c-peptide and Endometrial-Hyperplasia

Preclinical studies in endometrial cancer (EC) show that metformin reduces cellular proliferation by PI3K-AKT-mTOR inhibition. We tested the hypothesis that short-term presurgical metformin reduces cellular proliferation in atypical endometrial hyperplasia (AEH) and endometrioid EC, and assessed the feasibility of using phosphorylated PI3K-AKT-mTOR proteins as tissue end points.. Women with AEH or EC received metformin 850 mg twice a day or no drug in the presurgical window between diagnosis and hysterectomy. Before and after the window, tissue samples were obtained; serum markers of insulin resistance (e.g. homeostasis model of assessment of insulin resistance index) were determined; and anthropometrics measured (e.g. BMI). Cell proliferation (Ki-67) and PI3K-AKT-mTOR phosphostatus were assessed by immunohistochemistry and scored blinded to treatment.. Twenty-eight metformin-treated and 12 untreated patients, well matched for age and BMI, completed the study. Metformin treatment (median 20 days, range 7-34) was associated with a 17.2% reduction in tumour Ki-67 (95% CI -27.4, -7.0, P=0.002), in a dose-dependent manner. Tumour PI3K-AKT-mTOR protein phosphostatus varied but the effects were not significant after adjusting for changes in controls.. Short-term metformin was associated with reduced Ki-67 expression in EC. Changes in tumour PI3K-AKT-mTOR protein phosphostatus were seen in both groups. Future studies should address the variability attributed to different sampling techniques including devascularisation of the uterus at hysterectomy.

Topics: Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Carcinoma, Endometrioid; Endometrial Hyperplasia; Endometrial Neoplasms; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypoglycemic Agents; Hysterectomy; Immunohistochemistry; Insulin; Insulin Resistance; Ki-67 Antigen; Metformin; Middle Aged; Myometrium; Neoadjuvant Therapy; Neoplasm Grading; Neoplasm Invasiveness; Phosphatidylinositol 3-Kinases; Phosphorylation; Preoperative Care; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Treatment Outcome

To investigate the mRNA, protein expression and tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) in endometrial carcinoma.. Sixty-three endometrial carcinoma (EC) patients, 21 endometrial atypical hyperplasia (AHE) patients and 22 normal control (NE) entered this study. Their clinical information were collected. Fasting serum C-peptide concentration was measured. Expression of IRS-1 in endometrium was examined by RT-PCR and western blot. Immunoprecipitation was used to measure the tyrosine phosphorylation of IRS-1.. C-peptide concentration in EC group was higher than that in NE group [(3.2 +/- 1.1) vs (2.5 +/- 0.7) microg/L, P=0.007]. There were no significant differences in IRS-1 mRNA and protein expression among the three groups. Tyrosine phosphorylation of IRS-1 in EC group [(62 +/- 36) %] was higher than that in AHE and NE groups [(53 +/-34)% and (35 +/- 33)%; P=0.048, 0.002]. IRS-1 activation in AHE group was also higher than normal control (P=0.045). IRS-1 activation in endometrioid carcinoma [(69 +/- 33) %] was higher than that in other histological types [(34 +/- 31)%; t=2.300, P=0.025]. IRS-1 tyrosine phosphorylation was significantly higher in patients with advanced stage, high grade, deep myometrial invasion and pelvic lymph node metastasis. IRS-1 activation in endometrium was positively correlated with fasting serum C-peptide concentration (r=0.491, P=0.001).. There is excessive activation of IRS-1 in endometrial carcinoma and atypical hyperplasia. Activation of IRS-1 in endometrial carcinoma is related with poor clinical-pathologic features and may be a prognostic predictor for this tumor. Over-activation of IRS-1 may be an intermediate event linking the hyperinsulinemia and endometrial carcinoma.

Topics: Adenocarcinoma; C-Peptide; Case-Control Studies; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Female; Humans; Insulin Receptor Substrate Proteins; Lymphatic Metastasis; Middle Aged; Neoplasm Staging; Phosphorylation; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tyrosine

A total of 97 patients suffering from endometrial polyposis, hyperplasia, adenomatous hyperplasia, and carcinoma were examined. The levels of malonic dialdehyde as an index of lipid peroxidation, average-mass molecules, C peptide, humoral immunity parameters were studied. The content of circulating immune complexes were also determined. Specific changes which might be an auxiliary factor in predicting the therapy and forming cancer risk groups were identified.

Topics: C-Peptide; Endometrial Hyperplasia; Female; Humans; Lipid Peroxidation; Malondialdehyde; Molecular Weight; Risk Factors; Toxins, Biological; Uterine Neoplasms