ACTA ENDOCRINOLOGICA (BUC)

Introduction. Wolfram Syndrome (WS) is a rare autosomal recessively inherited disorder characterized by juvenile-onset diabetes mellitus (DM), diabetes insipidus, optic atrophy (OA), hearing loss and neurodegeneration. This report describes three cases with WS. Case report. The first case was diagnosed with DM and OA at the age of 6 and 11 years, respectively. Second patient was the sibling of the first patient, also had DM and was investigated for WS after his brothers’ diagnosis. The third patient was diagnosed with DM at the age of 5 years and developed bilateral sensorineural hearing loss and OA at the ages of 7 and 12 years, respectively. Preliminary diagnoses of all patients were confirmed by Sanger sequencing of the WFS1 gene. Two previously reported and a novel mutation were detected. While our first patient was diagnosed with attention deficit hyperactivity disorder previously described in WS patients, obsessive compulsive disorder observed in case 2, was not previously reported in WS to the best of our knowledge. Puberty delay was detected in our first patient and was diagnosed as constitutional delay of puberty and growth. Conclusion. Early diagnosis of WS can lead to early detection of associated pathologies and to decrease complications, morbidity and mortality.

The beta 3 agonists have antiobesity, thermogenetic and lipolytic properties. Starting from BRL35135 structure, a well-known beta 3 agonist, 3 new phenylethylamine derivates (A, B, C) and 2 new pyrazol derivates (D, E) were synthesized.\r\nPurpose. The aim of this study was to evaluate the effect of five new compounds derived from of BRL35135 on glycemia in normal and diabetic rats.\r\nMethods. For each experiment, test and control groups of 6, 8 or 10 male Wistar rats were used. For inducing experimental diabetes mellitus, alloxan (100 mg/kg body weight) was intravenously injected. Tested substances were intraperitoneally injected (1 or 100 mg/kg body weight) and glycemia values were measured before and at 3 hours after their administration. Control groups received propyleneglycol, the solvent of the new compounds. Glycemia values were measured with a calibrated glucometer.\r\nResults. In normal rats one of the phenylethylamine compounds (substance C) (100 mg/kg body weight) had a hypoglycemic effect comparative to control (p=0.03). In glucose tolerance test, substance E (100 mg/kg body weight) stopped the increase of glycemic values determined by glucose oral administration in the first 60 minutes comparative to control (p=0.03). In the alloxanic diabetes model, before insulin administration the substances hypoglycemic effect could not be measured with the glucometer because of very high values of glycemia. After insulin administration no significant differences between the treated and the control groups were registered. Further studies on the hypoglycemic effect of substances C and E are needed in order to establish their possible antidiabetic effect.\r\nConclusion. A phenylethylamine derivate and a pyrazol derivate of BRL35135 had a hypoglycemic effect in normal rats, but this effect could not be confirmed in rats with alloxanic diabetes.

Increased frequency of adrenal tumours and adrenal myelolipoma has been reported in patients with 21-hydroxylase deficiency (21-OHD). Adrenal myelolipoma is an uncommon, benign, biochemically non-functioning tumor and occasionally reported in association with endocrine disorders. Diagnosis of myelolipomas is based on imaging with ultrasonography, CT or MRI being effective in more than 90% of cases. We present a 34-year-old man with massive bilateral adrenal masses which was detected on computed tomography and was diagnosed as 21-hydroxylase deficiency (21-OHD) based on biochemical findings. Computerized tomography of the abdomen demonstrated bilaterally very low-density adrenal masses (16x28 mm on the right side and 91x88 and 33x30 mm on the left side) consistent with adrenal myelolipomas. Since myelolipomas are considered as benign tumors, he was not operated. Tumor size did not increase during two year follow-up periods. It is recommended to the physicians to be aware of increased frequency of benign adrenal tumors that occur frequently in patients with 21-OHD. Untreated CAH with prolonged excessive ACTH stimulation might contribute to the growth of adrenal masses. CAH should always be ruled out in incidentally detected adrenal masses to avoid unnecessary surgical procedures.

Background. Molecular defects in the SHOX gene including deletions, duplications or pathogenic point mutations are responsible for well-known pathologies involving short stature as a clinical manifestation: Léri–Weill dyschondrosteosis, Langer mesomelic dysplasia, Turner syndrome or idiopathic short stature. Duplications flanking the SHOX gene (upstream or downstream of the intact SHOX gene involving conserved non-coding cis-regulatory DNA elements - CNEs) have been described but their clinical involvement is still difficult to understand. Results. We describe two cases with short stature and normal GH-IGF1 status. Multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (arrayCGH) identified in both cases heterozygous duplications involving downstream regions of SHOX gene, within CNEs (CNE8, CNE9 and CNE4, CNE5, CNE6, ECR1, CNE8, CNE9 and surrounding areas, respectively). One of the cases showed a maternally inherited duplication. Although every case has several particularities, we consider that duplications in these non-coding regions of SHOX gene may explain the short stature phenotype. Conclusion. To our knowledge, these are the first Romanian-reported cases of ISS with a large duplication of downstream SHOX enhancers CNEs region. The spectrum of phenotypic consequences and the exact mechanism of the presumed clinical expression of these genetic alterations still needs to be evaluated and described.

Background. There are many systemic illnesses that constitute risk factors for cerebral vein thrombosis (CVT).The association between cerebral venous sinus thrombosis and polycystic ovary syndrome (PCOS) has been rarely reported in the literature. This report\r\ndescribes a case of cerebral venous sinus thrombosis following intake of contraceptive pill (cyproterone acetate 2mg + etinil-estradiol 35 micrograms), for dysfunctional uterine bleeding secondary polycystic ovary syndrome in young women.\r\nCase report. We reported a 22-year-old women presented with severe headache associated with vomiting sudden onset; she had been taking contraceptive pills for the previous ten days. CVT was diagnosed with CT scan, MRI and MR venography. Laboratory investigations showed no evidence of inherited thrombophilia. The patient was treated with classic heparine, followed by acenocumarol with good clinical outcome.\r\nConclusions. This case illustrates that patients with polycystic ovary syndrome may develop thrombosis, if the patient is treated with combined contraceptives, even for short period of time. The role of PCOS as independent prothrombotic factor and the risk associated with oral contraceptive as first line treatement in PCOS need to be further investigated.

Objective: The goal of this research is to investigate whether melatonin, a circadian informant, is implicated in idiopathic oligospermia in men.\r\nSubjects and methods: 12 men (mean age 30.5 yr) with normal sexual function diagnosed with idiopathic oligospermia and 8 healthy men were included. In urine 6-sulfatoxymelatonin (aMT6s), a reliable index of melatonin secretion and gonadotropins, LH and FSH were assayed. In plasma LH, FSH, DHEA-S, 17-OH progesterone, testosterone, free testosterone, SHBG were measured at 08:00.\r\nResults: As expected, in the infertile group reproductive hormones were within normal limits but persisted low testosterone and high gonadotropins. Estimated bioavailable testosterone also showed a significant decrease (p=0.03). Evaluation of individual differences in circadian production of both melatonin and gonadotropins exhibited substantial changes in their secretion pattern from the phase shifts to loss of rhythm for aMT6s. The reduced amplitudes (p=0.04) of aMT6s were associated with a longer duration of melatonin secretion (p< 0.001) as estimated from onset/offset time and a reduced ratio between night- and daytime; the mean 24h amount of aMT6s tended to decrease at significant limit (p=0.05); no significant correlation between aMT6s and gonadotropins was observed compared with the control group. The amplitudes of gonadotropins were lower while their mean 24 h amount showed a moderate increase.\r\nConclusions: The present findings suggest that the significant increase in the duration of melatonin secretion may contribute to the imbalance of reproductive hormones that affect spermatogenesis; aMT6s, urinary metabolite of melatonin may be a sensitive predictor in circadian disorders of reproductive axis.

The development of cancer in humans involves genetic and epigenetic changes that\r\nlead to cell cycle progression, inhibition of apoptosis, cell immortalisation, angiogenesis and\r\nthe ability to metastasise. One signalling pathway common to these events is the activation\r\nof phosphatidylinositol-3-kinase (PI3K) that affects downstream molecules involved in\r\nmalignant transformation. The article reviews the present data on the PI3K signalling, its\r\nderegulation in endocrine tumours, and new therapeutic strategies targeting this pathway in\r\nhuman neoplasia.

Aims. To provide growth references for school-aged children in western Romania, to compare them with other national and\r\ninternational growth charts and evaluate the prevalence of overweight and obesity.\r\nMethods. A total of 3731 children, aged 7-19 years, from Timis county, were examined by medical students, between\r\nFebruary 2010-June 2011. Growth references for height, weight, and body mass index (BMI) were constructed with LMS method and LMSChartMaker software. The Romanian 3rd, 50th and 95th percentile for height and BMI were compared with national and international growth references. The prevalence of overweight and obesity was determined with IOTF definition.\r\nResults. Crude and smoothed percentiles for weight, height and BMI were shown for this population. The comparison\r\nprovided data regarding the variation of growth models in different populations. Our results demonstrated a high prevalence of overweight (18.2%) and obesity (7.2%) in our\r\npopulation, higher in boys versus girls.\r\nConclusions. Our study constructed growth references for a Romanian population. The comparison with other growth references reflected the regional differences in growth\r\npatterns between populations.

Context. Coronary artery disease (CAD) is one of the common diseases in patients with type two diabetes mellitus (T2DM). The nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPARγ) plays a vital role in dyslipidemia, and oxidative stress is involved in atherogenesis. Objective. The study aimed to determine the association between Pro12Ala polymorphism of the PPARγ2 gene(rs1801282) and CAD risk in T2DM patients in the Iranian population. Design. A group of 145 T2DM patients with a history of CAD were enrolled, together with 145 sex and gender-matched individuals who had neither CAD nor history of T2DM who were enrolled in a case-control study. Subjects and Methods. Polymerase chain reactionrestriction fragment length polymorphism technique was applied to genotype the PPARγ2 gene polymorphisms. Statistical analysis was done using SPSS version 22. Results. CC and GC genotypes of Pro12Ala had a higher frequency in the control and case groups, respectively. The GC genotype was associated with a significantly increased CAD risk compared to the CC genotype (adjusted OR= 2.66, 95% CI = 1.5-29.5, p<0.01). The mean triglycerides and total cholesterol level were significantly higher in the CC genotype than the GC genotype in both case and control groups (p<0.05). The mean level of fasting blood glucose was significantly higher in the CC genotype compared to GC genotype in the case group (p<0.05). The mean of creatinine, lipid profiles, microalbuminuria, and hemoglobin A1c had no significant difference between CC and GC genotypes in both groups (p>0.05). Conclusion. PPARγ2 Pro12Ala polymorphism could be an essential indicator for the increased risk of CAD in the Iranian people with T2DM.

Testosterone influences cancer development. This in vitro experiment was exerted to determine the association of testosterone with human colorectal cancer(HT29), glioblastoma (A172) and human embryonic kidney(HEK293) cells proliferation. HT-29, A172 and HEK293 cell lines were cultured in standard growth medium, then randomly divided into control group (not exposed to testosterone) and groups exposed to 1, 10, 100 and 1000 μg/mL of testosterone. Cell viability was quantified by MTT assay. Statistical analysis was performed using ANOVA. Viability of HEK293 cells significantly increased in groups exposed to 1 μg/mL and decreased in groups exposed to 100 and 1000 μg/mL of testosterone compared to control group (P<0.05, P<0.05 and P<0.001, respectively). Viability of HT29 cells significantly increased in groups exposed to 10 and 100 μg/mL of testosterone and significantly decreased when exposed to 1000 μg/mL of testosterone compared to control group (P<0.05, P<0.001 and P<0.001, respectively). Viability of A172 cells significantly decreased in groups exposed to 100 and 1000 μg/mL of testosterone compared to control group (P<0.001). In conclusion, different doses of testosterone have enhancing or suppressive effects on HEK293, HT29 and A172 cells proliferation; according to which, considering clinical use of testosterone therapy for cancer treatment is a highly controversial issue.