagnosed with atrophic endometrium (AE). Outcome data were obtained until February 2018. The main outcomes were risk of progression to endometrial carcinoma and risk of persistence, recurrence or new development of endometrial hyperplasia (EH) ('persistent EH'). Logistic regression analysis was used to identify covariates that were independent risk factors for progression to endometrial cancer or persistent EH. During the study period, 1808 women aged 55 or older underwent endometrial sampling. The median surveillance time was 10.0 years. Seventy-two women were found to have a current or recent diagnosis of NEH and were compared with 722 women with AE. When compared to women with AE, women with NEH had significantly higher body mass index (33.9 kg/m2 vs 30.6 kg/m2 ; P = 0.01), greater endometrial thickness (10.00 mm vs 6.00 mm; P = 0.01) and higher rates of progression to type-1 endometrial cancer (8.3% vs 0.8%; P = 0.0003) and persistent NEH (22.2% vs 0.7%; P < 0.0001). They also had a higher rate of progression to any type of uterine cancer or persistent EH (33.3% vs 3.5%; P < 0.0001). Women with NEH had a significantly higher rate of future surgical intervention (51.4% vs 15.8%; P < 0.0001), including future hysterectomy (34.7% vs 9.8%; P < 0.0001). On multivariable logistic regression analysis, only NEH remained a significant risk factor for progression to endometrial cancer or persistence of EH. Postmenopausal women with NEH are at significant risk for persistent EH and progression to endometrial cancer, at rates higher than those reported previously. Guidelines for the appropriate management of postmenopausal women with NEH are needed in order to decrease the rate of persistent disease or progression to cancer. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Ассоциация полиморфизма RS2498796 гена АКТ1 с риском развития гиперплазии эндометрия у женщин

The purpose — to estimate the prevalence of rs2498796 polymorphism of the АКТ1 gene and reveal its association with the risk of endometrial hyperplasia. Material and methods. The study included 180 residents of the Republic of Tatarstan: 79 patients with endometrial hyperplasia, 101 women without endometrial pathology. Determination of rs2498796 polymorphism of the АКТ1 gene was carried out by the method of real time polymerase chain reaction. The study performed a χ2 test and evaluated the odds ratio. Results. The ratio of homozygous for the allele C (C/C), heterozygous (C/T) and homozygous for the allele T (T/T) rs2498796 of the AKT1 gene was in the main group 35 (44,3%), 30 (38%), and 14 (17,7%), in the control group – 46 (45,5%), 45 (44,6%), and 10 (9,9%) respectively. The frequency of the T allele and the C allele rs2498796 in women with endometrial polyps was comparable to that in the control group (χ2=0,81, р=0,37). Conclusion. Among 180 females of the Republic of Tatarstan included into the study, the associations of rs2498796 polymorphism of the АКТ1 gene with the risk of endometrial hyperplasia were not identified.

Metformin alleviates endometrial hyperplasia through the UCA1/miR‑144/TGF‑β1/AKT signaling pathway.

The objective of the present study was to investigate the molecular mechanism underlying the role of metformin (Met) in reducing the risk of endometrial hyperplasia (EH). Reverse transcription‑quantitative polymerase chain reaction, western blot and immunohistochemistry (IHC) assays were used to study the effects of Met and tamoxifen on the expression levels of urothelial cancer associated 1 (UCA1), microRNA‑144 (miR‑144) and other factors along the transforming growth factor‑β1 (TGF‑β1)/protein kinase B (AKT) signaling pathway. In addition, MTT and flow cytometry assays were performed to detect the effect of Met on cell proliferation and apoptosis. Tamoxifen treatment increased the weight of the uterus and the level of UCA1, while decreasing the expression of miR‑144. In addition, treatment with tamoxifen (2.0 and 3.5µg) upregulated the protein expression levels of TGF‑β and p‑AKT, while downregulating the protein expression of active Caspase‑3 in a dose‑dependent manner. By contrast, Met reduced cell viability, promoted cell apoptosis, and reduced the expression levels of UCA1, TGF‑β and p‑AKT, while upregulating the expression of miR‑144 and active Caspase‑3 in a dose‑dependent manner. Furthermore, Met also reduced the weight of uterus. However, tamoxifen and Met did not exert any effect on the protein levels of total AKT and total Caspase‑3. The levels of TGF‑β and p‑AKT proteins in the EH group were much higher when compared with those in the sham group, while Met treatment reduced these protein levels to a certain extent. In addition, the expression of active Caspase‑3 in the EH group was much lower than that in the sham group, while Met treatment increased its level to a certain extent. In conclusion, the current study suggested that Met reduces the risk of EH by reducing the expression levels of UCA1, TGF‑β and p‑AKT, while increasing the levels of miR‑144 and active Caspase‑3 in a dose‑dependent manner.

Treatment with metformin and sorafenib alleviates endometrial hyperplasia in polycystic ovary syndrome by promoting apoptosis via synergically regulating autophagy.

This study aimed to investigate the molecular mechanisms underlying the roles of metformin (MET) and Sorafenib (SOR) in the treatment of endometrial hyperplasia (EH) in polycystic ovary syndrome (PCOS). Effects of MET and SOR on the area of endometrium and myometrium were detected. Western blot analysis and immunohistochemistry assays were carried out to detect the levels of mammalian target of rapamycin complex 1 (mTORC1), mTORC2, LC3-II, P62, and Caspase-3 in rats and cultured cells. Furthermore, cell counting kit-8 assay and flow cytometry analysis was carried out to determine the apoptotic profiles of treated cells. MET and SOR could apparently decrease the areas of endometrium and myometrium in PCOS. MET notably enhanced the expression of LC3-II and Caspase-3 in PCOS while substantially reducing the level of mTORC1 and P62. Similarly, SOR also enhanced the expression of LC3-II and Caspase-3 in PCOS while substantially reducing the level of mTORC2 and P62. Treatment with MET and SOR significantly inhibited the proliferation of HCC-94 and HEC-1-A cells while promoting their apoptosis by upregulating the expression of Caspase-3. In cells treated with MET, the expression of mTORC1 and LC3-II was upregulated while the expression of P62 was downregulated. Similarly, in cells treated with SOR, the expression of mTORC2 and LC3-II was also upregulated while the expression of P62 was also downregulated. Furthermore, MET showed no effect on mTORC2 expression, while SOR showed no effect on mTORC1 expression. In this study, we suggested that MET and SOR alleviated the risk of EH in PCOS via the mTORC1/autophagy/apoptosis axis and mTORC2/autophagy/apoptosis axis, respectively.

Topical vaginal estrogen use and risk of endometrial hyperplasia or cancer

Topical vaginal estrogen use and risk of endometrial hyperplasia or cancer

Abstract 2203: A prospective study of endometrial cancer detection in women presenting for evaluation of abnormal peri- and postmenopausal bleeding

Abstract Background: Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries and the incidence and mortality of EC continue to rise in the US. When detected early, EC is highly curable, suggesting that early detection strategies could reduce EC mortality. Women who develop EC often have a prolonged history of abnormal bleeding, offering a window for identifying many at-risk women prior to the development of advanced cancer. To evaluate risk prediction, novel sampling and early detection strategies in women at increased risk of EC, we established a prospective cohort of women with abnormal bleeding that is followed for endometrial hyperplasia and cancer endpoints. Methods: We consecutively enrolled women ≥45 years old presenting to the Mayo Clinic for evaluation of abnormal uterine bleeding (AUB), postmenopausal bleeding (PMB), thickened endometrial stripe (ES) on imaging, or Lynch Syndrome (LS). From all women, an intravaginal tampon and an endometrial brushing via Tao brush were collected before endometrial biopsy. Epidemiological EC risk factor data, clinical data, and endometrial biopsy histology results were abstracted from medical records. Absolute risk of endometrial hyperplasia and EC were calculated overall and in strata based on clinical symptoms and risk factors. Results: Among the first 1,000 women enrolled into the study, 712 (71%) were overweight or obese, 534 (53%) were postmenopausal, and 214 (22%) were current hormone replacement therapy (HRT) users. Endometrial biopsy and, if indicated, subsequent hysterectomy, detected 39 ECs, 16 atypical hyperplasias, and 28 hyperplasias without atypia at baseline evaluation. Among 534 postmenopausal women, 453 (85%) reported any type of bleeding, with spotting (39%) and light bleeding (27%) being more common than heavy bleeding (14%). Among perimenopausal women with AUB (n=452), the absolute risk of EC at baseline was 0.9% and among women with PMB, the absolute risk of EC at baseline was 7.5%. Among women with PMB, EC risk was modified by HRT use (risk of 2.6% in women on HRT and 8.2% in women not on HRT, respectively), obesity (risk of 5.3%, 8.1% and 9.5% for women with normal, overweight, and obese BMI, respectively), and type of bleeding (risk of 9.7%, 4.9%, and 8.2% in women with spotting, light or heavy bleeding, respectively). Discussion: While risk of endometrial cancer in perimenopausal women with AUB is low, approximately 8% of women presenting for clinical work up of PMB have underlying EC. Clinical presentation and risk factors modify the absolute risk of EC and may inform clinical management. Additional recruitment and prospective follow-up is underway to improve estimates of short- and long-term EC risk in women with PMB. With its collection of tampon and Tao brush samples, the study will provide a unique resource to evaluate molecular markers of EC and EC risk in elevated-risk women. Citation Format: Nicolas A. Wentzensen, Megan Clarke, Viji Shridhar, Maureen Lemens, Matthew Hopkins, Lisa Ahlberg, Shannon Laughlin-Tommaso, Karl Podratz, Mark Sherman, Jamie Bakkum-Gamez. A prospective study of endometrial cancer detection in women presenting for evaluation of abnormal peri- and postmenopausal bleeding [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2203.