ACTA ENDOCRINOLOGICA (BUC)

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Background. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancers. Antibodies directed against programmed cell death receptor 1 (PD-1) interrupt the ability of the cancerous cell to depress the immune system. Methods and results. We report three patients who developed different endocrine abnormalities after treatment with nivolumab, a monoclonal antibody directed against PD-1. First, we report a 76-year-old male presenting with generalized fat loss after treatment with nivolumab which predominantly affected his face and trunk. Second, we described the development of thyroiditis that presented with thyrotoxicosis and the expression of thyroid-stimulating hormone receptor antibodies (TRAb). Finally, we observed the emergence of adrenal insufficiency due to hypophysitis in another case. Conclusion. Although immune checkpoint inhibitors are an effective anticancer treatment modality, adverse effects are evident that can affect the endocrine system. These adverse events may relate to different endocrine systems that include the thyroid and pituitary glands. Also, acquired generalized lipodystrophy should be suspected in patients developing unusual fat loss after treatment with ICIs.

Background. Glycogen synthase kinase.3β (GSK.3β) has an important role in several signaling pathway including Wnt signaling pathway. Recent evidence has shown that this pathway is involved in follicle development, ovulation and Corpus luteum formation. Aim. In this study we have investigated the effect of LiCl (as a GSK.3β inhibitor) on the ovulation and corpus luteum formation in rat. Materials and methods. Immature 23-day female rats were injected with PMSG (15 IU) to induce follicular development, followed 48h later by HCG (15IU) to induce ovulation. To inhibit GSK3β activity 250 mg/kg LiCl were administerted at the time of LiCl injection. The ovaries were removed at 1,4,8,12,24 h after LiCl treatment and prepared for histological studies. Results. Our results show that the number of preovulatory follicle in LiCl treatment rats was not increased compared with control group. The number of corpus luteum blood vessels were decreased in comparison with control group (p<0.05). Conclusions. These findings show that although LiCl does not inhibit ovulation, it disrupts blood vessel formation in the corpus luteum.

Background. Mosaic karyotype 45,X/46,XY related mixed gonadal dysgenesis. Aim. To report a case of mosaic karyotype and petroclival meningioma. Methods. Presentation of a clinical case with comments. Results. The case of a 37-year-old woman mosaic karyotype - 45,X/46,XY, infertility, virilisation, Turner syndrome-like phenotype, primary amenorrhea, the absence of labia majora and petroclival meningioma. Concentrations of dehydroepiandrosterone sulphate (DHEAS), testosterone, luteinizing hormone (LH) and follicular stimulating hormone (FSH) were increased indicating hypergonadotropic hypogonadism. Low and high dose dexamethasone suppression tests demonstrated incomplete suppression of DHEAS concentration without connection between pulses of LH/FSH and DHEAS. Response to adrenocorticotropic hormone (ACTH) was normal. The morning/evening concentration ratio of DHEAS was very low in comparison with cortisol, ACTH and testosterone. Head magnetic resonance imaging (MRI) demonstrated petroclival meningioma without any adrenal or ovary abnormality. Menstruation started after treatment with 2 mg of estradiol. At control visit 1.5 years later she had no complaints. MRI did not demonstrate any signs of tumour progression. Conclusions. The main lesson learned from this case is that in searching the DHEAS secreting tumours one can find unusual cases with sustained high DHEAS and lack of confirmations of polycystic ovary syndrome, adrenal or ovary tumours using available ultrasound, CT and MRI.

Context. Mealtime insulin bolus is traditionally administered before meals in children with type 1 diabetes (T1D). Controlled studies on the use of pre-and postprandial insulin bolus have shown variable results. There are no realworld studies on postprandial bolusing of insulin in young children with T1D. Methods. Children with T1D aged <7 years were grouped into preprandial (Group 1) or postprandial (Group 2) groups according to the practice of prandial insulin use. Their retrospective data on mean glycosylated hemoglobin (HbA1c), hypoglycemic events, and diabetic ketoacidosis (DKA) episodes were compared. Results. Forty-four children (mean age 4.1±1.3 years, range 2-7 years) with mean diabetes duration of 2.0±0.7 years (range, 1-4 years) were identified; 23 (52.3%) belonged to Group 1 and 21 (47.7%) to Group 2. There were no differences in the mean HbA1c levels, mean hypoglycemic events, and DKA episodes between the two groups during a mean follow-up duration of two years. Conclusion. Young children with T1D administered insulin bolus during or immediately after meals showed similar long-term glycemic control and diabetesrelated adverse event profile compared to the premeal timing of insulin bolus. Larger real-world studies are needed on flexible insulin bolus timing in young children with T1D.

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Context. Hepatitis C and diabetes represent important health problems globally. The new-onset diabetes after transplantation is a particular entity that appears due to the use of immunosuppression among transplanted patients. Objective. We aim to describe the clinical and biological aspects of severe hyperglycemia in a kidney transplant recipient undergoing Interferon-free therapy for chronic hepatitis C, discussing the interference of different factors with the glucose metabolism. Design. The occurrence of diabetes in a patient with history of renal transplantation and Interferon-free treated hepatitis C was studied from both clinical and paraclinical points of view. Subjects and methods. When presenting to the hospital, extensive blood tests were performed on the patient, revealing significant hyperglycemia and an elevated level of blood tacrolimus. Creatinine clearance was calculated. ECG presented T-wave alterations. Intensive insulin protocol was applied, the case being managed in a multidisciplinary approach. Results. Blood glucose and tacrolimus were slowly normalized, under therapy. The antiviral treatment was continued, with the achievement of sustained virologic response. Conclusions. Diabetes mellitus can have many causes, hepatitis C and transplantation both having an impact on glucose metabolism. The association of the three entities should be carefully managed, due to its enhancing effect on morbidity and mortality.

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We describe clinical features of women with extremely low bone density, and investigate secondary causes of osteoporosis. Our hypothesis was that this population would be enriched in identifiable causes of osteoporosis. We performed a retrospective review of medical records of all women seen at our university over 4 years with T-score on bone densitometry at/below -4 at any site. Historical and fracture details were abstracted. We considered a thorough work up to include Vitamin D, PTH, CBC, chemistry panel, cortisol, transglutaminase, myeloma screen, tryptase and 24-hour urine calcium. Results. 137 women were identified with T-score at/below -4. Percent identified as Asian was 26% (higher than local prevalence of 8%). Average BMI was 21.6 kg/ m2. Clearly identifiable causes of osteoporosis were noted in 57% (inflammatory disorder, glucocorticoid or antacid exposure, prolonged immobilization and alcoholism were most prevalent). Of the remainder, full work up was performed only in 8%. Endocrine consultation and white race predicted thoroughness of secondary work-up. Conclusion. Fragility fractures, leanness and Asian race were common in women with very low T-score. However, few new causes were identified. Underlying etiology was either immediately evident or inadequately studied, especially in minorities.

Background. The involvement of IGF 1 in renal pathophysiology has been studied in many details in type 1 diabetes but the role of IGF 1 in early nephropathy in patients with type 2 diabetes is less well characteristic. Objective. To determine whether serum IGF1 and GFBP-1 levels were different between patients with and without diabetic nephropathy and also to investigate the association between them and insulin resistance. Subjects and methods. Insulin resistance (HOMA-IR), IGF 1 and IGFBP-1 were measured in 20 type 2 diabetic patients with nephropathy, 20 type 2 diabetic patients without nephropathy and 15 control subjects. Results. Serum IGF 1 in diabetic nephropathy (333.3 +/-16.44 ng/mL) was significantly higher than in both diabetic patients without nephropathy (133.16 +/- 3.43 ng/mL) and in control subjects (174.33+/-6.23) (P <0.001). A significant negative correlation was observed between IGF 1 and HOMA, (r = -0.72) in diabetic patients without nephropathy and a positive correlation in diabetic nephropathy patients (r = 0.49). Conclusion. High IGF 1 and insulin levels in diabetic nephropathy patients in addition to the significant positive association between IGF 1 and HOMA suggest that both IGF 1 and insulin resistance may play major role in early renal changes in type 2 diabetes.