ACTA ENDOCRINOLOGICA (BUC)

Introduction. The blood brain barrier (BBB) restricts the transport of hydrophilic molecules such as peptidic pituitary hormones into the brain tissue. The blood-cerebrospinal fluid (CSF) is a part of the BBB.\r\nAim To compare the pituitary hormone levels on the two sides of the BBB in a group of subjects without endocrine diseases.\r\nPatients and methods. We investigated, with the approval of the local ethics committee, 78 subjects without endocrine diseases. Growth hormone (GH), prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and thyroid stimulating hormone (TSH) were measured by rapid fluoroimmunoassay with Europium in the blood and cerebrospinal fluid (CSF)sampled simultaneously before rachianestesia for minor surgery.\r\nResults. CSF concentrations are significantly lower than the corresponding serum ones for all hormones studied: 0.04 ? 0.009 mU/mL vs 2.29 ? 0.57 mU/mL for GH, 1.49 ? 0.078 ng/mL vs 10.07 ? 1.42 ng/mL for PRL, 0.57 ? 0.078 U/L vs 22.71 ? 3.65 U/L for FSH, 0.39 ? 0.038 U/L vs 11.11 ? 1.55 U/L for LH and 0.01 ? 0.003 &#956;U/mL vs 1.36 ? 0.17&#956;U/mL for TSH (mean ? SEM; p<0.001). The CSF/serum ratio was below 1 in the vast majority of cases (from all subjects studied we only found 3 cases with supraunitary CSF/serum ratio). The serum and CSF levels were not significantly correlated for\r\nany of the pituitary hormones. Comparing preand postmenopausal women the CSF gonadotropin levels were slightly but nonsignificantly increased after menopause,\r\ndespite marked differences in the serum concentrations: CSF FSH 1.21 ?0.17U/L after vs 0.84? 0.4U/L before menopause, CSF LH 0.60? 0.047U/L after vs 0.43? 0.14U/L before\r\nmenopause. The CSF/ serum ratio for FSH markedly decreased after menopause (0.02?0.003 vs 0.22?0.11) although the effect did not reach statistical significance. The same\r\nwas true for CSF/serum LH ratio (0.026?0.005 vs 0.09?0.002). For none of the hormones studied the CSF levels correlated with age.\r\nConclusion. Pituitary hormones are normally found in the CSF at much lower levels than in the serum. The CSF hormonal\r\nconcentrations do not significantly correlate with the serum ones.

A 63-years old patient with severe thyrotoxicosis with cachexia and high frequency atrial fibrillation showed an inadequate secretion of TSH. A pituitary macroadenoma was revealed by computed tomography. Acute octreotide administration decreased serum TSH\r\nfrom 2.48 mU/mL to 0.06 mU/mL and T3 from 3.1 ng/mL to normal values (0.93 ng/mL) in 3 days; at the same time serum T4 remained unchanged (raised).The response to octreotide supported the diagnosis of TSH-secreting adenoma. T3 suppression test is no longer useful at present for diagnosis.Administration of long- acting somatostatin analogues (lanreotide) together with antithyroid drugs (ATD) was initially necessary. However, after removal of pituitary tumor the clinical symptoms (including atrial fibrillation) disappeared.ATD administration was no longer necessary, nor was octreotide or lanreotide. Immunohistochemistry certified that the pituitary tumor was a pure thyrotropinoma (without plurihormonal expression). Complete cure of severe thyrotoxicosis due to a TSH-secreting pituitary adenoma by pituitary surgery is possible. Thyroidectomy is not indicated.

Hyperosmolar hyperglycemic non-ketotic state is a life-threatening emergency manifested by a marked elevation of blood glucose, hyperosmolarity, and little or no ketosis. It most frequently develops in middle-aged or elderly patients, often in the setting of previously mild type 2 diabetes and in the presence of one of the established risk factors (e.g. infection, cerebrovascular accident, myocardial infarction). We present the case of a 48 years old woman with no past history of diabetes who developed hyperosmolar hyperglycemic nonketotic state after transsphenoidal surgery for a large macroprolactinoma. Despite having symptoms (secondary amenorrhoea and galactorrhoea) for many years the patient only had inconsistent medical follow-up and eventually she developed optic chiasm syndrome. She was referred for pituitary surgery performed by transsphenoidal route. After surgery there was marked improvement of the visual signs but few days after intervention the patient presented with polydipsia, polyuria and paresthesiae. Based on laboratory tests that showed a markedly elevated blood glucose level (1088 mg/dl), hyperosmolarity, no acidosis therefore, a diagnosis of hyperglycemic hyperosmolar state was made. With rehydration and insulinotherapy she recovered and the evolution was favourable over weeks with discontinuation of insulin administration. The patient still had high prolactin level after surgery (3060.3 ng/dl) so we also initiated dopamine agonist bromocriptine treatment. In addition to the well known effects of dopamine agonist upon prolactinoma it also has beneficial effects on glycemic control in diabetics (it reduces insulin resistance, both fasting and postprandial plasma glucose levels and HbA1c levels). We discuss the possible explanations of the syndrome and the effects of bromocriptine treatment.

Background: Germline aryl hydrocarbon receptor-interacting protein (AIP) mutations are found in familial isolated pituitary adenoma syndrome (FIPA) families and in a small number of sporadic pituitary adenoma (PA) patients. Although the tumorigenic mechanisms of AIP mutations are unclear, truncating mutations are considered pathogenic, but missense mutations are difficult to evaluate. p.R16H (c.47G>A) is a controversial AIP variant of unknown significance. Aim: To describe a new PA case associated with AIP p.R16H. Patients and methods: One AIP p.R16H non-functioning pituitary adenoma (NFPA) case identified by mutation sequencing screening of sporadic PA patients; 108 controls were screened for p.R16H. Results: The 38 yrs. old male NFPA patient had no family history of PA and harboured a heterozygous p.R16H variant. The proband and two brothers presented severe intellectual disability. Severe visual impairment was the initial symptom and clinical, biochemical and imaging examination demonstrated a large NFPA invading the right cavernous sinus. After transsphenoidal debulking, the remaining tumor continued growth. One of proband’s sisters was negative for p.R16H. Among controls, we identified one heterozygous p.R16H carrier, presenting a thyroid follicular neoplasm. Loss of heterozygosity analysis of the pituitary and thyroid tumors was not performed. Conclusions: We report two new occurrences of AIP p.R16H, associated with a NFPA and with a thyroid tumor. The NFPA patient was young and presented an invasive macroadenoma, features typical of AIP-mutated patients. Because the association between p.R16H and PAs has not been conclusively established, further research of p.R16H is warranted, in view of its implications for AIP genetic testing.

Introduction. Vitamin D (VD) deficiency is highly prevalent worldwide. Aim. To assess the prevalence of hypovitaminosis D in HIV-positive Romanian patients compared to controls. Methods. Serum 25OHD concentration was measured in HIV-infected patients and a control sample, matched by age, sex and menopausal status. The 25OHD status was defined as: deficiency < 20 ng/mL (severe deficiency <10 ng/mL), insufficiency 20-30 ng/mL, normal >30 ng/mL. Results. We evaluated 118 HIV-positive patients (72 males, 46 females), aged 36.9±12.2 years. 98.14% of them were on complex antiviral regimens. The B/C hepatitis coinfection rate was 9.3%. The control sample consisted of 119 subjects, (74 males, 45 women). The median and interquartile range for serum 25OHD concentration in patients was 17.6 (9.7, 26.9) ng/mL and 23.7 (18.4, 27.5) ng/mL in controls (p=0.001). Only 15.96% of HIV-positive cases and 12.71% of controls had normal VD status. The percentage of cases with severe VD deficiency was significantly higher in HIV positive cases (23.52%) compared to HIV-negative controls (4.2%, p=0.001). Conclusions. Hypovitaminosis D was identified in 84.04% of HIV-infected patients, but the serum 25OHD concentration was not associated with specific HIV-related factors in our sample. Clinical guidelines regarding VD status determination and supplementation in HIV patients are needed.

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of fragility fractures compared to the general population. The pathogenesis of the elevated fracture risk is multifactorial and still largely elusive. In contrast to primary osteoporosis, in T2DM the bone mineral density (BMD) is increased compared to controls, suggesting that specific alterations in bone quality occur in diabetic patients. Even more, the specific increase in BMD observed in these patients impairs at least in part both the classical diagnosis of osteoporosis by dual-energy X-ray absorptiometry (DXA) and the current fracture risk estimation by FRAX (fracture risk assessment tool). Trabecular bone score (TBS) and TBS-adjusted FRAX could improve fracture risk estimation in patients with T2DM but improved tools are needed in the future as well as specific risk stratification criteria. Decreases in the fracture risk of patients with T2DM can be obtained by optimal diabetes control and standard treatment of osteoporosis (most drugs appear to have similar efficacy in patients with T2DM and primary osteoporosis).

Background. Usually, silver stain is needed to differentiate between normal or hyperplastic hypophysis and pituitary adenomas. Many papers reported the lack of reticular fibers network as mandatory for pituitary adenoma diagnosis. \r\nAim. Differences between the architecture of reticular fibers in normal pituitary and pituitary adenomas \r\nMethods. Gordon- Sweet silver staining of pituitary specimens, prelevated during pituitary surgery performed in 138 patients with the endocrine and imagistic diagnosis of pituitary macro-adenomas. \r\nResults.Pituitary specimens of pituitary adenomas was confirmed in 133 cases; 3 specimens were with normal pituitary tissue, 1 with pituitary hyperplasia, 1 with pituitary apoplexy.Twelve of 133 pituitary adenomas specimens were associated also with normal pituitary tissue.There was a loss of acinar network of reticular fibres in 115 cases, but the present study describes the persistence of reticular fibers networks in 18 (13,53%) of 133 pituitary adenomas. We identified five distribution patterns of remanent reticular fibers network in pituitary adenomas using silver staining. \r\nIn conclusion, persistence of reticular fibers in a small number of pituitary adenomas could be a possible pitfall in the discrimination between the normal hypophysis and pituitary adenoma.

Non-functioning pituitary tumors (NFPA) are usually large at the time of diagnosis and present with symptoms caused by compression on the neighbouring structures. Transsphenoidal resection of the tumor is the firstline treatment but in many cases complete tumor resection cannot be attained. Close follow-up with repeated hormonal assessment and pituitary imaging is recommended after surgery. During follow-up of the tumor remnant sometimes radiotherapy is used to stop or prevent tumor progression. Medical treatment with dopamine agonists (DA) is the mainstay in the management of prolactinomas. For NFPA several small series or case reports suggested beneficial effects with tumor shrinkage in some cases. The aim of the current paper is to summarize the available evidence related to the potential efficacy of DA medical treatment in NFPA while underlining that in the absence of randomized, placebocontrolled studies, no final conclusion on the efficacy of these drugs in the treatment of NFPA can be drawn.

Craniopharyngiomas (CP) are rare, dysembryoplastic tumors of the hypothalamo-pituitary area. There are two very distinct pathological types: adamantinomatous (ACP) and papillary (PCP). ACP and PCP also have significant clinical differences, pointing to a different pathogenesis. This only began to be elucidated lately and indeed discovered specific, mutually exclusive mutations with pathogenetic role in ACP and PCP, respectively. The vast majority of ACP harbor an activating mutation of the CTNNB1 gene coding for β-catenin (member of the Wnt pathway). The mutation was proved to be pathogenetic in animal models and a tumorigenesis model has already been created. In contrast, in PCP, BRAF (gene coding for a main actor in the MAPkinase pathway) mutations have been found in the majority of cases. These findings can improve the differential diagnosis of intracranian tumors (by specifically designed immunohistochemistry-antibodies) and the design of molecules to inhibit the disordered intracellular pathways. Such molecules are already available and promising for the BRAF/MAPkinase pathway. In conclusion, extremely significant progresses have been made in revealing the complex process of tumorigenesis in CP and they are likely to solve in the foreseeable future many challenges we typically face in the clear positive diagnosis and optimal management of these rare tumors.

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