ACTA ENDOCRINOLOGICA (BUC)

Denosumab,a monoclonal IgG2 antibody directed against RANK-L,is used as a neoadjuvant therapy for inoperable or metastatic giant cell tumor of bone. Many side effects like as hypocalcemia during treatment and rarely severe hypercalcemia especially in children after discontinuation of denosumab occurred. The unpredictable onset and recurrent episodes of severe hypercalcemia increase the duration of hospitalization and the risk of complications. Persistent hypercalcemia and difficulties in management have prompted the search for different more effective therapeutic options. Objectives. To share our experience with the use of oral bisphosphonate in acute and long-term therapy of severe hypercalcemia following high-dose denosumab therapy and to review the literature on this subject Case. We report the management of a case of severe hypercalcemia that developed 4 months after the completion of 18-month denosumab treatment in a 9-year-old girl who was followed up with a giant cell bone tumor for 6 years. Based on an evaluation aiming to determine etiology, hypercalcemia was considered as "rebound-linked" upon denosumab discontinuation. Severe hypercalcemia attacks recurring with an interval of 2 weeks were treated with IV bisphosphonate, but when mild hypercalcemia developed again, treatment with 70 mg per week of oral bisphosphonate was planned. After the second dose of alendronate, the calcium level always remained below 10.5 mg/dl. In the 14-month follow-up, no hypercalcemia attack was observed again. Results. Rebound hypercalcemia can occur as an unpredictable recurrent episode at any time after denosumab cessation. Thus, the patient should be closely monitored especially in childhood due to rapid bone cycle. In longterm follow-up, oral biphosphonates can be used effectively to reduce hospitalization time and the management of especially life-threatening recurrent attacks.

An 81-year-old woman presented with a history of essential hypertension for eight years and an asymptomatic multinodular goiter that had been incidentally discovered on neck ultrasonography two years ago and an-isohypoechoic mass lesion located adjacent to the right lobe inferior pole of the thyroid gland. Parathyroid adenoma or lymphadenopathy were the differential diagnosis. After two years, the endocrine surgeon decided to operate her multinodular goiter and her probably benign lesion. Intraoperatively, the blood pressure and pulse rate increased markedly and intravenous antihypertensive treatment was administered. She was discharged after blood pressure control. A 2 mm micromedullary thyroid carcinoma with C-cell hyperplasia located on the left lobe of the thyroid was detected. The aforementioned mass lesion was also reported as typical cervical paraganglioma. Because of concomitant medullary thyroid carcinoma with C-cell hyperplasia and paraganglioma the patient was subjected to genetic counseling and molecular testing for hereditary cancer syndromes. A variation of the succinate dehydrogenase gene D (SDHD) NM_003002.3: c.325C> T (Gln109Term) has been reported as the disease-causing mutation. Herein we present a case diagnosed for neck paraganglioma and medullary thyroid carcinoma after an intraoperative hypertensive crisis.

Branched chained amino acids (BCAA) are essential components of the human diet and important nutrient signals, which regain particular interest in recent years with the avenue of metabolomics studies suggesting their potential role as biomarkers. There is now compelling evidence for predictive role of BCAA in progression of diabetes, but causality relationship is still debated concerning insulin resistance and genetic versus nongenetic pathogenesis. Mendelian randomization studies in large cohorts of diabetes indicated pathogenic role of PPM1K (protein phosphatase Mg2+/Mn2+ dependent 1K) on Chr 4q22.1 gene, encoding for a phosphatase that activate BCKDH (branched chain keto acid dehydrogenase) complex. Recent studies indicated that insulin rapidly and dose-dependently regulates gene expression of the same complex, but the relationship with systemic insulin resistance and glucose levels is complex. Rare genetic syndromes due to Mendelian mutations in key genes in BCAA catabolism may be good models to understand potential role of gene of BCAA catabolism. However, in studying complex disorders geneticists are faced to complete new aspects of metabolic regulation complicating understanding genetics of obesity, diabetes or metabolic syndrome. A review of genetic syndromes of BCAA metabolism suggests that insulin resistance is not present, except rare cases of methylmalonic aciduria due to MUT (methylmalonyl-coA mutase) gene on Chr 6p12.3. Another aspect that complicates understanding is the new role of central nervous system (CNS) in insulin resistance. For long time the hypothalamic hunger/satiety neuronal system was considered a key site of nutrient regulation. Genes may also affect the brain rewarding system (BRS) that would regulate food intake by modulating the motivation to obtain food and considering hedonic properties. Nutrigenomic and nutrigenetic investigations taking into account concurrently BCAA intake, metabolic regulation and gene variation have large perspectives to merge genetic and nutritional understanding in complex disorders.

Context. Osteonecrosis (ON) is bone death caused by inadequate blood supply and its optimal management remains uncertain. Objective. We describe the outcomes of BP (pamidronate) treatment in our patients. Design. Data regarding clinical, laboratory, magnetic resonance imaging (MRI) studies, and bone mineral density measurements (BMD) were recorded before and one year after treatment (reevaluation). The severity of the clinical picture was assessed using the criteria of the common terminology criteria for adverse events (CTCAE). Subjects and Methods. There were four female patients (patient 1, acute lymphoblastic leukemia; patient 2, immune thrombocytopenic purpura; patients 3 and 4, systemic lupus erythematosus) .All of them had been treated with high-dose prednisolone. Clinical picture of all patients were consistent with grade 3 according to CTCAE(: severe symptoms, limiting self-care ). Results. ON lesions were multifocal in the lower limbs in all of them and none of them had any fractures. All of them had been treated with high-dose glucocorticoid. Patients were treated with pamidronate (1 mg/kg/day, with maximum dose of 60 mg/day, for two days, quarterly). At the time of re-evaluation(one year after treatment), the lesions were stable on MRI, and their clinical condition was consistent with grade 1 according to CTCAE(asymptomatic). No side effects related to the use of bisphosphonates were observed except for increased BMD (SD score of 2.9) in one of the patients. Conclusions. Pamidronate may be an effective treatment for the improvement of functional impairment and pain among patients with severe osteonecrosis (ON) lesions.

Sotos syndrome is characterized by overgrowth, macrocephaly, distinctive facial features, and learning disabilities and is associated with alterations in the nuclear receptor binding SET domain protein 1 (NSD1) gene. Due to the advanced bone age, the eventual adult height is usually at the upper limit of normal. In this case report, a 6-year and 10-month old boy who presented with Sotos syndrome was described. He also had increased testicular volumes with advanced bone age. The stimulated levels of gonadotropins revealed central precocious puberty and brain magnetic resonance imaging (MRI) showed a pineal cyst. A heterozygous duplication variant [NM_022455.4:c.4560dup; p.(His1521Thrfs*9)] in the NSD1 was identified. Triptorelin acetate treatment was started. The aim was to report the novel duplication variant in the NSD-1 in a patient with Sotos syndrome accompanied by a pineal cyst and central precocious puberty, and also to discuss the rationale for treating precocious puberty.

Background and aims. There are numerous intrinsic and extrinsic factors associated with the pathophysiology of rosacea, including immune dysregulation. The aim of this study is to determine the relationship between rosacea and thyroid autoimmunity. Methods. Seventy-two patients with rosacea and 62 rosacea-free control subjects were included in the study. Serum free triiodothyronine (fT3), free thyroxine (fT4), thyrotropin releasing hormone (TSH), antithyroidperoxidase antibody (ATPO), antithyroglobulin (anti-Tg), prolactin, dehydroepiandrosterone sulfate (DHEAS), basal cortisol, serum CRP concentrations and erythrocyte sedimentation rate were measured. Results. The number of the cases with high levels of CRP, anti-M and prolactin in rosacea group were significantly higher than the controls (p<0.05), there was no significant difference according to other parameters in both groups (p>0.05). There was no significant difference according to the presence of a thyroid disease in both groups (p>0.05). The decrease in the CRP parameter in patients with the disease duration of 1-5 years was found to be statistically significant (βCRP=-0.251, pCRP<0.05). There was no statistically significant difference according to disease severity or disease duration (p>0.05). Conclusions. Rosacea may be associated with high thyroid autoantibodies, prolactin and CRP levels, in which immune-endocrine interactions are important.

Context. Comparison of GnRH analogues and their impact on IVF treatment to improve pregnancy outcome.\r\nObjective. To compare the effects of GnRH agonists and GnRH antagonists on pregnancy rates.\r\nDesign. A total of 458 women who had embryo transfers completed were analyzed retrospectively in a university\r\nhospital setting.\r\nMethods. Comparative data were gathered on pregnancy rates, FSH dosage, and number of follicles, retrieved oocytes\r\nand embryos.\r\nResults. The use of GnRH agonist showed a strong association with the number of follicles (GnRH antagonist: 11.45; GnRH agonist: 15.17), oocytes retrieved (GnRH antagonist: 10.66; GnRH agonist: 13.68) and embryos transferred (GnRH antagonist: 2.54; GnRH agonist: 2.89) (p<0.01). The use of GnRH antagonist showed a significant association with &#946;-\r\nhCG > 5 mIU/mL pregnancy (GnRH antagonist 30.8%; GnRH agonist: 21.8%) (p<0.05). Ongoing pregnancy rates between\r\nthe two GnRH analogues showed no statistically significant differences (GnRH antagonist 72.1%; GnRH agonist: 64.1%)\r\n(p>0.05).\r\nConclusion. On the basis of current evidence, it is still unclear which GnRH analogue is the first choice for achieving a higher rate of pregnancy.

Introduction. Diabetes mellitus, a chronic metabolic disorder stemming from pancreatic dysfunction, is surging in India, notably among those aged 60 and above. The escalating disease prevalence in this demographic necessitates heightened medication use, escalating the risk of Adverse Drug Reactions (ADRs). This underscores the vital role of ADR monitoring to curtail potential harm. Method. A 12-month cross-sectional, prospective, observational study engaged 200 participants from the geriatric Outpatient Department (OPD). Diabetic patients in the geriatric OPD, willing to participate, underwent faceto- face evaluations using a structured questionnaire focused on adverse reactions to anti-diabetic medications. The study also included a Knowledge, Attitude, and Practice (KAP) assessment. Results. Of the 200 patients, 57% were male, 43% female. Thirteen participants (7 male, 6 female) reported ADR encounters during therapy, predominantly categorized as mild in causality and severity. KAP assessments unveiled a robust understanding of ADRs, primarily shaped by physicians and reinforced by pharmacists. Anticipation of ADR occurrence was noted in 70% of respondents, linked to non-compliance and lifestyle factors. Conclusion. Educating caregivers about the critical importance of monitoring medication adherence among the elderly is imperative. Cultivating an attitude of reporting even minor ADRs to appropriate authorities is essential for harm prevention.

Objective. Hyperkalemia is one of the most common acute life-threatening metabolic emergencies. Alterations in serum potassium (K+) levels can have dramatic effects on\r\ncardiac cell conduction and may lead to electrocardiographic (ECG) changes. But in some\r\npatients ECG changes do not accompany serum K+ abnormalities. Severe hyperkalemia secondary to Addison Disease (AD) is rare.\r\nCase. A 40-year-old woman with AD was admitted to emergency service with generalized pain. The patient?s serum K+ level was found to be at the highest level that can be detected in our laboratory (>10.0 mmol/L, normal 3.5-4.5 mmol/L) and repeated serum K+ confirmed the previous result. Results of repeated ECGs have revealed a normal sinus rhythm. Our case is particularly interesting because it demonstrates an Addison patient that has an extremely high level of K+ (>10 mmol/L) without any accompanying ECG changes.\r\nConclusion. Our case confirms that diagnostic ECG changes do not always accompany severe hyperkalemia. Therefore, clinicians should be careful that ECG may look\r\nnormal in the presence of severe hyperkalemia.

Context. Vitamin D, a fat-soluble prohormone, is synthesized in response to sunlight and plays several roles in the body. Objectives. To determine Vitamin D status among healthy, young female medical students studying at King Saud University, Riyadh, Saudi Arabia, and to study the effects of nutritional and environmental factors on Vitamin D level. Study design. It is a prospective, observational, cross-sectional study conducted between December 2012 and March 2013. Subjects and methods. One hundred and seventy eight healthy medical students participated in the study. Each subject completed a questionnaire about vitamin D deficiency and attitude towards related environmental and nutritional factors, including duration of sunlight exposure, and vitamin D supplements. Serum levels of 25-hydroxyvitamin D, parathyroid hormone, calcium, phosphorus, and alkaline phosphatase were obtained.Results. The mean serum vitamin D level of the study group was 41.41±29.31 mmol/L (normal 75–250 mmol/L). Out of 178 participants, 126 (70.8%) were vitamin D deficient (<50 mmol/L), 29 (16.3%) had insufficient vitamin D (50–75 mmol/L), and 23 (12.9%) had normal vitamin D level (>75 mmol/L), with mean serum levels of 25.52±10.89, 62.84±7.04 and 101.41±9.1 mmol/L, respectively. In comparison between vitamin D deficient and nondeficient groups, daily milk consumption (P < 0.001), use of vitamin D supplements (P < 0.0001), and frequency of sun exposure for ≥ 5 days/week (P < 0.006) were significantly higher in the nondeficient group. Conclusion. Prevalence of vitamin D deficiency among female medical students in Riyadh is high and may be attributed to nutritional, social and environmental factors.