Nesfatin-1 expression and blood plasma concentration in female dogs suffering from cystic endometrial hyperplasia and pyometra and its possible interaction with phoenixin-14.

BACKGROUND: Nesfatin-1 is a neuropeptide that regulates the hypothalamic-pituitary-gonadal axis and may play a role in uterus function. It is co-expressed with other peptides, such as phoenixin, which can influence sex hormone secretion. Our previous research has confirmed that phoenixin-14 is involved in the development of cystic endometrial hyperplasia (CEH) and pyometra in dogs. Therefore, based on the similarities and interactions between these neuropeptides, we hypothesized that nesfatin-1 might also regulate the reproductive system in dogs. This study aimed to determine the expression of nesfatin-1 and its interaction with phoenixin-14 in dogs with CEH or pyometra compared to healthy females, and concerning animals' body condition score (BCS 4-5/9 vs. BCS > 5/9). RESULTS: The analysis of nesfatin-1 in the uterus of bitches consisted of qPCR, western blot and immunofluorescence assays, and ELISAs. The results showed significantly higher nesfatin-1 encoding gene, nucleobindin-2 mRNA (Nucb2) and nesfatin-1 protein expression in overweight females and those suffering from CEH or pyometra compared to healthy animals. The immunoreactivity of nesfatin-1 was elevated in the uteri of bitches with higher BCS > 5/9. Moreover, nesfatin-1 blood concentrations increased in all examined overweight bitches. In the case of phoenixin signals, we found opposite results, regardless of the female body condition score. CONCLUSION: The etiology of CEH and pyometra are not fully known, although we have expanded the level of knowledge with respect to the possible interaction of nesfatin-1 and phoenixin in female dogs' uteri. They interact oppositely. With increasing female body weight, the expression of nesfatin-1 in the uterus and its peripheral blood concentration increased. However, for female dogs affected by CEH and pyometra, a decreased level of phoenixin-14, irrespective of their body condition score is characteristic. This knowledge could be crucial in the development of biomarkers for these conditions, which may lead to earlier recognition.

Plasma-based proteomic profiling identifies the distinct regulation of proteins in hyperplasia and endometrial cancer.

BACKGROUND: Among gynaecological malignancies, endometrial cancer (EC) is the most prevalent type of uterine cancer affecting women. This study explored the proteomic profiles of plasma samples obtained from EC patients, those with hyperplasia (Hy), and a control group (CO). A combination of techniques, such as 2D-DIGE, mass spectrometry, and bioinformatics, including pathway analysis, was used to identify proteins with modified expression levels, biomarkers and their associated metabolic pathways in these groups. METHODS: Thirty-four patients, categorized into three groups-10 with EC, 12 with Hy, and 12 CO-between the ages of 46 and 75 years old were included in the study. Untargeted proteomic analysis was carried out using two-dimensional difference in gel electrophoresis (2D-DIGE) coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). RESULTS: In all three groups, 114 proteins that were significantly (p ≤ 0.05 and fold change ≥ 1.5) altered were successfully identified using peptide mass fingerprints (PMFs). Compared with those in the control group (CO), the EC samples had 85 differentially expressed proteins (39 upregulated and 46 downregulated), and in the Hy group, 81 proteins were dysregulated (40 upregulated and 41 downregulated) compared to those in the CO group, while 33 proteins exhibited differential regulation (12 upregulated and 21 downregulated) in the EC plasma samples compared to those in the Hy group. Vitamin D binding protein and complement C3 distinguished Hy and EC from CO with the greatest changes in expression. Among the differentially expressed proteins identified, enzymes with catalytic activity represented the largest group (42.9%). In terms of biological processes, most of the proteins were involved in cellular processes (28.8%), followed by metabolic processes (16.7%). STRING analysis for protein interactions revealed that the significantly differentially abundant proteins in the three groups are involved in three main biological processes: signalling of complement and coagulation cascades, regulation of insulin-like growth factor (IGF) transport and uptake by insulin-like growth factor binding proteins (IGFBPs), and plasma lipoprotein assembly, remodelling, and clearance. CONCLUSION: The identified plasma protein markers have the potential to serve as biomarkers for differentiating between EC and Hy, as well as for early diagnosis and monitoring of cancer progression.

Effects of melatonin on disease improvement and serum levels of pro-inflammatory cytokines in patients with non-atypical endometrial hyperplasia.

BACKGROUND: Endometrial hyperplasia (EH), an abnormal proliferation of the endometrial cells, is considered as one of the most common causes of abnormal uterine bleeding. Previous studies have reported that melatonin plays a fundamental role in disease treatment. This study aimed the comparison of the effects of progesterone, as the most common therapeutic approach, and melatonin with progesterone alone in improvement of non-atypical endometrial hyperplasia (NEH) and changes in pro-inflammatory cytokine levels. METHODS: Study population consisted of 40 patients with NEH. Patients were divided into two groups, including 20 subjects treated with melatonin and progesterone and 20 individuals treated with progesterone alone. The blood and endometrial sampling was performed from participants before and after a three-month treatment. The histological examination was microscopically done. The serum levels of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) were measured using ELISA. RESULTS: There was no significant difference in the diabetes status and mean age between patients treated with progesterone and melatonin and those treated with progesterone alone. The improvement rate in the EH was significantly higher in individuals treated with progesterone and melatonin than those treated with progesterone alone (p < 0.05). Additionally, the patients treated with progesterone and melatonin showed significant increases inIFN-γ and TNF-αlevels compared to the control group (p < 0.001-P < 0.05). CONCLUSION: Melatonin supplementation has a beneficial effect in the treatment of EH due perhaps to enhance the level of IFN-γ and TNF-α.

Diagnostic, prognostic, and predictive importance of neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and CA125 in endometrial hyperplasia and carcinoma.

BACKGROUND: Inflammation has an important role in the progression of endometrial carcinoma. AIMS: The aim of this study is to find the association between neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and CA125 in endometrial hyperplasia and endometrial carcinoma. The study also focuses on the association of CA125, NLR, and PLR with histopathological parameters in endometrial carcinoma that are of prognostic importance. MATERIALS AND METHODS: This is a prospective cross-sectional study on 57 biopsy-proven cases of endometrial hyperplasia and carcinoma conducted over a period of two years. The NLR, PLR, and CA125 were calculated and recorded in all the 57 cases. RESULTS: The 57 cases were divided into three groups: endometrial hyperplasia without atypia group which included 36 cases, endometrial atypical hyperplasia group which included 10 cases, and the endometrial carcinoma group which included 11 cases. Comparison was done between the groups, and parity, NLR, PLR, and CA125 were found to be significant, but patient age and postmenopausal status were not significant. NLR, PLR, and CA125 were found to increase with higher grade, pT-stage, and nodal stage for the endometrial carcinoma cases. CONCLUSION: NLR, PLR, and CA125 were marginally increased or normal in the case of endometrial hyperplasia without atypia and endometrial atypical hyperplasia, while they were significantly increased in endometrial carcinoma, and also correlated with an increase in grade, pT-stage, and nodal stage. Hence, these can be considered for additional screening as diagnostic, prognostic, and predictive markers in case of abnormal uterine bleeding with endometrial pathology.

Is hemoglobin A1c valuable for predicting concurrent endometrial cancer in diabetic women with endometrial intraepithelial neoplasia?

AIM: The purpose of this study was to determine the predictive value of preoperative hemoglobin A1c (HgA1c) level for endometrial cancer in diabetic women with endometrial intraepithelial neoplasia (EIN). MATERIALS AND METHODS: Six hundred patients with EIN were retrospectively studied in a tertiary referral center in Turkey between January 2014 and December 2021. One hundred and thirteen diabetic patients with EIN who met the inclusion criteria were enrolled in the study and divided into three groups according to the final pathological results: Group 1 with benign findings (n = 29), Group 2 with EIN (n = 34) and Group 3 with endometrial cancer (n = 50). Demographic, clinical and biochemical characteristics were compared among the three groups. Receiver operating characteristic analysis (ROC) was used to evaluate the predictive value of HgA1c for concurrent endometrial cancer in EIN. RESULTS: Mean preoperative HgA1c levels were different among three groups (5.41 ± 0.64, 6.01 ± 0.72, 6.65 ± 1.15, p < 0.001, respectively). The highest value of HgA1c level was found in cancer group and difference within pairs was statistically significant (p < 0.001). Age and duration of menopause were also different among groups (p < 0.005). After adjustment of HgA1c level for age and duration of menopause differences were maintained (p < 0.001), the cutoff value was detected as ≥6.05% for HgA1c and sensitivity, specificity was 60%, 70%, respectively (p < 0.001). CONCLUSIONS: HgA1c could be used in prediction of endometrial cancer. The optimal cutoff value determined in our study could be considered in predicting endometrial cancer in diabetic women with EIN.

High level of visfatin and the activation of Akt and ERK1/2 signaling pathways are associated with endometrium malignant transformation in polycystic ovary syndrome.

This study aimed to assess the clinicopathological significance of serum levels and endometrium tissue expression of visfatin in polycystic ovary syndrome (PCOS) patients. A total of 80 PCOS patients and 80 matching controls were included in this study. We analyzed the relationship between the expression of visfatin in endometrium and clinicopathological characteristics in PCOS patients. The correlation between the expression of visfatin and p-Akt, Akt, p-ERK1/2, and ERK1/2 in PCOS tissues was evaluated as well. Visfatin expression in PCOS endometrial tissues were significantly higher than those in controls (p = .001). The expression of phosphorylation of Akt and ERK1/2 were significantly higher in PCOS endometrium tissues compared to controls (p < .05). Moreover, a high expression of tissue visfatin in PCOS tissues was positively correlated with the expression of p-Akt (p = .015), and p-ERK1/2 (p = .013). Western blotting revealed that protein expression of visfatin in PCOS patients with endometrial hyperplasia and cancer was higher than that in patients with normal endometrium tissues, and the difference was statistically significant (p = .027). The expression of p-Akt (p = .018) and p-ERK1/2 (p = .035) in PCOS patients with endometrial hyperplasia and cancer was significantly higher than that in patients with normal endometrium tissues. Visfatin may be a potential biomarker for endometrial malignant transformation in PCOS patients.

Plasma growth differentiation factor-15 is an independent marker for aggressive disease in endometrial cancer.

OBJECTIVE: Better biomarkers are needed in order to identify patients with endometrial carcinoma at risk of recurrence and who may profit from a more aggressive treatment regimen. Our objective was to explore the applicability of plasma growth differentiation factor 15 (GDF-15) as a marker for recurrent disease, as well as a marker for poor prognosis and lymph node metastases. METHODS: EDTA-blood samples were obtained from 235 patients with endometrial cancer before primary surgery. For 36 of these patients, matching blood samples were collected at time of recurrence. Blood samples were also collected from 78 patients with endometrial hyperplasia. Plasma GDF-15 was measured by an enzyme-linked immunosorbent assay (ELISA). Preoperative pelvic MRI scans for 141 patients were investigated in parallel for imaging variables. RESULTS: Preoperative plasma level of GDF-15 was significantly higher for patients who experienced recurrence (1780 ng/L; 95% CI; 518-9475 ng/L) than for patients who did not develop recurrent disease (1236 ng/L; 95% CI; 307-7030 ng/L) (p<0.001). Plasma levels of GDF-15 at recurrence (2818 ng/L, 95% CI 2088-3548 ng/L) were significantly higher than plasma levels of GDF-15 measured at time of primary diagnosis (1857 ng/L, 95% CI; 1317-2398 ng/L) (p = 0.001). High plasma level GDF-15 independently predicts recurrent disease (OR = 3.14; 95% CI 2.10-4.76) and lymph node metastases (OR = 2.64; 95% CI 1.52-4.61). Patients with high plasma level of GDF-15 had significantly larger tumor volume (p = 0.008). CONCLUSION: Elevated plasma level of GDF-15 is associated with aggressive disease and lymph node metastasis in endometrial carcinoma. GDF-15 may be helpful in indicating recurrent disease.

Quantification of Leydig cells and stromal hyperplasia in the postmenopausal ovary of women with endometrial carcinoma.

Endometrioid endometrial carcinomas (EECs) are correlated with high serum levels of androgens and estrogen. We hypothesized that Leydig cells and ovarian stromal hyperplasia contribute to postmenopausal ovarian androgen production and are observed more frequently in EEC patients. Ovaries of postmenopausal women with EEC (n = 36) or non-endometrioid endometrial carcinoma (NEEC; n = 19) were examined for the presence of hilar Leydig cells and compared with ovaries resected for benign conditions (n = 22). Leydig cells were counted manually, and a Leydig cell density was calculated per millimeter squared hilar surface. Ovarian stromal hyperplasia was scored as atrophic, moderate hyperplastic, or marked hyperplastic. In all endometrial carcinomas, these findings were correlated with the serum levels of sex steroids and hormone receptor expression in their endometrial carcinomas. In EEC patients, mean number of Leydig cells was 282.8 cells compared with 76.3 cells in NEEC patients and 66.4 cells in controls. Leydig cells, marked stromal hyperplasia, and combined presence were observed more frequently in EEC patients compared with NEEC and controls. Combined presence was associated with higher serum sex steroid levels and increased tumor expression of estrogen and progesterone receptor. A cutoff value for Leydig cell hyperplasia could be proposed at a total of 300 Leydig cells bilaterally, examining a representative cross section of both hili. Concluding, we have quantified hilar Leydig cells and demonstrated that Leydig cells may contribute to the development of EEC by increased androgen production in postmenopausal women. The correlation between sex hormone levels and Leydig cell hyperplasia may support endometrial pathology screening in these women.

The Effects of Folic Acid Supplementation on Recurrence and Metabolic Status in Endometrial Hyperplasia: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Data on the effects of folic acid supplementation on clinical symptoms and metabolic profiles of patients with endometrial hyperplasia (EH) are limited. This investigation was performed to evaluate the effects of folic acid supplementation on clinical symptoms and metabolic status of patients with EH. METHODS: This randomized, double-blind, placebo-controlled trial was conducted among 60 women diagnosed with EH. Diagnosis of EH was made based on biopsy results. Participants were randomly allocated to 2 groups to take 5 mg/d folic acid supplements (n = 30) or placebo (n = 30) for 12 weeks. RESULTS: After the 12-week intervention, folic acid supplementation significantly decreased fasting plasma glucose (ß -3.99 mg/ dL; 95% CI, -7.39, -0.59; P = 0.02), serum insulin levels (ß -2.82 µIU/mL; 95% CI, -4.86, -0.77; P = 0.008), homeostasis model assessment for insulin resistance (ß -0.68; 95% CI, -1.20, -0.17; P = 0.009), triglycerides (ß -16.47 mg/dL; 95% CI, -28.72, -4.22; P = 0.009) and very-low-density lipoprotein (VLDL) cholesterol (ß -3.29 mg/dL; 95% CI, -5.74, -0.84; P = 0.009), and significantly increased the quantitative insulin sensitivity check index (ß 0.01; 95% CI, 0.004, 0.03; P = 0.01) compared with the placebo. Additionally, folic acid intake resulted in a significant reduction in serum high sensitivity C-reactive protein (hs-CRP) (ß -0.36 mg/L; 95% CI, -0.52, -0.21; P < 0.001) compared with the placebo. Folic acid supplementation did not affect other metabolic parameters. CONCLUSION: In conclusion, we found that folic acid administration for 12 weeks to subjects with EH improved glycemic control, triglycerides, VLDL-cholesterol and hs-CRP levels, but did not influence recurrence and other metabolic profiles.

Predictive Value of Hematological Inflammatory Markers in Endometrial Neoplasia

Objective: To investigate the predictive role of neutrophil lymphocyte ratio (NLR) and the platelet lymphocyte ratio (PLR) as hematological inflammatory markers in cases of endometrial hyperplasia and cancer. Material and Method: This retrospective study was performed between 2005-2015 with 247 cases of 83 endometrial adenocarcinoma (group 1), 64 of endometrial hyperplasia (group 2) and 100 controls (group 3) who underwent a curettage due to abnormal uterine bleeding and had a normal histopathology in our tertiary clinic. The cases were chosen from patients without chronic diseases, that do not have infection or medication that could affect the systemic inflammatory response. Preintervention blood parameters were taken into account. The neutrophil/ lymphocyte and platelet/lymphocyte ratios were and statistical comparisons of the groups were conducted. Results: The age distribution of 247 patients was between 26 and 85 years, and the mean age was 48.8 ± 8.92.The median age was 54 in group 1, 46 in group 2 and 45 in group 3. The age was significant between group 1 and the other groups (p=0.001). Some 71% of the cases were premenopausal and 29% were postmenopausal, the latter being significantly more frequent in group 1 (62.7%; p=0.001). Of the cases with endometrial hyperplasia, 42 (65.6%) had simple and 22 (34.4%) have atypical-complex lesions. The median NLRs in groups 1, 2, and 3 were 2.15, 2.10, and 1.92, respectively, with median PLRs of 135.1, 134.0 and 145.6. There was a statistically significant difference between the NLR measurements of the cases from different groups (p=0.048; p<0.05). The NLR value for the endometrial adenocarcinoma group was significantly higher than for the control group (p=0.033; p<0.05). The optimum cut-off value was calculated to be ≥4, at which sensitivity was 20.5%, specificity 99%, positive predictive value (PPV) 94.4% and negative predictive value (NPV) 60%. Conclusion: The value of NLR ≥4 has predictive significance in distinguishing endometrial pathologies before intervention in patients with abnormal uterine bleeding. Simple, cheap and easy-to-perform, the NLR can be used as a potential hematological marker for endometrial malignancy.

Matrix Metalloproteinases and Their Tissue Inhibitors in Blood Serum of Patients with Endometrial Cancer: Clinical and Morphological Correlations.

In patients with endometrial cancer (N=94), endometrial polyps (N=28), endometrial hyperplasia (N=25), and healthy women (N=77), the serum contents of MMP-2, MMP-7, MMP-9, TIMP-1, and TIMP-2 were measured by ELISA. Both carcinoma and benign neoplasms were accompanied by significant elevation of MMP-7 and TIMP-2 in blood serum. The greatest elevation (in comparison with the control) was observed for MMP-7, although serum concentration of this marker was practically identical in patients with carcinoma and benign tumors. In contrast, the levels of MMP-2 and TIMP-1 were lower in cancer patients in comparison with the control; in these patients, the levels of MMP-9 and TIMP-1 were also lower than the corresponding levels in patients with polyps and endometrial hyperplasia. There were no significant correlations between the levels of examined markers with tumor metastasizing, its histological structure, and differentiation degree of endometrial cancer. No differences were observed between examined serological markers in patients with polyps and endometrial hyperplasia of various severities. The examined MMPs and TIMPs cannot be advanced as potential diagnostic markers of endometrial cancer, but they can be used to monitor and prognosticate the disease and to assess effectiveness of the targeted therapy.

Chronic low-dose exposure of nonylphenol alters energy homeostasis in the reproductive system of female rats.

Nonylphenol (NP) as a confirmed endocrine disrupt chemical that causes reproductive and developmental toxicity. Previous studies focused only on short-term, high-dose exposure in vivo, or in vitro on female reproductive toxicity, which cannot accurately simulate the real human exposure scenario. The present study aims to explore NP toxicity and the underlying mechanisms of chronic low-dose NP exposure (500 µg/kg·bw/day, for 8 weeks) in the reproductive system of female rats. The results indicated that NP exposure caused female reproductive toxicity, including alterations in serum 17ß-estradiol (E2) levels, endometria hyperplasia, altered oogenesis and significant changes in the metabolic profile observed in urine, serum, uterus and ovary. Furthermore, expression of the energy-sensitive proteins carnitine palmitoyltransferase I (CPTI), adenosine 5'-monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma (PPAR-γ) were found to be down-regulated in uterus under NP exposure, which suggested the impaired fatty acid oxidation. Accordingly, a comprehensive metabolomics study in key reproductive tissues and body fluids revealed that 12 metabolites were associated with energy metabolism as potential biomarkers for the evaluation of low toxicity at early stages, with L-carnitines being the most representative ones. The present findings provide evidence that chronic low-dose NP exposure can significantly disrupt energy homeostasis in females, thus offering further insights into NP reproductive toxicity.

Administration of Cabergoline Contributes to Preserving Fertility in Young Hyperprolactinemic Patients With Endometrial Cancer Treated With Medroxyprogesterone Acetate.

BACKGROUND: An association between high levels of serum prolactin and endometrial cancer (EC) has been reported. However, the effect of antiprolactin drugs on hyperprolactinemic patients with EC has not been determined. The aim of this study was to confirm the effect of cabergoline on young hyperprolactinemic patients treated with medroxyprogesterone acetate (MPA) for the preservation of fertility. METHODS: A retrospective observational study was conducted to identify patients with atypical endometrial hyperplasia or early-stage EC aged 40 years or younger who were treated with oral MPA in Kumamoto University Hospital between 1998 and 2016. RESULTS: Thirty-four patients were identified and divided into two groups of 17 patients each, including a nonadministration of cabergoline group (noncabergoline group) and an administration of cabergoline group (cabergoline group). The ratio of pathological diagnoses of EC in the noncabergoline group was significantly lower than that in the cabergoline group (29.4% vs 70.6%, P = 0.016). The mean serum prolactin levels showed a significant decrease after the administration of cabergoline in the cabergoline group (25.2 [24.0] vs 5.2 [4.2] ng/mL, P = 0.003), and this decreased level was also significantly lower than that in the noncabergoline group (5.2 [4.2] vs 12.0 [5.0] ng/mL, P < 0.001). Kaplan-Meier analysis conducted for 150 months revealed that the estimated mean period until hysterectomy in the noncabergoline group was significantly shorter than that in the cabergoline group (83.5 vs 140.8 months, P = 0.007). Significant differences were observed in EC but not atypical endometrial hyperplasia based on histological classification (25.6 vs 138.0 months, P = 0.001). CONCLUSIONS: The administration of cabergoline may contribute to preserving fertility in young hyperprolactinemic patients with EC who were treated with MPA.

The utility of sentinel lymph node mapping in the management of endometrial atypical hyperplasia.

OBJECTIVES: To determine the risk of endometrial cancer (EC) and lymph node involvement in patients with a preoperative diagnosis of "AH-only" versus "AH - cannot rule out carcinoma" and to study the value of SLN mapping. METHODS: We reviewed all patients with a preoperative diagnosis of atypical hyperplasia, who underwent primary surgery with SLN mapping followed by pelvic lymphadenectomy. Sensitivity and negative predictive value (NPV) of SLN and rates of endometrial cancer were calculated. RESULTS: Overall, 64/120 (53.3%) patients were found to have EC on final pathology: 58 stage IA, 3 IB, and 3 IIIC1. In patients with preoperative diagnosis of "AH", 44.3% (31/70) had EC on final pathology compared to 66% (33/50) in patients with "AH - cannot rule out cancer" (p=0.02). Overall, 3.3% of the patients (4/120) had lymph node involvement. In patients with EC with a pre-operative diagnosis of "AH", none had lymph node metastasis (0/31), compared to 12.1% (4/33) in patients with "AH - cannot rule out cancer" (p=0.06). Elevated preoperative CA125 levels (>25U/mL) were statistically associated with the risk of lymph node metastasis on final pathology (p=0.024). Unilateral and bilateral SLN detection occurred in 93.7% and 78.1% respectively. In patients with EC and bilateral SLN mapping, sensitivity and NPV were respectively 66.6% and 97.9%. There was one false negative (ITCs in non-SLN). CONCLUSION: Our data indicate that the risk of lymph node involvement in patients with a preoperative diagnosis of "AH-only" is null. Lymph node assessment could be omitted in those patients. Conversely this risk is significant in patients with "AH - cannot rule out cancer". SLN mapping could be a valuable staging procedure in these patients.

The role of human epididymis secretory protein E4 in patients with endometrial cancer and premalignant endometrial lesions.

We evaluated the concentrations of human epididymis secretory protein E4 (HE4) and Ca-125 in relation to clinicopathologic features in patients with endometrial cancer and premalignant endometrial lesions. Women with abnormal uterine bleeding (n = 167) who underwent endometrial sampling were divided into four groups. Group 1: endometrial cancer (n = 68), group 2: atypical endometrial hyperplasia (n = 12), group 3: endometrial hyperplasia without atypia (n = 39) and group 4: controls (n = 48). Women with endometrial cancer exhibited higher concentrations of HE4 levels than controls (91.4 pmol/L vs. 46.2 pmol/L, p < 0.001). HE4 levels were significantly higher in patients with lymphatic involvement, deep myometrial invasion, lymphovascular space involvement and non-endometrioid histology (p < 0.001). The sensitivity, specificity, positive and negative predictive values for HE4 in detecting endometrial cancer were 72.7%, 84.4%, 80% and 78.4%, respectively. Preoperative HE4 levels are more elevated in women with endometrial cancer than those with benign endometrium as well as in women with prognostic high-risk factors with endometrial cancer. HE4 may be used as an additional marker in combination with other clinicopathologic features for planning the treatment.

Antioxidant status and sex hormones in women with complex endometrial hyperplasia.

Endometrial tissue is under a strong influence of sex hormones. These hormones are considered as developmental factors of endometrial hyperplasia and endometrial cancer. We examined the influence of gonadotropins (follicle-stimulating and luteinizing hormone) and sex hormones (estradiol, progesterone) on oxidant/antioxidant parameters in blood and endometrial tissue of women with complex endometrial hyperplasia. In blood, superoxide dismutase activity was significantly higher in luteal phase and postmenopause compared to the follicular phase. A significant phase-related difference of glutathione peroxidase and glutathione reductase activity was recorded in the endometrium. Both enzymes had lower activity in luteal phase and postmenopause compared to the follicular phase. The linear regression analysis of individual hormonal variables against antioxidant parameters showed negative correlation between glutathione peroxidase activity and gonadotropin concentrations in the endometrium. The regression of hyperplastic to normal endometrium is the purpose of conservative treatment based on administration of progestogens or gonadotropin-releasing hormone analogues. Our findings indicate that gonadotropins influence the antioxidant enzymes activity in women with complex endometrial hyperplasia, which may affect disease development. Further studies are needed to clarify the molecular basis of hormone action on antioxidant system that may potentially initiate a development of treatments based on redox-dependent mechanism.

Effects of sulpiride and ethylene glycol monomethyl ether on endometrial carcinogenicity in Donryu rats.

Sulpiride and ethylene glycol monomethyl ether (EGME) are known ovarian toxicants that stimulate prolactin (PRL) secretion, resulting in hypertrophy of the corpora lutea and increased progesterone (P4) production. The purpose of the present study was to investigate how the PRL stimulatory agents affected uterine carcinogenesis and to clarify the effects of PRL on endometrial adenocarcinoma progression in rats. Ten-week-old female Donryu rats were treated once with N-ethyl-N'-nitro-N-nitrosoguanidine (20 mg kg(-1) ), followed by treatment with sulpiride (200 ppm) or EGME (1250 ppm) from 11 weeks of age to 12 months of age. Sulpiride treatment inhibited the incidence of uterine adenocarcinoma and precancerous lesions of atypical endometrial hyperplasia, whereas EGME had no effect on uterine carcinogenesis. Sulpiride markedly prevented the onset of persistent estrus throughout the study period, and EGME delayed and inhibited the onset of persistent estrus. Moreover, sulpiride-treated animals showed high PRL and P4 serum levels without changes in the levels of estradiol-17ß, low uterine weights and histological luteal cell hypertrophy. EGME did not affect serum PRL and P4 levels. These results suggest that the prolonged low estradiol-17ß to P4 ratio accompanied by persistent estrous cycle abnormalities secondary to the luteal stimulatory effects of PRL may explain the inhibitory effects of sulpiride on uterine carcinogenesis in rats. Copyright © 2015 John Wiley & Sons, Ltd.

Prognostic factors of oncological and reproductive outcomes in fertility-sparing treatment of complex atypical hyperplasia and low-grade endometrial cancer using oral progestin in Chinese patients.

OBJECTIVE: To evaluate the efficacy and fertility outcomes of progestin treatment for complex atypical hyperplasia (CAH)/grade I endometrial cancer (G1EC) in Chinese patients (≤40years old). METHODS: Women ≤40years old who were treated with progestin for CAH or G1EC were identified from 9 provinces of China. The time to achieve complete response (CR) and the time from CR to recurrence or pregnancy were censored for patients without events and were analyzed for associations between patient and treatment characteristics. RESULTS: Thirty-two patients were included: 13 with CAH and 19 with G1EC. Nine patients exhibited elevated serum HbA1C before treatment. After a mean follow-up of 32.5months, the CR rate was 84.4%. Patients who exhibited elevated HbA1C were more likely to experience CR, while those with polycystic ovarian syndrome (PCOS) exhibited the opposite outcome (p=0.01, 0.03). Nine of 21 patients experienced clinical pregnancies. Eight patients underwent assisted reproductive technology (ART). Five patients had newborn infants. Patients undergoing ART were more likely to become pregnant (p=0.04). CONCLUSION: Oral progestin is an effective fertility-sparing treatment for women with CAH/G1EC in China. Patients with elevated HbA1C receiving both metformin and progestin were more likely to achieve CR, whereas those with PCOS were not. ART is a good choice for clinical pregnancy after treatment.

Relations of Platelet Indices with Endometrial Hyperplasia and Endometrial Cancer.

BACKGROUND: Platelets are blood elements thought to play a role in the immune system and therefore tumor development and metastasis. Platelet activation parameters such as mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT) can be easily evaluated with the whole blood count and have been studied as markers of systemic inflammatory responses in various cancer types. Our aim in this study was to evaluate the correlation between endometrial pathologies and MPV, PDW and PCT. MATERIALS AND METHODS: A total of 194 patients who presented to our clinic with abnormal vaginal bleeding were included in our study. The patients were divided into 3 groups (endometrial hyperplasia, endometrial cancer, control) according to their pathology results. The groups were compared for MPV, PDW, and PCT values obtained from the blood samples taken on endometrial biopsy day. RESULTS: The endometrial cancer patients were the oldest group (p=0.04). There was no significant difference between the three groups in terms of white blood cell count (WBC), platelet count (PC), and hemoglobin (Hb) level. The highest MPV (p<0.001), PDW (p=0.002), and PCT (p<0.001) levels were in the endometrial cancer group, and the lowest levels were in the control group. CONCLUSIONS: The easy evaluation of platelet parameters in patients who are suspected of having endometrial pathology is a significant advantage. We found MPV, PDW, and PCT to be correlated with the severity of endometrial pathology with the highest values in endometrial cancer. Studies to be conducted together with different laboratory parameters will further help evaluate the diagnosis and severity of endometrial cancer and precursor lesions.

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in patients with endometrial hyperplasia and endometrial cancer.

AIM: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and platelet distribution width (PDW) may indicate the systemic inflammatory response associated with various cancers. We aimed to investigate the relationship between NLR, PLR, PDW and endometrial pathologies including hyperplasia and cancer. METHODS: In this study, 472 cases who underwent endometrial biopsy were included. Three groups were constituted with respect to biopsy results: group 1, endometrial cancer patients (n = 54); group 2, endometrial hyperplasia patients (n = 152); and group 3, patients with normal biopsy results (n = 281). White blood cell and platelet counts as well as NLR, PLR and PDW recorded from complete blood counts obtained on the same day of biopsy were compared in the three groups. RESULTS: Endometrial cancer patients were significantly older than the cases in the other two groups (P < 0.001). The NLR in group 1 was significantly higher than group 3 (P = 0.02). However, there was no difference between the three groups with respect to PLR (P = 0.167). PDW was increased in group 1 compared to group 3 (P < 0.001). CONCLUSION: Results of our study have shown that NLR, PLR and PDW are simple, readily available and robust inflammatory markers that may be used in the management of endometrial pathologies. However, the actual predictive potential of these biomarkers still warrants further trials.