ACTA ENDOCRINOLOGICA (BUC)

Background. Virilizing syndrome in a postmenopausal woman is a concerning matter, raising the suspicion of androgen-secreting tumour. Case report. A 65 years old woman presented with severe virilization features evolving rapidly over 4 years, accompanied by: severe polyglobulia, severe hypertension, dyslipidemia and uterine fibromatosis compressing both ureters, producing first degree hydroureteronephrosis. The hormonal dosages showed very high levels of both testosterone (15.5 ng/mL) and estradiol (299 pg/mL), meanwhile DHEAS level was normal, indicating an ovarian pathological secretion. The endovaginal ultrasound and computed tomography scan revealed an enlarged right ovary of 5.5/2.8 cm. A total hysterectomy and bilateral oophorectomy was performed. Pathological examination confirmed the diagnosis of right ovarian hilum Leydig cell tumour. After surgery, the testosterone and estradiol levels normalized (concordant to the age and menopausal status), the virilizing syndrome progressively improved and polyglobulia, hypertension and dyslipidemia remitted showing their secondary etiology. Conclusion. We present a very rare case of secreting ovarian Leydig cell tumour in a postmenopausal woman, showing besides the virilizing syndrome, four unusual features: severe polyglobulia, due to androgen excess, severe hypertension and dyslipidemia, all remitted after tumour removal, and severe compressive uterine fibromatosis that was the consequence of the estrogen excess.

Context. Adrenocortical carcinoma (ACC) is a rare neoplasm with an aggressive course and poor prognosis. The worldwide incidence is about 0.5 to 2 cases per million population per year. Oncocytic adrenocortical carcinoma is a rare histopathological variant of ACC with only a few reported cases in the literature. Case report. We report a case of an oncocytic variant of adrenocortical carcinoma in a 21-year-old male patient who presented with a left adrenal mass. Imaging studies confirmed a large left adrenal mass with involvement of the left renal vein and inferior vena cava. Endocrine workup showed mildly elevated serum cortisol levels. Discussion. Oncocytic AAC is a rare histopathological variant of ACC, as well as a rare subgroup of oncocytic adrenal neoplasms Hormonally active or functioning adrenocortical carcinomas most commonly secrete cortisol whereas co-secretion of multiple steroid hormones is a rare phenomenon. Conclusions. Surgery remains the mainstay of treatment, but most of the patients present late with large masses and eventually become unsuitable for curative resection.

Hyperinsulinism/hyperammonemia (HI/HA) syndrome is caused by activating mutations in GLUD1 gene, and causes fasting as well as protein sensitive symptomatic hypoglycemia, in addition to persistently elevated plasma ammonia levels. First-line treatment is diazoxide, and most patients respond well to this agent, however side effects may be observed. The most frequent side effect of diazoxide is fluid retention and hypertrichosis, while hyperuricemia and hematologic side effects are observed less often. Herein, we report a case who had a heterozygous mutation of GLUD1 gene and who developed diazoxide related neutropenia 8 years after the start of treatment. On follow-up, leucopenia and mild neutropenia persisted and the treatment was changed to somatostatin analogues. However, she developed persistent severe symptomatic hypoglycemia and required diazoxide retreatment. A lower dose of diazoxide (6 mg/kg/day) successfully controlled hypoglycemia and cell counts increased even though they were not normalized. Neutropenia in current case presented after a long period of time of diazoxide use and this period is the longest defined in the literature. Long-term endocrine and hematologic follow-up of this patient up to 18 years old will also be presented.

As the medical utility of injectable therapeutic peptides is expanding, so is the challenge of developing technologies that allow the administration of such molecules via alternative routes, considering that chronic patients requiring treatment with parenteral formulations are less adherent and compliant to the therapeutic regimens. Hence, substantial efforts have been made to develop technologies that allow the oral formulation of peptides. Due to their importance in the field of pharmaceutical technology, we describe the latest advancements made in the development of oral salmon calcitonin and oral semaglutide, in co-formulation with absorption enhancers such as 8-[(5-chloro-2-hydroxybenzoyl) amino] octanoic acid (or 5-CNAC) and N-[8-(2-hydroxybenzoyl) amino] caprylate (or SNAC). Oral semaglutide is considered to be a landmark for oral peptide delivery technology, as it is one of the very few successful examples of peptides that can be administered orally. Unlike semaglutide, oral calcitonin is still not approved by the regulatory authorities because it failed to demonstrate the anticipated effects in phase III clinical trials conducted so far. However, the efforts for obtaining an oral form of calcitonin have significantly contributed to the development of technologies that facilitate the absorption of peptide-structure macromolecules.

Background. Polycystic ovarian syndrome (PCOS) involves various changes within folliculogenesis. Aside from its systemic action, metformin seems to exert a local direct effect independent of insulinemia. The IGF system appears to be an important local target for metformin although the evidence we possess is circumstantial. Objective. The aim of this study was to evaluate the impact of metformin on insulin growth factor (IGF) system proteins and steroids production in PCOS patients and to analyze potential involvement in oocyte quality. Material and methods. This prospective study was performed on 86 in vitro fertilization (IVF) patients who were categorized into three groups as follows: Group 1 formed of PCOS patients who received metformin (n=27); Group 2 with PCOS patients who did not receive metformin (n=29) and Group 3 with controls (n=30). Interventions. Interventions included controlled ovarian stimulation for IVF and metformin (at least 16 weeks prior to the time of ovarian puncture). Main Outcome Measures.Follicular fluid analysis was performed using radioimmunoassay with specific kits (estradiol, testosterone, progesterone, IGF I, IGF II, IGF binding protein 1 - IGFBP1, IGFBP2, IGFBP3, IGFBP4). Results. Important differences were measured for the three types of steroids among the three studied groups (PCOS treated, PCOS not treated, controls) estradiol (538 vs. 466 vs. 688 ng/mL p < 0.0001), testosterone (6.7 vs. 7.6 vs. 5.1 ng/mL p<0.01), progesterone (8899 vs. 7878 vs. 9755 pg/mL p<0.0001) while for IGF system proteins important differences were noted only regarding IGFBP1 (114 vs. 107 vs. 121 p<0.002) IGFBP2 (263 vs. 268 vs. 252 ng/mL p<0.04), and IGFBP4 (128 vs. 138 vs. 118 p<0001). Correlations were also established between fertilization rate and estradiol (R: 0.53 p<0.5), testosterone (R: -0.39 p<0.05), IGFBP1 (R: 0.48 p< 0.05), IGFBP4 (R: 0.39, p<0.05). Conclusions. Patients with PCOS and hyperinsulinemia have the greatest benefit from metformin treatment. However, metformin action surpasses correction of systemic differences having a direct action at the level of follicular structures. Alteration of IGF system proteins does not concern only hyperinsulinic patients and can be partially amended by metformin administration.

5% of all cases of primary hyperparathyroidism and it is an exceedingly rare endocrine malignancy first described in 1933. Most experts recommend en bloc excision at initial surgery as the only chance for its cure. Both chemotherapy and radiotherapy have not been demonstrated to be beneficial in parathyroid carcinoma. Some patients have multiple recurrences or metastases. Therefore, new therapies are urgently needed. Inhibition of the interaction between Programmed Death Receptor 1 (PD-1) and Programmed Death Receptor Ligand 1 (PD-L1) enhances T-cell responses in vitro and mediates clinical antitumour activity. Aim. We analysed the expression of PD-L1 in parathyroid cancer to evaluate its potential as target for immunotherapeutic strategy. Subjects and methods. A cohort of 18 patients were diagnosed with primary or metastatic parathyroid cancer. Immunohistochemistry was performed in 18 formalin-fixed paraffin-embedded specimens using a rabbit monoclonal antibody. A 5% cut-off value was applied for PD-L1 positivity. Results. The anti PD-L1 antibody showed a predominantly membranous staining pattern in parathyroid cancer cells. Programmed Death Receptor Ligand-1 expression was found in 22.2% of all parathyroid carcinoma cases. There was no correlation between the expression of PD-L1 with lymph node metastasis, gender and age (P> 0.05). Conclusion. This expression of PD-L1 in human parathyroid cancer suggests that patients with parathyroid cancer could profit from immunotherapeutic strategies using anti-PDL1 antibodies.

Previous studies have correlated the expression of PAR proteins with breast cancer invasiveness. The scope of this study was to evaluate the expression of PAR-1 in human breast cancer specimens and investigate possible correlations with tumor size, grade and lymph node status, as well as covariations with estrogen and progesterone receptors, c-erbB-2 protein and lysosomal protease Cathepsin D. Formalin-fixed paraffin-embedded sections of 75 mastectomy specimens deriving from patients with primary breast carcinomas were implemented. Expression of PAR-1 was detected employing immunohistochemical assays utilizing a goat polyclonal PAR-1 antibody. The granular pattern of cytoplasmic immunoreaction was considered indicative for the protein?s expression. Statistical assessment was performed using SPSS 13.0 statistical package, Pearson?s correlation, &#967;2 and Fisher?s exact test. Expression of PAR-1 protein had a statistically significant correlation (p<0.001) with tumor grade, while in invasive tumors a similar relationship (p<0.001) was documented between PAR-1 expression and presence of positive axillary lymph nodes. However, PAR-1 expression did not exhibit a significant correlation with tumor size or with the expression of ER, PR, c-erbB-2, or Cathepsin D molecules. PAR-1 possesses a role in tumor invasion and contributes to the metastatic potential of certain types of breast carcinomas. The disassociation between expression of PAR-1 and that of the ER, PR, c-erbB-2, or Cathepsin D might imply participation in alternative pathways of malignant transformation and tumor progression.

Obesity is an important risk factor for obstructive sleep apnea syndrome (OSAS). One would expect that effective treatment by continuous positive airway pressure (CPAP) would lead to weight loss due to decreased daytime sleepiness and improved physical activity. However, many papers suggest that shortage of sleep is a risk factor for obesity.\r\nAim. To assess the weight change after 1 year of effective CPAP treatment for OSAS.\r\nMethods. In this retrospective study OSAS was diagnosed in 109 subjects (50 women, 59 men; age 58?13 years). Eighty subjects used CPAP > 5 h per night in > 70% of nights and were considered treatment subjects. Twenty-nine subjects used CPAP < 5 hours per night or < 70% of nights and were considered control subjects. Patients were diagnosed using complete full-night or split-night polysomnography (70 and 39 patients respectively). Mean effective titrated CPAP pressure was 9.8 cm H2O. CPAP compliance was assessed through downloadable data from CPAP machine (19 patients) or clinical exam (90 patients). Body mass\r\nindex (BMI) was determined at the time of diagnosis and 1 year later (range 10-15 months).\r\nResults. Treatment and control subjects were similar regarding age, sex, BMI and apnea hypopnea index (AHI) at baseline. Weight increased in CPAP users (n=80) by 1.3 kg (CI 95% 0.4, 2.25; p<0.01) but not in control subjects (n=29) (mean difference in controls 0.37 kg, CI 95% -1.8, 2.5; p>0.05). BMI significantly increased in men (p<0.005), in subjects with severe OSAS (AHI>30 events/hour) (p<0.009) and in those younger than 65 years (p<0.01). Sleep architecture was investigated by full-night polysomnography in 50 regular CPAP users and 20 controls. In the subgroup of 18 treatment patients with lack of slow wave sleep (SWS) the increase in body weight was 2.6 kg (CI 95% 0.4, 4.9, p=0.02), more than double as compared with patients with SWS at baseline (n=32).\r\nConclusion. Effective CPAP treatment leads to a modest, but significant weight gain after 1 year in OSAS patients, especially in men with severe sleep apnea. This seems to be in relation to lack of SWS at baseline. An independent medical intervention for weight loss should be associated with CPAP treatment in sleep apnea syndrome.

Context. Diabetes insipidus (DI) is rare in the neonatal period but of great importance due to increased renal risk and mental retardation despite treatment. Objective. This report describes the case of a patient with congenital nephrogenic diabetes insipidus (NDI). Detection of this pathology during the neonatal period, especially in premature newborns, is difficult because of the electrolyte variations that occur as a result of the immature kidney function. Subjects and methods. The subject was a preterm infant with very low birth weight (VLBW) and persistent hypernatremic hyperosmolarity that developed polyuria and polydipsia in the first weeks of life. Results. Taking into account blood and urine laboratory tests, vasopressin levels, as well as family history, the infant was diagnosed with congenital NDI. Early treatment allowed a good development, proving that the prevention of long-term complications is possible through multidisciplinary care and frequent monitoring. The particularity of this case was the presence of persistently elevated presepsin levels. This association prompted the investigation into underlying renal hypernatremia. Conclusions. NDI is a rare condition and the onset in the neonatal period is a sign of severity and hereditary causality. Early diagnosis, symptomatic treatment and multidisciplinary monitoring may decrease the risk of longterm complications.

Purpose. Assessing cardiovascular risk in patients with acromegaly using traditional cardiovascular risk factors is inadequate. Endothelial dysfunction seems to be a much better indicator for assessing cardiovascular risk in acromegaly. The study aims to compare from this point of view two groups of patients, with hypertension and with acromegaly. Methods. The first group consists of 54 patients with acromegaly and the second group of 64 hypertensive patients. Endothelial dysfunction was evaluated by the FMD method. The relationship between endothelial dysfunction, specific humoral markers of acromegaly and traditional cardiovascular risk factors was analysed in both groups. Results. Although the presence of cardiovascular risk factors was statistically significantly higher in the group of hypertensives (the most important were age, blood pressure, glycemia, hypertriglyceridemia and SCORE), the presence of endothelial dysfunction was higher in the acromegaly group (61.10% vs. 32.10%, p=0.02). The best correlation with endothelial dysfunction in acromegaly group was the level of GH (28.9±28 vs. 11.7±10.3, p=0.003). Conclusions. The presence of endothelial dysfunction in patients with acromegaly is highly dependent on the level of GH and traditional cardiovascular risk factors are less important. In these patients the cardiovascular risk should not be evaluated in the same way as in normal population.