Evaluation of the expression of necroptosis pathway mediators and its association with tumor characteristics in functional and non-functional pituitary adenomas.

BACKGROUND: Pituitary adenomas impose a burden of morbidity on patients and characterizing the molecular mechanisms underlying its pathogenesis received remarkable attention. Despite the appealing role of necroptosis as an alternative cell death pathway in cancer pathogenesis, its relevance to pituitary adenoma pathogenesis has yet to be determined that is perused in the current study. METHODS: The total number of 109 specimens including pituitary adenomas and cadaveric healthy pituitary tissues were enrolled in the current study. Tumor and healthy pituitary tissues were subjected to RNA extraction and gene analysis using Real-Time PCR. The expression levels of necroptosis markers (RIP1K, RIP3K and, MLKL) and their association with the patient's demographic features were evaluated, also the protein level of MLKL was assessed using immunohistochemistry in tissues. RESULTS: Based on our data, the remarkable reduction in RIP3K and MLKL expression were detected in nonfunctional and GH-secreting pituitary tumors compared to pituitary normal tissues. Invasive tumors revealed lower expression of RIP3K and MLKL compared to non-invasive tumors, also the attenuated level of MLKL was associated with the tumor size in invasive NFPA. The simultaneous down-regulation of MLKL protein in pituitary adenoma tissues was observed which was in line with its gene expression. While, RIP1K over-expressed significantly in both types of pituitary tumors which showed no significant correlation with patient's age, gender and tumor size in GHPPA and NFPA group. Notably, MLKL and RIP3K gene expression was significantly correlated in the GHPPA group. CONCLUSIONS: According to our data, the reduced expression of necroptosis mediators (RIP3K, MLKL) in pituitary adenoma reinforces the hypothesis that the necroptosis pathway can be effective in regulating the proliferation and growth of pituitary tumor cells and tumor recurrence.

Up-regulation of sex-determining region Y-box 9 (SOX9) in growth hormone-secreting pituitary adenomas.

BACKGROUND: Pituitary adenomas are benign brain tumors that cause considerable morbidity and neurological symptoms. SOX9 as a regulatory transcriptional mediator affects normal and tumor cell growth with an undefined role in pituitary adenomas pathogenesis. Thus, in the present study, the expression pattern of SOX9 in GH-secreting pituitary tumors and normal pituitary tissues is investigated. METHODS: The SOX9 gene expression level was evaluated in 60 pituitary tissues including different types of GH-secreting adenomas and normal pituitary tissues through Real-Time PCR. The protein level of SOX9 was assessed using immunohistochemistry. The correlations of SOX9 gene and protein expression level with the patient's clinical and pathological features were considered. RESULTS: The SOX9 over-expression was detected in GH-secreting adenomas tumor tissues compared to normal pituitary tissues which were accompanied by overexpression of SOX9 protein in tumor tissues. The over-expression of SOX9 had a significant impact on GH-secreting adenomas tumor incidence with the odds ratio of 8.4 and the diagnostic value of SOX9 was considerable. The higher level of SOX9 expression was associated with invasive and macro tumors in GH-secreting pituitary adenoma patients. The positive correlation of SOX9 gene and protein level was observed and the tumor size and tumor invasive features were valuable in predicting SOX9 expression level in GH-producing pituitary tumors. CONCLUSION: The study provided the first shreds of evidence regarding the expression pattern of SOX9 in the GH- secreting pituitary adenomas at both gene and protein levels which may emphasize the possible involvement of SOX9 as a mediator in pituitary adenoma tumor formation also open up new intrinsic molecular mechanism regarding pituitary adenoma pathogenesis.

Up-regulation of 15-lipoxygenase enzymes and products in functional and non-functional pituitary adenomas.

BACKGROUND: Pituitary adenoma accounts as a complex and multifactorial intracranial neoplasm with wide range of clinical symptoms which its underlying molecular mechanism has yet to be determined. The bioactive lipid mediators received attentions toward their contribution in cancer cell proliferation, progression and death. Amongst, 15-Lipoxygense (15-Lox) enzymes and products display appealing role in cancer pathogenesis which their possible effect in pituitary adenoma tumor genesis is perused in the current study. METHODS: The 15-Lipoxygenses isoforms expression level was evaluated in tumor tissues of prevalent functional and non-functional pituitary adenomas and normal pituitary tissues via Real-Time PCR. The circulating levels of 15(S) HETE and 13(S) HODE as 15-Lox main products were assessed in serum of patients and healthy subjects using enzyme immunoassay kits. RESULTS: Our results revealed that 15-Lox-1 and 15-Lox-2 expression levels were elevated in tumor tissues of pituitary adenomas comparing to normal pituitary tissues. The elevated levels of both isoforms were accompanied with 15(S) HETE and 13(S) HODE elevation in the serum of patients. The 15-Lox-1 expression and activity was higher in invasive tumors as well as tumors with bigger size indicating the possible pro-tumorigenic role of 15-Lox-1, more than 15-Lox-2 in pituitary adenomas. The diagnostic value of 15-Lipoxygense isoforms and products were considerable between patients and healthy groups. CONCLUSION: The possible involvement of 15-Lipoxygense pathway especially 15-Lox-1 in the regulation of pituitary tumor growth and progression may open up new molecular mechanism regarding pituitary adenoma pathogenesis and might shed light on its new therapeutic strategies.

COMPARISON OF CABERGOLINE VERSUS RALOXIFENE ADD-ON THERAPY TO LONG-ACTING SOMATOSTATIN ANALOGUE IN PATIENTS WITH INADEQUATELY CONTROLLED ACROMEGALY: A RANDOMIZED OPEN LABEL CLINICAL TRIAL.

OBJECTIVE: The present study aimed to evaluate the efficacy of add-on therapy of cabergoline versus raloxifene to long-acting somatostatin analogues (SAs) in patients with inadequately controlled acromegaly. METHODS: This was a prospective, randomized open label clinical trial. Forty-four patients (22 per group) completed the study; where participants received either cabergoline (3 mg/week) or raloxifene (60 mg twice daily) add-on therapy for 12 weeks in a parallel manner. The primary outcome was the rate of reduction in serum insulin-like growth factor 1 (IGF-1) from baseline. Secondary outcomes comprised normalization of serum IGF-1 for age and sex. RESULTS: Serum IGF-1 was significantly decreased in both the cabergoline (40.3 ± 25.6%, P<.001) and raloxifene (31.5 ± 24.6%, P<.001) groups, with no significant difference between arms ( P>.05). Normalization in serum IGF-1 values occurred in 40.9% of patients who were on cabergoline compared to 45.5% of those receiving raloxifene ( P = .76). The subsequent logistic regression analysis highlighted baseline IGF-1 as a significant predictor of IGF-1 normalization (odds ratio, 0.995; 95% confidence interval, 0.990-0.999; P = .02). Using the receiver operating characteristic (ROC) curve analysis for the entire group, the baseline IGF-1 value of 1.47 the upper limit of normal (ULN) was the best cut-off point to identify patients with normal IGF-1 at the end of the study (sensitivity: 52.6%, specificity: 84.0%, Yoden's index: 0.366). Full biochemical control of acromegaly was achieved in 22.7% of patients in the cabergoline group compared to 13.6% of those in the raloxifene group ( P = .43). CONCLUSION: Cabergoline and raloxifene add-on therapy could effectively decrease serum IGF-1 level in patients with inadequately controlled acromegaly. The efficacy profiles of both drugs are comparable. ABBREVIATIONS: DA = dopamine agonist; FBG = fasting blood glucose; GH = growth hormone; IGF1 = insulin-like growth factor-1; IQR = interquartile range; OR = odds ratio; ROC = receiver operating characteristic; SA = somatostatin analogue; SERM = selective estrogen modulator receptor; ULN = upper limit of normal.

Prostaglandin F2 alpha plasma concentration predicts glycemic control and oxidation status in patients with type 2 diabetes mellitus.

BACKGROUND: 8-iso-PGF2α is a family of PGF2α that could be offered as a non-invasive tool to represent in vivo oxidation status, as a link between oxidative milieus and vascular dysfunction. METHODS: A total of 45 patients with type 2 diabetes and 45 healthy adults were studied in this cross-sectional analysis. Blood samples were collected to measure the level of lipid profile, oxidative stress, and glycemic control indices. The sensitivity and specificity of 8-iso-PGF2α as a screening test were analyzed in the cut-off range 252 - 377.5 pg/mL and the corresponding receiver operating characteristics (ROC) were plotted to assess performance of the test. RESULTS: 8-iso-PGF2α level was significantly higher in the diabetic group (439.11 pg/mL ± 181.13 vs. 380.93 pg/mL ± 146.52). After adjustments for age, gender, and body mass index (BMI), linear regression analysis revealed that homeostasis model assessment of insulin resistance (HOMA-IR), blood pressure, fasting blood sugar (FBS), serum creatinine, insulin, oxLDL, and CRP levels are directly correlated with 8-iso-PGF2α in the 25% - 75% quartiles. Moreover, their mean levels were higher in quartiles with greater 8-iso-PGF2α levels. The cut-offs showing the best equilibrium between sensitivity and specificity approached 269.5 pg/mL with 83% and 62.5% sensitivity and specificity, respectively. CONCLUSIONS: Our study provides evidence for the application of serum 8-isoPGF2α in the 25 - 75% quartile ranges to screen for the severity of oxidative reactions and glycemic control in vivo without need for any further in vitro enzymatic reactions, with higher levels, reflecting more severe oxidation and poor glycemic control.

Iran Pituitary Tumor Registry: Description of the Program and Initial Results.

BACKGROUND: This study was designed to present initial results on clinical presentation, therapeutic modalities, and outcome information of patients with pituitary tumors registered in Iran Pituitary Tumor Registry (IPTR). METHODS: We collected data from a web-based electronic medical records of patients with various pituitary tumors referred to four tertiary care centers in the country. Retrospective analysis was performed on demographic, clinical, and therapeutic information of 298 patients including 51 clinically nonfunctioning adenoma (CNFA), 85 acromegaly, 135 prolactinoma, and 27 Cushing's disease (CD). RESULTS: From October 2014 to July 2016, 298 people with the diagnosis of pituitary tumor were registered. Prolactinoma was the most prevalent tumor (45.3%), followed by Acromegaly (28.6%), CNFPA (17.1%), and CD (9%). Female dominance was seen among patients with prolactinoma and CD, while the majority of patients with CNFPA were male and acromegaly was equally distributed between men and women. Hypogonadal symptoms were almost always seen in all types of pituitary groups. Surgery alone was the most common therapeutic modality used in cases of acromegaly, CNFPA, and CD. However, medical therapy alone was frequently applied for cases of prolactinoma. Finally, biochemical cure was achieved in most cases of prolactinoma and CD, but only in 36.5% of acromegalics. Moreover, 80% of patients suffering from CNFPA showed no residual tumor in their imaging. CONCLUSION: In conclusion, this comprehensive tumor registry enables early identification, selection of best therapeutic approaches, and evaluation of long-term treatment outcomes. Furthermore, this registry can be used to improve surveillance protocols.

The lost correlation between heat shock protein 70 (HSPA1A) and plasminogen activator inhibitor-1 in patients with type 2 diabetes and albuminuria.

We aimed to study the relation between plasma levels of stress-induced heat shock protein 70 (HSPA1A) with plasminogen activator inhibitor-1 (PAI-1) and high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (Apo-A1), and HDL-C/Apo-A1 ratio. In a matched case-control study on patients with diabetes (40 patients with albuminuria and 40 without albuminuria matched for age, sex, and body mass index), we observed that plasma levels of HSPA1A and PAI-1 are increased in patients with albuminuria (0.55 ± 0.02 vs. 0.77 ± 0.04 ng/ml, p value <0.001 for HSPA1A; 25.9 ± 2 vs. 31.8 ± 2.4 ng/ml, p value <0.05 for PAI-1). There was a significant correlation between HSPA1A and PAI-1 in diabetic patients without albuminuria (r = 0.28; p value = 0.04), but not in those with albuminuria (r = 0.07; p value = 0.63). No association was found between HSPA1A and HDL-C, between HSPA1A and Apo-A1, or between HSPA1A and HDL-C/Apo-A1 ratio. We concluded that there is a direct correlation between plasma HSPA1A and PAI-1 levels in patients with diabetes, which is lost when they develop albuminuria.

Metabolic syndrome in premenopausal and postmenopausal women with type 2 diabetes: loss of protective effects of premenopausal status.

BACKGROUND: Diabetes is probably responsible for worsening of metabolic syndrome (MetS)components. The aim of the present study was to compare the components of MetS between premenopausal and postmenopausal women with type 2 diabetes (T2DM). METHOD: In this cross sectional study, we studied 639 women with T2DM that were divided in pre-menopausal (n = 221) and post-menopausal (n = 418) group. They were selected from participants of a diabetes clinic and assessed for MetS and its components. All MetS components were evaluated to follow age and duration of diabetes adjusted according to the ATP III criteria. RESULTS: The mean ages of pre-menopausal and post-menopausal were 43.33 ± 0.47 and 60.35 ± 0.38 years, respectively. MetS was defined for 88.3% of total subjects (87.5% and 87.7% in pre-menopausal and post-menopausal women with T2DM respectively). Systolic blood pressure (SBP) and waist circumference (WC) were significantly higher in post-menopausal women with T2DM in comparison with pre-menopausal ones. There were no significant differences in triglyceride (T.G) level, diastolic blood pressure (DBP) and high density lipoprotein cholesterol (HDL-C) between the two groups. Myocardial infarction (MI) occurred in 1% total subjects (1.3% and 1.8%) in pre-menopausal and post-menopausal women with T2DM, respectively (p = 0.21). CONCLUSION: Worsening of MetS and its components except for SBP and waist circumference has been shown in pre-menopausal women with T2DM similar to post-menopausal ones. The observed differences may be explained by increasing age. With respect to increasing of myocardial infarction in premenopausal subjects, we suggest that diabetes can abolish the protective effects of premenopausal status for MetS and MI.