Halit Diri

The effects of metformin on endothelial dysfunction, lipid metabolism and oxidative stress in women with polycystic ovary syndrome

Abstract Polycystic ovary syndrome (PCOS) is a heterogeneous disorder, which is considered not only a reproductive disease but also a metabolic disorder associated with long-term health risks. The aim of this study was to assess the effects of metformin on insulin resistance, oxidant–antioxidant status, endothelial dysfunction, lipid metabolism and their contribution to the risks of cardiovascular disease in women with PCOS. Fifteen women with PCOS and 17 healthy women were included in this case–control study. Nitric oxide (NO), endothelin-1 (ET-1), malondialdehyde (MDA), Apo A1, Apo B, small, dense LDL cholesterol (sdLDL-C), lipid levels and paraoxonase 1 (PON1) activity were measured in serum/plasma obtained from study groups. Insulin resistance (HOMA index – Homeostasis Model Assessment) and serum sex hormone profiles were also evaluated. Significantly decreased NO levels and PON1 activities, but increased MDA, ET-1 and sdLDL-C were found in PCOS patients compared to those of controls. Serum MDA, ET-1, HOMA and sdLDL-C levels decreased and PON1 activity and NO levels increased significantly after the metformin treatment. There was a positive correlation between MDA and free testosterone (fT), ET-1 and fT; and a negative correlation between PON1 activity and fT. Insulin resistance, dyslipidemia, endothelial dysfunction and oxidative stress might contribute to the excess risk of cardiovascular disease reported in PCOS. Metformin seemed to decrease oxidative stress and improve insulin resistance, dyslipidemia and endothelial dysfunction in PCOS patients.

EXTENSIVE INVESTIGATION OF 114 PATIENTS WITH SHEEHAN'S SYNDROME: A CONTINUING DISORDER

OBJECTIVE Sheehans syndrome (SS) is a well-known cause of hypopituitarism resulting from postpartum pituitary necrosis. Because of its rarity in Western society, its diagnosis is often overlooked. We aimed to investigate the clinical, laboratory, and radiological aspects of SS in a large number of patients. STUDY DESIGN A retrospective assessment of the medical records of 114 patients with SS was conducted. In addition, sella turcica volumes of 29 healthy women were compared with those of patients by magnetic resonance imaging examinations. RESULTS The mean period of diagnostic delay was 19.7 years in patients with SS. It was found that 52.6% of patients had nonspecific complaints, 30.7% had complaints related to adrenal insufficiency, and 9.6% had complaints related to hypogonadism when diagnosed. At the time of diagnosis, 55.3% of the patients had panhypopituitarism, while 44.7% had partial hypopituitarism. The number of deficient hormones was found to be increased over the years. None of the patients whose basal prolactin was below 4.0 ng/ml had adequate prolactin responses to TRH test, while all patients whose basal prolactin was above 7.8 ng/ml had adequate responses. Mean sella volume was found to be significantly lower in the SS group (340.5±214 mm(3)) than that in the healthy group (602.5±192 mm(3)). CONCLUSIONS SS is a common cause of hypopituitarism in underdeveloped and developing countries. The main reasons for diagnostic delay seem to be the high frequency of patients with nonspecific complaints and neglect of SS. In addition, the TRH stimulation test was found to have a high sensitivity and specificity to recognize PRL deficiency. Furthermore, small sella size may have an important contributing role in the etiopathogenesis of SS.

Sheehan’s syndrome: new insights into an old disease

Sheehan’s syndrome (SS) is a parturition-related pituitary disease resulting from severe postpartum hemorrhage and can present with varying degrees of pituitary insufficiency. Pathological and clinical findings of SS were first described by Harold L. Sheehan in the previous century. Although his definitions are still valid, various studies and reports including new data have subsequently been published. Additionally, the diagnosis of SS has often been overlooked and thus delayed for long years due to its nonspecific signs and symptoms. Therefore, a large number of patients may be remained undiagnosed and untreated. SS is not as rare as assumed in developed countries, probably due to migrant women and unawareness of physicians regarding the syndrome. In this review, we provide a detailed review of the epidemiology, etiopathogenesis, clinical, laboratory and radiological features, new diagnostic criteria, differential diagnosis, and treatment of SS.

Increased micronucleus, nucleoplasmic bridge, nuclear bud frequency and oxidative DNA damage associated with prolactin levels and pituitary adenoma diameters in patients with prolactinoma

Prolactinoma is the most common pituitary tumor. Most pituitary tumors are benign, but they often are clinically significant. We investigated cytokinesis-block micronucleus cytome (CBMN cyt) assay parameters and oxidative DNA damage in patients with prolactinoma to assess the relations among age, prolactin level, pituitary adenoma diameter and 8-hydroxy-2’-deoxyguanosine (8-OHdG) level in patients with prolactinoma. We investigated 27 patients diagnosed with prolactinoma and 20 age- and sex-matched healthy controls. We measured CBMN cyt parameters and plasma 8-OHdG levels in peripheral blood lymphocytes of patients with prolactinoma and controls. The frequencies of micronucleus (MN), nucleoplasmic bridge, nuclear bud, apoptotic and necrotic cells, and plasma 8-OHdG levels in patients with prolactinoma were significantly greater than controls. MN frequency was correlated positively with age, prolactin levels and pituitary adenoma diameters in patients with prolactinoma. The increased chromosomal and oxidative DNA damage, and the positive correlation between MN frequency, prolactin levels and pituitary adenoma diameters may be associated with increased risk of cancer in patients with prolactinoma, because increased MN frequency is a predictor of cancer risk.

Etiopathogenesis of Sheehan’s Syndrome: Roles of Coagulation Factors and TNF-Alpha

Sheehans Syndrome (SS) is defined as pituitary hormone deficiency due to ischemic infarction of the pituitary gland as a result of massive postpartum uterine hemorrhage. Herein, we aimed to investigate the roles of Factor II (G20210A), Factor V (G1691A), MTHFR (C677T and A1298C), PAI-1 4G/5G, and TNF-α (−308  G > A) gene polymorphisms in the etiopathogenesis of SS. Venous blood samples were obtained from 53 cases with SS and 43 healthy women. Standard methods were used to extract the genomic DNAs. Factor II (G20210A), Factor V (G1691A), and MTHFR (C677T and A1298C) polymorphisms were identified by real-time PCR. PAI-1 4G/5G and TNF-α (−308  G > A) gene polymorphisms were detected with polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. According to statistical analysis, none of the polymorphisms were found to be significantly higher in the SS group compared to the control group. Hence, we suggest that genetic factors other than Factor II, Factor V, MTHFR, PAI-1, and TNF-α gene polymorphisms should be researched in the etiopathogenesis of SS.

Comparison of spironolactone and spironolactone plus metformin in the treatment of polycystic ovary syndrome

Abstract The aim of this study was to evaluate and compare the effects of spironolactone and spironolactone plus metformin treatments on body mass index (BMI), hirsutism score, hormone levels, and insulin resistance in women with polycystic ovary syndrome (PCOS). Thirty-seven patients with PCOS were randomly assigned to receive spironolactone 100 mg/d (spironolactone group, 18 patients) or spironolactone 100 mg/d plus metformin 2000 mg/d (combination group, 19 patients) for 12 months. BMI, modified Ferriman–Gallway score (FGS), serum levels of regarding hormones, and homeostasis model assessment of insulin resistance (HOMA-IR) index were assessed before and after the treatments. Six patients in the spironolactone group and four patients in the combination group reported inter-menstrual vaginal bleeding during treatments. In hirsutism scores, the spironolactone therapy resulted in 25.2% reduction, while combination therapy resulted in 28.3% reduction (p > 0.05, between groups). When the groups were compared in terms of percent changes in BMI, FGS, HOMA-IR, and hormone values other than free testosterone, no significant difference was noted. In the present study, FGSs were significantly decreased in both groups; however, combination therapy was not more effective than spironolactone alone in terms of BMI, FGS, hormone levels, or insulin resistance.

Genetic expressions of thrombophilic factors in patients with Sheehan’s syndrome

Abstract Purpose: The aim of this study was to evaluate the roles of factors associated with coagulation in the etiology and pathogenesis of Sheehan’s syndrome (SS) which is a frequent cause of hypopituitarism in underdeveloped and developing regions of the world. Methods: Mean prothrombin time (PT), activated partial thromboplastin time (APTT) and expression levels of genes, which included methylenetetrahydrofolate reductase (MTHFR), angiotensin I converting enzyme (ACE), coagulation factor V (FV), FVII, FVIII and FIX in 44 patients with SS were compared with 43 healthy subjects. Results: The mean expression level of the ACE gene was significantly lower, while that of the FV gene was significantly higher in the patients with SS. No significant difference was found between the patients with SS and the healthy subjects in the comparisons of the remaining gene expression values, as well as in the PT and APTT values. Conclusion: An increased expression of the FV gene may be a contributing factor for the development of SS in some patients. Further studies are required to clarify the roles of coagulation disorders in the development of SS.

Prognostic factors obtained from long-term follow-up of pituitary adenomas and other sellar tumors.

AIM Pituitary adenomas do not have a single factor of aggressive behavior or recurrence. The objective of this study was to determine factors influencing the prognosis in pituitary adenomas. MATERIAL AND METHODS 243 patients who were operated between January 2000 and June 2012 were included in this retrospective study. Demographic data, age at diagnosis, date of diagnosis, date of operation, type of operation, post-operative medications, pre- and postoperative hormone levels, and MRI findings were evaluated in each patient. RESULTS The rate of total resection of sellar tumors was less than 50% in our patient population. The prognosis was better in cases with total resection. Tumor size was a poor prognostic factor in sellar tumors. Female sex was a poor prognostic factor in acromegaly and male sex in prolactinoma. The prognosis was worse in patients with cavernous sinus invasion. In acromegaly, pre-operative level of 850 ng/ml for IGF-1 was noted as a possible prognostic cut-off value. CONCLUSION Long-term follow-up results of our study suggest that factors common to all sellar tumors including tumor type, tumor size, total resection, and cavernous sinus invasion and tumor type-specific factors including sex and hormone levels play important roles in the prognosis.

Investigation of glucose intolerance in patients with normocalcemic primary hyperparathyroidism: 4-year follow-up.

Normocalcemic primary hyperparathyroidism (NPHPT) is a clinical phenomenon in which elevated serum PTH levels are observed with normal serum calcium concentrations in lack of secondary causes such as vitamin D deficiency, renal or liver disease or malabsorption [1, 2]. While derangements in glucose and lipid metabolism in primary hyperparathyroid patients are well-defined, only a few reports exist regarding metabolic abnormalities in patients with NPHPT. Recently, we have shown in 18 patients with NPHPT that those patients do not exhibit increased rates of insulin resistance and glucose intolerance [3]. Similarly, Tassone et al. [4] also showed that patients with NPHPT have similar insulin sensitivity and glucose tolerance with age and sexmatched control subjects. Since there is no prospective study in patients with NPHPT, we have evaluated the changes regarding insulin resistance and glucose intolerance in the same patient group after 4 years of follow-up. Sixteen patients (2 males and 14 females) out of 18 with NPHPT were admitted to regular visits during the 4 years after their first diagnosis as NPHPT. Two patients did not come to visits. The whole data of the patients were described previously [3]. All subjects underwent a physical examination and biochemical data including serum calcium, phosphate, alkaline phosphatase (ALP), albumin, creatinine, glucose, serum lipids, 25 (OH) D levels were determined regularly after an overnight fast. Standart oral glucose tolerance test (OGTT) with 75 g glucose were started between 08:00 and 09:00 h. Blood samples were taken just before (0 min) and 30, 60, 90 and 120 min after administration of glucose with 300 ml water orally for the measurement of serum glucose and insulin concentrations. Area under the curves (AUC) of glucose and insulin during OGTT were calculated according to trapezoid rule. Glucose tolerance was evaluated by using the criteria of the American Diabetes Association, and impaired glucose tolerance (IGT) was defined as a 2-h post-load glucose of C140 and \200 mg/dl. Statistical analysis was performed using the SPSS 15.0 program. All data were subjected to a Kolmogorov–Smirnov test for normality and data was presented as mean ± SEM. Paired t test was used to compare differences at the beginning and at the end of the study. P \ 0.05 was accepted as significancy. Four years of data after initial diagnosis for each patient were evaluated. One (6.25 %) patient developed hypercalcemic hyperparathyroidism. The data of this patient was not used in the analysis. Serum PTH level was significantly higher (103.8 ± 12.5 pg/ml) than normal limits (5–65 pg/ml) at the end of the 4 years. None of the patients had vitamin D deficiency [mean serum 25 (OH) D level was 54.6 ± 5.9 ng/ml]. Three out of five patients with IGT had diabetes mellitus and the two others remained as IGT at the end of the 4 years. None of the patients with normal glucose tolerance developed glucose intolerance during follow-up. The patient who developed hypercalcemia and three patients with diabetes mellitus were excluded from the analysis and we found that insulin responses to OGTT were not significantly different before (AUCinsulin 5059 ± 765 mg/dl 9 120 min) and after 4 years (AUCinsulin 4293 ± 537 mg/dl 9 120 min) of follow-up. Serum lipid levels, kidney and liver function tests were also normal during 4 years follow-up. Several previous data demonstrated close relationship between primary hyperparathroidism (PHPT) and impaired H. Diri K. Unluhizarci (&) F. Kelestimur Department of Endocrinology, Erciyes University Medical School, 38039 Kayseri, Turkey e-mail: kursad@erciyes.edu.tr

Evaluation of Aggressive Behavior and Invasive Features of Pituitary Adenomas Using Radiological, Surgical, Clinical and Histopathological Markers.

AIM Total surgical resection of pituitary macroadenomas is difficult due to the location of the adenoma and the propensity to invade surrounding tissues. The purpose of this study was to evaluate the risk factors for invasive and aggressive pituitary macroadenomas using radiological, hormonal, clinical, and immunohistochemical markers. MATERIAL AND METHODS Seventy cases of pituitary macroadenoma were examined. Age, gender, symptoms, the presence of fibrosis within the adenoma, hormonal levels, radiological findings, pathological results and immunohistochemical staining of the patients were evaluated using statistical methods. RESULTS We observed that the patients with macroadenomas in our study most frequently presented during their 5th decade. The most frequent pituitary adenomas were non-functional, GH-secreting and PRL-secreting macroadenomas. The most frequent complaint was vision loss, headache and acral growth. Based on Magnetic Resonance Imaging (MRI) results, it was observed that the degree of invasion into surrounding tissues increased as the size of the macroadenoma increased. Macroadenomas that had invaded into the cavernous sinus invasion or that had a fibrotic tumor structure had a low probability of being resectable. There were no significant relationships between invasive behavior and p53, telomerase, ghrelin and CD46. CONCLUSION It is not possible to identify only one factor that affects the prognosis of patients with pituitary macroadenomas. The contribution of the experience of surgeon to the treatment is surely beyond dispute. Fibrotic tumor structure, the surgical technique, the type of hormone, and cavernous sinus invasion affect the ability to perform a total resection and the overall prognosis.