The purpose of the present clinical case is to remind clinicians that craniopharyngiomas, which are benign neoplasms with a high incidence of local recurrences, may also present ectopic recurrences which may at first go unsuspected. These tumors most commonly arise in the suprasellar region and despite their benign histology, they may infiltrate the surrounding neurovascular structures making total removal challenging. Ectopic recurrences of craniopharyngiomas are very rare. We describe an adult patient with ectopic recurrence of craniopharyngioma, emphasizing unique features of the case presentation and its physiopathological aspects. A 49-year-old male presented with headache and visual field defect and was diagnosed with a suprasellar tumor. He was submitted to neurosurgery and histological examination revealed an adamantinomatous craniopharyngioma. Postoperative magnetic resonance imaging (MRI) showed complete tumor resection. The patient remained asymptomatic with no imaging signs of local recurrence during follow up. Five years after surgery, the patient noticed a rapidly growing lump at the surgical incision site. He reported a mild to moderate local trauma 4 months before. A MRI showed a subgaleal cystic tumor arising in the pathway of the craniotomy. Surgical resection of that cystic lesion was performed and histological examination revealed an adamantinomatous craniopharyngioma. One year later no recurrences have been detected. The case reported has two particular features: the local trauma as a potential trigger for tumor progression and the rapidly growing pattern of the ectopic recurrent tumor. We emphasize that although ectopic recurrences of craniopharyngiomas are rare, they may occur away from the primary tumor and quite late in the follow up of the patient.

Estrogen receptor α has a role in regulating rat somatolactotroph tumor cell growth (GH3 cells). AMP-activated protein kinase (AMPK) is a metabolic checkpoint which is able to negatively regulate intracellular signaling downstream of growth factors receptors in conditions increasing cellular AMP levels. We have recently reported on the role of AMPK activation in affecting viability and proliferation of GH3 cells. In the present study, we investigated the interplay between ER- and AMPK-pathways. Results can be regarded as relevant to the development of novel multi-targeted pharmacological therapies against pituitary tumors. We confirmed that estradiol (E2) and the ER antagonist fulvestrant exert stimulatory and inhibitory effects, respectively on GH3 cell growth in a competitive manner. The upstream kinase LKB1 is known to phosphorylate and activate AMPK. Here we showed that neither E2 nor fulvestrant caused a downregulation of LKB1 expression and phospho-AMPK levels in GH3 cells. Actually, fulvestrant strongly reduced the phosphorylation of ACC, which is a direct target of AMPK and a known index of AMPK activity. 2-deoxyglucose, a compound reducing glucose utilization, caused an increase in AMPK activity vs baseline and was able to hinder the stimulatory effect of E2 on cell viability, confirming that the exposure of GH3 cells to estrogens does not prevent them from being responsive to the inhibitory activity of compounds activating AMPK. Finally, the AMPK activator AICAR (AMP analog) did not cause further decrease in cell viability in the course of co-treatments with fulvestrant versus fulvestrant alone, in agreement with impaired phospho-AMPK activity in the presence of the anti-estrogen.

Pituitary carcinoma is characterized by the presence of a metastatic lesion(s) in a location non-contiguous with the original pituitary tumor. The mechanism(s) of malignant transformation are not known. A 15 year-old male was diagnosed in 1982 with a pituitary macroadenoma and acromegaly (random GH 67 ng/ml and no suppression by oral glucose). His prolactin was normal between 18 and 23 ng/ml. Transcranial resection in July 1983 was followed by radiation therapy. The tumor was immunopositive for GH and prolactin. The proliferation MIB-1 index was 0-1 %. With aqueous Octreotide 100 mcg 4× daily both GH and IGF-1 became normal. The patient was lost to follow-up and was treated by his local physician. In 2001, his IGF-1 level was 1271 ng/ml, and his random GH was 1.8-2.4 ng/ml by ILMA despite progressive increase in the dose of Sandostatin LAR to 140 mg/month in divided doses. Prolactin remained normal or minimally increased between 15 and 25 ng/ml. In 2009 he was diagnosed with the tumor in the location of left endolymphatic sac. Histological examination showed low grade pituitary carcinoma strongly immunopositive for prolactin but negative for GH. MIB-1 antibody labeled 0-5 % cells. In 2012 endoscopic resection of the pituitary tumor remnant was attempted. Immunohistochemical stains were strongly immunopositive for both prolactin and GH, similar to his original pituitary tumor. The MIB-1 proliferation index was low from 0 to 1 %. To our knowledge this is the first case of pituitary carcinoma in the endolymphatic sac region. The dichotomy between the cell population of the pituitary lesion (GH/prolactin producing) and the metastasis (purely prolactin-producing) may suggest that the metastatic pituitary lesion derived from a clone distinct from the original one.

To report an unusual case of biopsy-proven autoimmune hypophysitis with predominant hypothalamic involvement associated with empty sella, panhypopituitarism, visual disturbances and antipituitary antibodies positivity. We present the history, physical findings, hormonal assay results, imaging, surgical findings and pathology at presentation, together with a 2-year follow-up. A literature review on the hypothalamic involvement of autoimmune hypophysitis with empty sella was performed. A 48-year-old woman presented with polyuria, polydipsia, asthenia, diarrhea and vomiting. The magnetic resonance imaging (MRI) revealed a clear suprasellar (hypothalamic) mass, while the pituitary gland appeared atrophic. Hormonal testing showed panhypopituitarism and hyperprolactinemia; visual field examination was normal. Pituitary serum antibodies were positive. Two months later an MRI documented a mild increase of the lesion. The patient underwent biopsy of the lesion via a transsphenoidal approach. Histological diagnosis was lymphocytic "hypothalamitis". Despite 6 months of corticosteroid therapy, the patient developed bitemporal hemianopia and blurred vision, without radiological evidence of chiasm compression, suggesting autoimmune optic neuritis with uveitis. Immunosuppressive treatment with azathioprine was then instituted. Two months later, an MRI documented a striking reduction of the hypothalamic lesion and visual field examination showed a significant improvement. The lesion is stable at the 2-year follow-up. For the first time we demonstrated that "hypothalamitis" might be the possible evolution of an autoimmune hypophysitis, resulting in pituitary atrophy, secondary empty sella and panhypopituitarism. Although steroid treatment is advisable as a first line therapy, immunosuppressive therapy with azathioprine might be necessary to achieve disease control.

Vasospasm and consequent cerebral ischaemia in aneurysmal subarachnoid haemorrhage are well-described. The development of cerebral ischaemia following pituitary tumour surgery is under-appreciated, and can be attributed to mainly cerebral vasospasm or internal carotid artery compression. We report on two patients with pituitary tumours who developed delayed cerebral ischaemia after transsphenoidal and transcranial pituitary macroadenoma decompression. The patients had vasospasm of intracranial vessels demonstrable on magnetic resonance angiogram. One recovered neurologically following nimodipine and hypertensive-hypervolaemia therapy while the other developed fulminant cerebral infarction. We discuss the complex multi-factorial mechanisms of cerebral ischaemia in pituitary disorders, as well as the management strategies and their limitations.

Fibromyalgia Syndrome (FMS) is a frequent idiopathic condition in which patients experience intense pain in specific tender points, profound fatigue and sleep disturbances. Although pain had not account so far in growth hormone deficiency syndrome (GHD) description, symptoms of FMS are very similar; and there is strong evidence of decreased GH secretion at least in a subset of FMS patients. Is there an overlap of the two diseases? A systematic Medline/Embase search for preliminary proof-of-concept trials, but also larger placebo-controlled studies, have shown that GH replacement in low-IGF1 patients can significantly improve some symptoms of FMS and quality of life, suggesting a direct causal effect of GH deficiency. Despite the use of relatively high doses of GH in these patients, treatment seems to be well tolerated. Several mechanisms of action for GH in FMS relief have been suggested, including both central modulation of pain and peripheral musculo-tendinous effects, as already described in classic GHD.

Cushing's syndrome (CS) has a considerable negative impact on patient health-related quality of life (HRQoL). Two disease-specific instruments (the CushingQoL and the Tuebingen CD-25 questionnaire) are now available to assess the impact of the disease and its treatment on HRQoL. The purpose of this review was to summarize the characteristics of the studies which have used these two instruments to date and summarize their findings regarding (a) the determinants of disease-specific HRQoL in patients with CS and (b) the impact of treatment for CS on disease-specific HRQoL. A total of 7 studies were identified, 5 with the CushingQoL and 2 with the Tuebingen CD-25. Most were observational studies, though the CushingQoL had been used in one randomized clinical trial. In terms of clinical factors, there was some evidence for an association between UFC levels and disease-specific HRQoL, though the presence and strength of the association varied between studies. There was also some evidence that a more recent diagnosis of CS could lead to poorer HRQoL, and that length of time with adrenal insufficiency may also affect HRQoL. There was no evidence for an impact on disease-specific HRQoL of etiology or of the clinical signs and symptoms associated with CS, such as bruising, rubor, and fat deposits. One factor which did have a significant negative effect on HRQoL was the presence of depression. No clear picture emerged as to the effect of demographic variables such as age and gender on HRQoL scores, though there was some evidence for poorer HRQoL in female patients. As regards treatment, the two interventions studied to date (transsphenoidal surgery and pasireotide) both showed significant gains in HRQoL, with moderate to large effect sizes. This type of review is useful in summarizing knowledge to date and suggesting future research directions.

To recommend an approach to monitoring and treating hyperglycemia in pasireotide-treated patients with Cushing's disease, a severe clinical condition caused by a pituitary adenoma hypersecreting adrenocorticotropic hormone. Advisory Board meeting of ten European experts in pituitary disease and diabetes mellitus in Munich, Germany, on February 23, 2012, to obtain expert recommendations. Cushing's disease presents a number of management challenges. Pasireotide, a novel agent for the treatment of Cushing's disease with proven biochemical and clinical efficacy, improves outcomes and expands treatment options. Clinical trials have shown that the pasireotide adverse event profile is similar to that of other somatostatin analogs, except for a higher frequency of hyperglycemia. Mechanistic studies in healthy volunteers suggest that pasireotide-associated hyperglycemia is due to reduced secretion of glucagon-like peptide (GLP)-1, glucose-dependent insulinotropic polypeptide, and insulin; however, it is associated with intact postprandial glucagon secretion. Individual patients' results demonstrate effective hyperglycemia management by following standard guidelines for the treatment of diabetes mellitus with individual adaptation to the specific underlying pathophysiology, i.e., preferential use of GLP-1 based-medications. Patients on pasireotide treatment should be monitored for changes in glucose metabolism and hyperglycemia. Diabetes mellitus should be managed by initiation of medical therapy with metformin and staged treatment intensification with a dipeptidyl peptidase-4 inhibitor, with a switch to a GLP-1 receptor agonist and initiation of insulin, as required, to achieve and maintain glycemic control. Further research into hyperglycemia following pasireotide treatment will help refine the optimal strategy in Cushing's disease.

Cardiovascular complications are the most common causes of morbidity and mortality in acromegaly. However, there is little data regarding cardiac autonomic functions in these patients. Herein, we aimed to investigate several parameters of cardiac autonomic functions in patients with acromegaly compared to healthy subjects. We enrolled 20 newly diagnosed acromegalic patients (55 % female, age:45.7 ± 12.6 years) and 32 age- and gender-matched healthy subjects. All participants underwent 24 h Holter recording. Heart rate recovery (HRR) indices were calculated by subtracting 1st, 2nd and 3rd minute heart rates from maximal heart rate. All patients underwent heart rate variability (HRV) and QT dynamicity analysis. Baseline characteristics were similar except diabetes mellitus and hypertension among groups. Mean HRR1 (29.2 ± 12.3 vs 42.6 ± 6.5, p = 0.001), HRR2 (43.5 ± 15.6 vs 61.1 ± 10.8, p = 0.001) and HRR3 (46.4 ± 16.2 vs 65.8 ± 9.8, p = 0.001) values were significantly higher in control group. HRV parameters as, SDNN [standard deviation of all NN intervals] (p = 0.001), SDANN [SD of the 5 min mean RR intervals] (p = 0.001), RMSSD [root square of successive differences in RR interval] (p = 0.001), PNN50 [proportion of differences in successive NN intervals >50 ms] (p = 0.001) and high-frequency [HF] (p = 0.001) were significantly decreased in patients with acromegaly; but low frequency [LF] (p = 0.046) and LF/HF (p = 0.001) were significantly higher in acromegaly patients. QTec (p = 0.009), QTac/RR slope (p = 0.017) and QTec/RR slope (p = 0.01) were significantly higher in patients with acromegaly. Additionally, there were significant negative correlation of disease duration with HRR2, HRR3, SDNN, PNN50, RMSSD, variability index. Our study results suggest that cardiac autonomic functions are impaired in patients with acromegaly. Further large scale studies are needed to exhibit the prognostic significance of impaired autonomic functions in patients with acromegaly.

Pasireotide has a broader somatostatin receptor binding profile than other somatostatin analogues. A 16-week, Phase II trial showed that pasireotide may be an effective treatment for acromegaly. An extension to this trial assessed the long-term efficacy and safety of pasireotide. This study was an open-label, single-arm, open-ended extension study (primary efficacy and safety evaluated at month 6). Patients could enter the extension if they achieved biochemical control (GH ≤ 2.5 μg/L and normal IGF-1) or showed clinically relevant improvements during the core study. Thirty of the 60 patients who received pasireotide (200-900 μg bid) in the core study entered the extension. At extension month 6, of the 26 evaluable patients, six were biochemically controlled, of whom five had achieved control during the core study. Normal IGF-1 was achieved by 13/26 patients and GH ≤ 2.5 μg/L by 12/26 at month 6. Nine patients received pasireotide for ≥24 months in the extension; three who were biochemically controlled at month 24 had achieved control during the core study. Of 29 patients with MRI data, nine had significant (≥20 %) tumor volume reduction during the core study; an additional eight had significant reduction during the extension. The most common adverse events were transient gastrointestinal disturbances; hyperglycemia-related events occurred in 14 patients. Twenty patients had fasting plasma glucose shifted to a higher category during the extension. However, last available glucose measurements were normal for 17 patients. Pasireotide has the potential to be an effective, long-term medical treatment for acromegaly, providing sustained biochemical control and significant reductions in tumor volume.