ACTA ENDOCRINOLOGICA (BUC)

At least one fifth of pituitary adenomas exhibit plurihormonality when using immunohistochemistry for anterior pituitary hormones. However, the correlation with clinical features is weak, without an agreement upon pathological predictors of tumor behavior. The aim was to determine the immunoreactivity for anterior pituitary hormones and alpha subunit in 276 consecutive pituitary adenomas patients, aged 22-79 years (44.3 ? 8), 154 F/ 122 M: 83 acromegalics (ACM), 173 nonfunctioning adenomas (NFA) and 20 prolactinomas (PRM) submitted to surgery via transfrontal (81) or transsphenoidal (195) along 10 years (1995-2005). In addition, clinical data, hormonal secretion and tumour size were evaluated before pituitary surgery. Local ethical committee approved the study design. The immunoreactivity performed by the avidin-biotin-complex method was evaluated for beta FSH, LH, TSH, alpha subunit, PRL and GH, using a semiquantitative scale of stained cells: strong (>20%), positive (10-20%), weak (5-10%) and negative (<5%). CT or MRI tumor size (less than 1 cm, 1-2 cm, 2-4 cm and over 4 cm on maximal diameter) were considered together with the Hardy neuroradiological stage. The results showed that 16/83 ACM, 53/173 NFA and 4/20 PRM exhibited immunoreactivity for beta FSH and LH. TSH immunoreactivity was positive in 13/83 ACM, 11/173 NFA and 1/20 PRM. Tumor size in gonadotrophin - positive group (> 10% of stained cells) was between 1-2 cm in 6 ACM, 21 NFA and 2 PRM, while positive bigger tumors (2-4 cm) were in 7 ACM, 24 NFA and 2 PRM. Giant, over 4 cm tumors were positive in 3 ACM, 8 NFA and no PRM. A similar trend of the tumor size distribution was observed in the monohormonal or null cell adenomas. In conclusion, tumor size and gonadotrophin plurihormonality are independent factors in the management of pituitary adenomas.

In this study we aimed to evaluate and quantify optic nerve damage caused by long standing compressive pituitary macroadenomas with conventional (ophthalmoscopy) and modern techniques such as fundus camera, confocal scanning laser tomography for quantitative measurements of the thickness of retinal layers as well as visual evoked potentials (VEP) for electrophysiological quantification. Seven patients with large, long standing pituitary macroadenomas were submitted to ophthalmologic evaluation, including a visual field (VF), visual acuity (VA) and eye fundus (F). Heidelberg retinal tomography (HRT) was used for retinal thickness and evaluation of nerve fibers loss, and VEP were measured by pattern reversal and flash stimulus. In addition, all patients underwent tumor imaging (MRI/CT) and specific endocrine evaluation. All cases presented with macroadenomas with suprasellar extension and residual or progressive optic chiasma syndrome; all but one (prolactinoma) were nonfunctioning adenomas, after radical treatment (surgery ? radiotherapy). Adrenal and thyroid substitutive treatment was instituted in all cases due to associated pituitary failure. Evaluation of VF showed 9 eyes with temporal hemianopia, 2 with nasal islands of vision and 1 with nasal hemianopia in a homonymous hemianopia case; another case presented for left 3rd nerve palsy due to a cavernous sinus syndrome, therefore the visual field was not measurable in 2 eyes. Visual acuity was very low (counting fingers) in 4 eyes, while in the rest the VA was between 0.5-0.9. The fundus revealed total atrophy in 2 eyes, band atrophy in 4, temporal pallor in 5 and global pallor in 1. Cup/disk ratio in the case with 3rd nerve palsy was 0.5 (RE) and 0.3 (LE). HRT II stereometric analysis of the optic nerve head showed abnormal values, documenting retinal nerve fiber layer (RNFL) loss that correlated with fundus appearance and visual field defects. Mean RNFL thickness had abnormal values in 8 eyes (from 0.074 to 0.173 &#956;m), correlated with RNFL cross sectional area in 7 eyes (from 0.362 to 0.846 &#956;m2) and 1 eye with low limit values (1000 &#956;m2). In agreement with these data, VEP&#8211;P100 presented increased latency over 120 ms in 8 eyes, borderline (100-120 ms) in 5 and 97.5 ms in only 1 eye. In conclusion, HRT can document the papilla and nerve fiber layer more objective, permitting quantification of the disc&#8217;s alterations due to compressive pituitary macroadenomas. HRT is useful in quantifying RNFL loss in other conditions than glaucoma, when other optic disc imaging tools are not available.

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.

Endogenous Cushing’s syndrome is rare, with an incidence of 0.7–2.4 per a million people a year. Clinical presentation of Cushing syndrome can be pleomorphic, and establishing diagnosis can be difficult. Early recognition and rapid control of hypercortisolaemia are necessary to decrease morbidity and mortality in these patients. We report a series of 6 endogenous Cushing’s syndromes of different etiologies (4 Cushing’s disease and 2 adrenal Cushing’s syndrome) assessed in our endocrine department over a decade (2009-2019). In order to highlight the diversity of clinical forms, diagnostic tools and specific management of this condition we labelled each case suggestively: the typical Cushing’s disease, the Pseudo Cushing’s, the elusive Cushing’s disease, the mild autonomous cortisol hypersecretion, Cushing’s syndrome in pregnancy and Cushing’s disease with thromboembolism. We discussed their particularities which were revelatory for the diagnosis, such as dermatologic, cardiovascular, musculoskeletal, neuropsychiatric, or reproductive signs, reviewing literature for each manifestation. We also discuss the commonalities and differences in laboratory and imagistic findings. Therapeutic approach can also differ with respect to the particular condition of each patient and the multiple choices of therapy will be reviewed.

Glycemic control can be impaired in active acromegaly and insulin sensitivity (IS) decreases with rising growth hormone (GH) levels.\r\nAim. To assess the short-term impact of transsphenoidal surgery for acromegaly on glycemic control. Methods. 11 patients with native active acromegaly due to pituitary macroadenoma were assessed before and after (2-3 months) transsphenoidal hypophysectomy. Serum glucose, GH and insulin levels were measured by immunoradiometric assay at 0, 30, 60 and 120 minutes during a 75 g OGTT before and after surgery. IGF-1 levels were measured by ELISA. Basal hepatic IS was assessed using HOMA-S% and QUICKI indexes and stimulated IS using OGTTISI. Basal and stimulated insulin secretion was assessed using HOMA-B% index and IGI respectively. Results. All patients had their acromegaly improved (mean?SD pretreatment nadir GH 34?24.7 ng/mL vs. 4.6?3.5 ng/mL postsurgery; p<0.001) but only one was cured (nadir GH<1 ng/mL, normal IGF- 1 level). Mean fasting serum glucose was lowered by 7.9 mg/dL (95% CI 1.3-14.4, p=0.03) and fasting serum insulin by 9.6 mU/mL (95% CI 1.0-18.1, p=0.02). IS increased after surgery as shown by HOMA-S% index which rose 0.25?0.18 to 0.5?0.36 (p<0.01), QUICKI which rose form 0.31?0.03 to 0.33?0.03 (p=0.001) and OGTTISI index which rose from 2.5?1.6 to 5.1 ? 3.5 (p=0.002). Insulin secretion was unchanged as shown by HOMA-B% index (313?229 presurgery vs. 227?139 postsurgery, p=NS) and IGI index (0.96 ? 0.86 presurgery vs. 0.55 ? 0.49, p=NS). Conclusions. Partial removal of the pituitary adenoma by transsphenoidal surgery in patients with acromegaly induces a significant increase in insulin sensitivity and an improvement in glycemic control at 3 months after surgery. This suggests that transsphenoidal surgery should be indicated even if complete removal of the pituitary adenoma is not achieved.

Introduction. Ectopic sphenoid sinus pituitary adenomas are a rare, benign pituitary tissue neoplasm, occurring separate from and without involvement of the anterior pituitary gland. We present a case of ectopic pituitary adenoma confined to the sphenoid sinus, asociated with an empty sella. Case report. A 52-year-old man was addmitted to our neurosurgical department with persistent headache and nasal obstruction of one year duration. Patient presented no endocrine abnormalities and no visual disturbances. MRI revealed a well-defined mass lesion in the sphenoid sinus, hypointense on T1-weighted images, hyperintense on T2-weighted images, with moderate heterogeneous gadoliniumenhancement. A primary empty sella was associated. Surgery was performed by transnasal transsphenoidal approach. The tumor was removed in a piecemeal fashion. The bony sellar floor was intraoperatively proven to be intact. The pathologic studies confirmed the diagnosis of ectopic nonfunctional pituitary adenoma of the sphenoid sinus. The postoperative course was uneventful. Conclusions. When encountering a tumor within the sphenoid sinus, an ectopic pituitary adenoma should be suspected. A clinical, imaging and endocrinologic evaluation must be undertaken, aiming to identify the nature of the lesion and to initiate the specific therapy. Surgery remains the only way of obtaining a definite diagnosis and cure.

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.

Our aim was to explore the interactions of intercellular adhesion molecule (sICAM-1), TNF-&#945; (tumor necrosis factor-&#945;), interleukin-1&#945; (IL-1&#945;) and interleukin-6 (IL-6) with\r\ndopamine agonists in a culture of adenomatous cells from an nonfunctional macroadenoma.\r\nMaterials and methods. Tissue specimen from pituitary macroadenoma removed in transsphenoidal surgery was prepared for primary culture. Cells were counted and plated at 105/well into 24-well plates in a final volume of 1ml. Cabergoline in molar doses of 10-6, 10-7, 10-8, 10-9 was added and the cells were incubated for 4 days. sICAM-1, TNF-&#945;, IL-1&#945;, IL-6 were measured from cell-culture supernatants by ELISA kits.\r\nResults. sICAM-1, TNF-&#945;, IL-1&#945; and IL-6 were detected in the untreated control cultures after a 4d period. There was a negative correlation between TNF&#945; and IL-1&#945; (p=0.007).\r\nThe levels of PRL and hGH had measurable values above those found in culture medium without tumor cells. PRL positively correlated with IL-1&#945; ( p=0.05). hGH positively correlated with cell proliferation (p=0.049). Cabergoline treatment showed that IL-6 progressively decreased with the dose, ranging from -27.41% to -76.44%. TNF-&#945; significantly decreased (-65.90%; p<0.03)at the cabergoline 10-7 M dose. IL-1&#945; progressively increased with cabergoline dose, ranging\r\nfrom -2.53% to 345 %. sICAM-1 was significantly reduced by cabergoline at 10-9 (-47.12 %; p=0.045) and 10-6 M (-59.16%; p=0.01) doses. TNF-&#945; positively correlated with PRL (p=0.025); IL-6 positively correlated with hGH (p=0.044); sICAM-1 negatively correlated with hGH\r\n(p=0.009), TNF&#945; (p=0.025) and IL-1&#945; (p=0.044).\r\nConclusions. These data support the existence of an immunoendocrine network in pituitary tumorigenesis; TNF-&#945;, IL-6, IL-1&#945;, sICAM-1 significantly interfered by cabergoline\r\ntreatment in a dose-dependent way. However, future studies on different types of pituitary tumours are needed to confirm these findings.