Chromosomal and oxidative DNA damage in non-functioning pituitary adenomas.

INTRODUCTION: Clinically non-functioning pituitary adenomas (NFPA) are common tumours of the pituitary gland and are mainly considered as benign. The primary aim of this study was to research the effects of NFPA on genome instability in patients with non-functioning pituitary adenoma by using the cytokinesis-block micronucleus cytome (CBMN-cyt) assay and 8-hydroxy- 2'-deoxyguanosine (8-OHdG) assay. The second objective of this study was to assess whether there is a relationship between age, pituitary adenoma diameters, 8-OHDG levels, CBMN site assay parameters, and tumour aggressiveness. MATERIAL AND METHODS: The study was performed on 30 patients who had been diagnosed with NFPA and were admitted to the Department of Endocrinology and Metabolism, and 20 healthy subjects of similar age and sex. RESULTS: Micronucleus (MN), nucleoplasmic bridges (NPBs), nuclear bud (NBUD) frequencies, and apoptotic and necrotic cell frequencies in patients with NFPA were found to be significantly higher than in control subjects, and plasma 8-OHdG levels in patients with NFPA were statistically significantly lower than control subjects in this study. CONCLUSIONS: It is believed that this is the first study to evaluate the aggressiveness of tumour with chromosome/oxidative DNA damage in patients with NFPA. However, further studies are needed in order to understand the cause of NFPA aggression and to evaluate these patients in terms of risk of cancer.

The significance of estrogen receptors in acromegaly: Are they useful as predictors of prognosis and therapy regimen?

OBJECTIVE: In this study, we considered to assess the presence of estrogen receptors (ER) and the expression of estrogen receptor genes (ESR) in the surgical tissue samples of acromegaly patients and the control group patients with nonfunctioning adenoma and their association with disease activity. We also aimed to determine the significance of ER positivity in acromegaly patients and to find out whether it carries a potential to be used as a predictor of prognosis and therapy regimen in the future. DESIGN: This study was conducted on a total of 67 patients over 18 years of age. The study group consisted of 34 patients with acromegaly and 33 patients with nonfunctioning pituitary adenoma. The pre- and post-operative basal pituitary hormone levels and magnetic resonance images (MRI) of all patients, as well as their remission status of all acromegaly patients were evaluated. Immunohistochemical (IHC) staining procedures for ER-α were performed on surgical tissue samples. Real-time quantitative polymerase chain reaction (RT-qPCR) method was used to determine the levels of ESR1 and ESR2 gene expressions. RESULTS: We found that IHC staining for ER-α was positive in 31.3% and 45.5% of the patients with acromegaly and nonfunctioning adenoma respectively. There was no statistically significant difference of ER-α positivity, ER-α immunoreactivity score and ESR1/ESR2 gene expression levels among the study groups (p > .05). Nevertheless, the expression of ESR1 gene was found to be 0.26 times more, and the ESR2 gene to be 0.11 times less in the acromegaly group compared to those of the nonfunctioning adenoma group. Additionally, we detected the positivity of ER-α only in acromegaly patients who were in remission. An inverse association was found between the pre-operative insulin-like growth factor-1 (IGF-1) levels and the expressions of ESR1/ESR2 gene in acromegaly patients. So these results indicated that the high ESR1 and ESR2 gene expressions in acromegaly patients are associated to the decrease of pre-operative IGF-1 values. Also an inverse association was found between the pre-operative adenoma volume and ESR1 Ct values, means that increase in ESR1 gene expression is associated to the decrease of adenoma volume. CONCLUSIONS: The current results may suggest the use of these parameters as useful prognostic markers because all ER-positive acromegaly patients were in remission and the high ESR1 and ESR2 gene expressions in acromegaly patients is associated to the decrease of pre-operative IGF-1 values. Our results need to be supported by further studies.

Five variants of the superoxide dismutase genes in Turkish women with polycystic ovary syndrome.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is one of the most common endocrine-reproductive-metabolic disorders of women at reproductive age. Many investigations have revealed that reactive oxygen species (ROS) level is significantly increased in patients with PCOS compared to healthy women. OBJECT: The goal of the current study is to investigate the association between superoxide dismutase (SOD) variants and the risk of PCOS among Turkish women. METHOD AND SUBJECTS: Three hundred twelve voluntary premenopausal women (148 healthy controls and 164 patients with PCOS) 18-45 years of age were include the study. All volunteers underwent physical examination and biochemical hormones evaluation. Five selected variants in SOD1 (+35 A/C (rs2234694) and SOD2 (-102 C > T, 3'UTRT > A (rs2842980), 3'UTRA > G (rs5746136), and Ala16ValC > T (rs4880) were analysed by using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. RESULT: 3'UTRA > G and Ala16ValC > T variants showed significant differences between study groups. In the additive model of rs5746136 variant having AG and GG genotype increased the PCOS risk 2-fold (OR: 1.7, 95% CI: 1.08-2.77, p = 0.003) and 5-fold (OR: 5, 95% CI: 1.7-14.2,p = 0.003) compared to AA genotype, respectively. To have a GG + AG genotype increased the PCOS risk 2-fold (OR: 2.95% Cl: 1.2-3.1, p = 0.003) compared to AA genotype in "G" dominant model. In case of the "G" recessive model, having a GG genotype increased the PCOS risk 4-fold (OR: 3.8, 95% CI: 1.3-10.4, p = 0.01) compared to AA + AG genotype. The TT genotype of rs4880 showed almost 2-fold (OR: 1.8, 95% CI: 1.12-3.0) increased PCOS risk in the "T" recessive model. CONCLUSION: It is quite likely that the variants which result in decreased function in the antioxidant defence mechanism related genes contribute to PCOS aetiology with inhibiting/reducing of ROS elimination.

Is biochemical hypoglycemia necessary during an insulin tolerance test?

ABSTRACT Objective The insulin tolerance test (ITT) has been accepted as the gold standard test for assessing the integrity of the growth hormone (GH) - insulin-like growth factor (IGF-1) axis and the hypothalamic-pituitary-adrenal (HPA) axis. The goal of the test is to achieve clinical and biochemical hypoglycemia at a blood glucose level ≤ 40 mg/dL to effectively and correctly assess the HPA and GH-IGF-1 axes. In this study, the GH and cortisol responses of patients who achieved and failed to achieve biochemical hypoglycemia during an ITT were compared. Subjects and methods One hundred thirty-five patients with pituitary disorders were included in the study. Samples for blood glucose levels were obtained after clear symptoms of clinical hypoglycemia developed. The patients were enrolled in the hypoglycemic and nonhypoglycemic groups according to whether their plasma glucose level ≤ 40 mg/dL or > 40 mg/dL during an ITT, and the groups were compared in terms of their GH and cortisol responses. Results The mean age, body mass index and waist circumference of the two patient groups were found to be similar. The mean blood glucose level was significantly lower in the hypoglycemic group than in the nonhypoglycemic group (19.3 and 52.0 mg/dL, respectively). When the two groups were compared in terms of peak cortisol and GH responses, no statistically significant differences were found. Conclusion The data presented suggest that clinically symptomatic hypoglycemia is as effective as biochemically confirmed hypoglycemia during an ITT. Arch Endocrinol Metab. 2020;64(1):82-8

Osteoporosis and Silent Vertebral Fractures in Nursing Home Resident Elderly Men in Turkey.

Osteoporosis is an important cause of vertebral fractures and there is an increased risk for osteoporosis in nursing home residents. Most of the men with osteoporosis and osteoporotic fractures are not diagnosed and do not receive treatment. Our study aim was to determine osteoporosis and silent vertebral fracture prevalence in male nursing home residents in Corum, Turkey. This cross-sectional study included 2 groups of patients: 71 male nursing home residents (nursing home group) with a mean age of 76.0 ± 0.8 years and 44 men living in their own homes (control group) with a mean age of 74.4 ± 0.7 years. Bone mineral densitometry was performed in all subjects, and results were evaluated according to the World Health Organization criteria. Vertebral deformity was evaluated using the spinal deformity index, and fracture risk was calculated using the Fracture Risk Assessment Tool. In all participants, serum calcium, phosphorus, 25 (OH) vitamin D, parathyroid hormone, and alkaline phosphates levels were measured and medical histories were recorded. Osteoporosis was detected in 25.3% of men residing in nursing homes and in 8.8% of men living in their own homes. Silent vertebral fracture was present in 27.8% of patients older than 65 years. Vertebral fracture rate was higher in nursing home residents (42.2%) than men living in their own homes (17.6%); 5.6% of nursing home group and 8.9% of control group patients were aware of their fractures. Our results demonstrated that male nursing home residents are at a higher risk for both osteoporosis and vertebral fractures compared to the men living in their own homes.

Is Positive Staining of Non-Functioning Pituitary Adenomas for Luteinizing Hormone Associated with a Poor Prognosis?

AIM: The aim of this study was to assess the relationships among immunohistochemical staining patterns and prognostic factors in patients with non-functioning pituitary adenoma (NFPA). MATERIAL AND METHODS: The study included 103 patients who had undergone pituitary surgery for NFPAs. The prognostic factors evaluated were initial tumor size, cavernous sinus invasion, compression of the optic chiasm, recurrence, residual tissue, reoperation, and hypopituitarism. RESULTS: Recurrence rates were higher for NFPAs with large initial tumor volume and preoperative cavernous sinus invasion. Tumor recurrence rates were higher for NPFAs positive (55.6%) than negative (10.3%) for luteinizing hormone (LH). Reoperation rate, but not recurrence rate, was higher in patients with tumors positive than negative for follicle-stimulating hormone (FSH) group. Recurrence and reoperation rates were lowest in patients with null-cell adenomas. CONCLUSION: In contrast to previous studies, we observed a higher recurrence rate in LH-positive than in LH-negative adenomas. To our knowledge, this is the first study showing an association between LH positivity and poorer prognosis; and in addition, optimal outcomes in patients with null-cell adenomas. Thus, additional studies are required to assess the relationship between LH positivity and poor prognosis in patients with NFPAs.

Genetic expressions of thrombophilic factors in patients with Sheehan's syndrome.

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.

Distribution of RET Mutations and Evaluation of Treatment Approaches in Hereditary Medullary Thyroid Carcinoma in Turkey.

OBJECTIVE: This retrospective multicenter study, centrally conducted and supported by the Society of Endocrinology and Metabolism of Turkey, aimed to evaluate the impact of free RET proto-oncogene testing in medullary thyroid carcinoma (MTC) patients. Surgical timing, adequacy of the treatment, and frequency of prophylactic thyroidectomy (PTx) in mutation carriers were also assessed. METHODS: Genetic testing for MTC and pheochromocytoma was conducted between July 2008 and January 2012 in 512 patients. Application forms and RET mutation analyses of these patients whose blood samples were sent from various centers around Turkey were assessed retrospectively. An evaluation form was sent to the physicians of the eligible 319 patients who had confirmed sporadic MTC, familial MTC (FMTC), multiple endocrine neoplasia type 2 (MEN2), or who were mutation carriers. Physicians were asked to give information about the surgical history, latest calcitonin levels, morbidity, mortality, genetic screening, and PTx among family members. Twenty-five centers responded by filling in the forms of 192 patients. RESULTS: Among the 319 patients, RET mutation was detected in 71 (22.3%). Cys634Arg mutation was the most prevalent mutation (43.7%), followed by Val804Met in 18 patients (25.4%), and Cys634Tyr in 6 patients (8.5%). Among 192 MTC patients, the diagnosis was sporadic MTC in 146 (76.4%), FMTC in 14 (7.3%), MEN2A in 15 patients (7.9%), and MEN2B in one patient. The number of mutation carriers among 154 apparently sporadic MTC patients was 8 (5.2%). Ten patients were submitted to PTx out of twenty-four mutation carriers at a mean age of 35±19 years. CONCLUSION: Turkish people have a similar RET proto-oncogene mutation distribution when compared to other Mediterranean countries. Despite free RET gene testing, the number of the PTx in Turkey is limited and relatively late in the life span of the carriers. This is mainly due to patient and family incompliance and incomplete family counselling.

Can a glucagon stimulation test characterized by lower GH cut-off value be used for the diagnosis of growth hormone deficiency in adults?

OBJECTIVE: The aim of this study was to assess diagnostic values of insulin tolerance test (ITT), glucagon stimulation test (GST), and insulin like growth factor-I (IGF-I) level, to find optimal GH cut-off values for GST, and to evaluate efficiencies of patient age, gender, body-mass index (BMI), and additional pituitary hormone deficiencies (PHDs) in the diagnosis of growth hormone deficiency (GHD). STUDY DESIGN: This retrospective study involved 216 patients with a pituitary disease and 26 healthy controls. Age, gender, BMI, medical histories, and hormonal data including baseline and stimulated hormone values were evaluated. Three cut-off values for peak GH responses to stimulation tests were evaluated: (a) 3.00 µg/L on ITT, (b) 3.00 µg/L on GST, and (c) 1.07 µg/L on GST. RESULTS: According to the ITT, GST with 3.00 µg/L cut-off, and GST with 1.07 µg/L cut-off, GHD was present in 86.1, 74.5, and 54.2 % patients, respectively. Patient age, BMI, and number of PHDs, but not gender, were found to be correlated with IGF-I and peak GH concentrations. All patients with an IGF-I concentration ≤95 ng/ml or ≥3 PHD had GHD. None of the patients with adequate GH response to the GST with 1.07 µg/L cut-off, but blunted responses to ITT and GST with 3.00 µg/L cut-off, had ≥3 PHDs. 12 out of 26 (46.2 %) healthy subjects failed the GST with 3.00 µg/L cut-off, but not with 1.07 µg/L cut-off. CONCLUSIONS: Patient age, IGF-I, BMI, and number of PHDs are efficient factors associated with the diagnosis of GHD. A 4 h GST with a diagnostic GH threshold of 1.07 µg/L seems to be a good diagnostic method for GHD.

A Pregnant Woman Who Underwent Laparoscopic Adrenalectomy due to Cushing's Syndrome.

Cushing's syndrome (CS) may lead to severe maternal and fetal morbidities and even mortalities in pregnancy. However, pregnancy complicates the diagnosis and treatment of CS. This study describes a 26-year-old pregnant woman admitted with hypertension-induced headache. Hormonal analyses performed due to her cushingoid phenotype revealed a diagnosis of adrenocorticotropic hormone- (ACTH-) independent CS. MRI showed a 3.5 cm adenoma in her right adrenal gland. After preoperative metyrapone therapy, she underwent a successful unilateral laparoscopic adrenalectomy at 14-week gestation. Although she had a temporary postoperative adrenal insufficiency, hormonal analyses showed that she has been in remission since delivery. Findings in this patient, as well as those in previous patients, indicate that pregnancy is not an absolute contraindication for laparoscopic adrenalectomy. Rather, such surgery should be considered a safe and efficient treatment method for pregnant women with cortisol-secreting adrenal adenomas.

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.

Increased genome instability and oxidative DNA damage and their association with IGF-1 levels in patients with active acromegaly.

OBJECTIVE: The objectives of this study were to assess cytokinesis-block micronucleus cytome (CBMN Cyt) assay parameters and also oxidative DNA damage in patients with active acromegaly and controls and to assess the relationship between age, serum insulin-like growth factor 1 (IGF-1) levels, pituitary adenoma diameters, 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels and CBMN Cyt assay parameters in patients with active acromegaly. DESIGN: The study population included 30 patients with active acromegaly and 30 age- and sex-matched healthy controls. CBMN Cyt assay parameters in peripheral blood lymphocytes of patients with active acromegaly and controls were evaluated and plasma 8-OHdG levels were measured. RESULTS: Frequencies of micronucleus (MN), nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) in lymphocytes of patients with acromegaly were found to be significantly higher than those in controls (p<0.001, p<0.001, p<0.001, respectively). The frequencies of apoptotic and necrotic cells in lymphocytes of patients with acromegaly were found to be significantly higher than those in controls (p<0.001 and p<0.001 respectively). No statistically significant differences in the number of cells in metaphase, the number of bi-nucleated cells (M2), the number of tri-nucleated cells (M3), the number of tetra-nucleated cells (M4) and nuclear division index (NDI) values were observed between patients and controls (p>0.05). Plasma 8-OHdG (ng/ml) levels in patients with acromegaly were found to be significantly higher than those in controls (p<0.005). MN frequency in the lymphocytes of patients with acromegaly increased with elevated serum IGF-1 levels (p<0.05), whereas the number of NPBs and the frequency of apoptotic cells decreased with elevated serum IGF-1 levels (p<0.01 and p<0.05 respectively). CONCLUSIONS: Both the increase in chromosomal/oxidative DNA damage and the positive association between MN frequency and serum IGF-1 levels may predict an increased risk of malignancy in acromegalic patients. Long-term follow-up of patients with acromegaly will be necessary to establish the degree of cancer risk in this population.

Subcutaneous sarcoidosis with plantar involvement.

Sarcoidosis is a multisystem granulomatous disorder of an unknown etiology. Subcutaneous sarcoidosis is a rare manifestation of sarcoidosis, and plantar involvement is extremely rare and there is only one such case report in the medical literature. Herein we present an interesting case of a patient who was diagnosed as having subcutaneous sarcoidosis at a plantar localization because plantar involvement is extremely rare and also because of the successful outcome after performing intralesional corticosteroid therapy.