Description

Pituitary is an international publication devoted to basic and clinical aspects of the pituitary gland. It is designed to publish original high quality research in both basic and pituitary function as well as clinical pituitary disease. The journal is divided into several sections including: Molecular Biology of Pituitary Hormones In Vitro Regulation of Pituitary Hormones Regulation of Hormone Secretion Comprehensive Basic Reviews with Clinical Focus Pituitary is directed at basic investigators physiologists clinical adult and pediatric endocrinologists neurosurgeons and reproductive endocrinologists interested in the broad field of the pituitary and its disorders. The Editorial Board has been drawn from international experts in basic and clinical endocrinology. The journal offers a rapid turnaround time for review of manuscripts and the high standard of the journal is maintained by a selective peer-review process which aims to publish only the highest quality manuscripts. Pituitary will therefore foster the publication of creative scholarship as it pertains to the pituitary and as such will provide a forum for basic scientists and clinicians to publish their high quality pituitary-related work.

Publisher details

Springer Verlag

Publications in this journal

• Venous thromboembolism in patients with Cushing's syndrome: need of a careful investigation of the prothrombotic risk profile.

  Authors: S Koutroumpi, V Daidone, M T Sartori, M G Cattini, N M Albiger, G Occhi, S Ferasin, A Frigo, F Mantero, A Casonato, C Scaroni

  Pituitary.

  A high incidence of venous thromboembolic (VTE) complications has been reported in Cushing's syndrome (CS), mostly post-operatively and attributable to hypercoagulability. The prevalence ofA high incidence of venous thromboembolic (VTE) complications has been reported in Cushing's syndrome (CS), mostly post-operatively and attributable to hypercoagulability. The prevalence of symptomatic VTE was investigated retrospectively in 58 consecutive CS patients in relation to acquired and genetic thrombotic risk factors. Eight CS patients (14 %) developed VTE (group A), 3 of them related and 5 unrelated to surgery. These patients had higher urinary free cortisol (p = 0.01) and VWF levels (p = 0.02) than the 50 patients without VTE (group B), as well an increase in the hemostatically more efficient, high-molecular-weight VWF multimers (p = 0.002). Factor V Leiden and the prothrombin gene 20210A variants (the most common inherited thrombophilic defects) were more represented in group A than in group B, as was the genotype GCAG/GCAG of the VWF gene promoter, known to hyperinduce VWF upregulation under cortisol excess. All but one of the patients with VTE unrelated to surgery had at least four acquired and at least one inherited risk factor. Severe hypercortisolism and VWF levels with increased haemostatic activity are strongly associated with VTE in CS. VTE episodes unrelated to surgery are attributable to the synergistic action of acquired and inherited thrombotic risk factors. Based on these observations, we believe that severely affected CS patients should be screened for coagulation disorders and receive antithrombotic prophylaxis whenever they have concomitant prothrombotic risk factors.

• Insulin-like growth factor-I correlates more closely than growth hormone with insulin resistance and glucose intolerance in patients with acromegaly.

  Authors: Dan Niculescu, Mariana Purice, Mihail Coculescu

  Pituitary.

  In normal subjects growth hormone (GH) and insulin-like growth factor-I (IGF-I) have opposing effects on glucose metabolism. Active acromegaly is associated with insulin resistance (IR) and glucoseIn normal subjects growth hormone (GH) and insulin-like growth factor-I (IGF-I) have opposing effects on glucose metabolism. Active acromegaly is associated with insulin resistance (IR) and glucose intolerance although both GH and IGF-I are elevated. Our objective was to compare whether GH or IGF-I correlates more closely with IR and glucose intolerance in acromegaly. Basal serum IGF-I and GH, glucose and insulin during an oral glucose tolerance test were measured in 70 normoglycemic and 44 hyperglycemic acromegalic patients (21 impaired fasting glucose, 11 impaired glucose tolerance and 12 diabetes mellitus) according to American Diabetes Association criteria. 55 patients were assessed before any treatment for acromegaly and 59 after surgery and/or radiotherapy (15 patients had normal IGF-I after treatment). Patients treated with somatostatin analogs, GH-receptor antagonists or antidiabetic drugs were excluded. IR was assessed by various basal and stimulated indices. Homeostatic Model Assessment 2-Insulin Resistance (HOMA2-IR) index correlated more closely with IGF-I (r = 0.65, p < 0.0001) than nadir (r = 0.23, p = 0.008) or random GH (r = 0.26, p = 0.002). HOMA2-IR correlated better with IGF-I than nadir or random GH also in normoglycemic (n = 70; r = 0.74, p < 0.0001 vs. r = 0.36, p = 0.001 vs. r = 0.39, p < 0.001) and hyperglycemic patients (n = 44; r = 0.54, p = 0.0002 vs. r = 0.09, p = 0.4 vs. r = 0.14, p = 0.26). In multivariate logistic regression analysis IGF-I but not GH was a significant risk factor for glucose intolerance after adjusting for age, sex, weight and acromegaly duration (OR = 1.56, p = 0.01). In acromegaly IGF-I correlates more closely than GH with IR. IGF-I levels but not GH are associated with glucose intolerance.

• Predictors of endoscopic transsphenoidal surgery outcome in acromegaly: patient and tumor characteristics evaluated by magnetic resonance imaging.

  Authors: Christa C van Bunderen, Nadège C van Varsseveld, Johannes C Baayen, Wouter R van Furth, Esther Sanchez Aliaga, Marieke J Hazewinkel, Charles B L M Majoie, Nicole J M Freling, Paul Lips, Eric Fliers, Peter H Bisschop, Madeleine L Drent

  Pituitary.

  The availability of various first-line treatment modalities for acromegaly and evolving surgical techniques emphasize the need for accurately defined predictors of surgical outcome. WeThe availability of various first-line treatment modalities for acromegaly and evolving surgical techniques emphasize the need for accurately defined predictors of surgical outcome. We retrospectively analysed the outcome of 30 patients with acromegaly after initial endoscopic transsphenoidal surgery in two university hospitals from 2001 until 2009, and reviewed comparable literature investigating predictive tumor characteristics. Medical records were monitored for patient characteristics. Each pituitary magnetic resonance imaging (MRI) scan was revised independently by two neuroradiologists using a standardised analysis form to record distinctive predefined tumor characteristics. All characteristics were independently analysed as predictors for persistent disease, and a multivariable predictive model was created. Literature from 2000 onwards was searched for studies describing tumor characteristics predictive for surgical outcome. The cohort consisted of 27 macroadenomas with 90 % demonstrating signs of parasellar extension. The surgical cure rate overall was 30 %. Independently, next to male sex and increasing tumor size, infrasellar and parasellar extension based on MRI staging tended to increase the risk of persistent disease. In a multivariable analysis, sex and parasellar extension of the tumor were demonstrated to be the variables allowing for the best fitted predictive model for persistent disease. Earlier studies on preoperative tumor characteristics showed comparable results, although these were based on several different tumor classification systems. This retrospective study demonstrates that accurately defined tumor characteristics based on imaging, especially for cavernous sinus invasion, can be helpful in predicting surgical outcome. Comparative studies on different treatment modalities are essential for clinical practice within the scope of re-evaluation of the role of surgery in GH-secreting adenomas.

• Thyroid cancer in patients with acromegaly: a case-control study.

  Authors: Maíra Cristina Carvalho Dos Santos, Gilvan Cortês Nascimento, Ana Gisélia Cortês Nascimento, Viviane Chaves Carvalho, Maria Honorina Cordeiro Lopes, Renan Montenegro, Lucio Vilar, Mônica Fiterman Albano, Alice Regina Vasconcelos Alves, Conceição Veiga Parente, Manuel Dos Santos Faria

  Pituitary.

  Several studies have associated acromegaly with an increased risk of benign and malignant tumors. While simple and multinodular goiters are common findings in acromegaly, the prevalence of thyroidSeveral studies have associated acromegaly with an increased risk of benign and malignant tumors. While simple and multinodular goiters are common findings in acromegaly, the prevalence of thyroid cancer is uncertain. The objective of this study was to estimate the prevalence of thyroid cancer in a series of acromegalic patients from three hospitals in northeast of Brazil. The methodology used included morphological, cytological and histological thyroid analysis of acromegalic patients and volunteers over 18 years, matched for age and sex and with nodule (s) ≥1 cm. The subjects of this study were 124 acromegalic patients, including 76 females (61.3%) and 48 men (38.7%), with a mean age 45.1 years. Results of the study showed that thyroid ultrasonography was normal in 31 cases (25%), 25 had diffuse goiter (20.1%), 67 had nodules (54%) and one agenesis of the right lobe (0.8%). Thirty-six patients underwent fine needle aspiration biopsy (FNAB) of their nodules and 9 cases of papillary cancer were found (7.2%). The control group consisted of 263 subjects, 156 females (59.3%) and 107 males (40.7%), mean age 44.7 years. In ultrasound assessment, 96 had nodules (36.5%). Of these, 13 were punctured and 2 cases of papillary carcinoma were found (0.7%). These results gave an odds ratio of 10.21 (p = 0.0011, 95% CI 2.17 to 48.01). These findings demonstrate an increased prevalence of thyroid cancer, statistically significant when compared to our control group. Thus, it is suggested that acromegalic patients should be routinely submitted to thyroid ultrasound evaluation, followed by FNAB of nodules when indicated.

• Clinical consequences of Cushing's syndrome.

  Authors: Elena Valassi, Iris Crespo, Alicia Santos, Susan M Webb

  Pituitary.

  Recent evidence suggests that correction of hypercortisolism in Cushing's syndrome (CS) may not lead to complete remission of the clinical abnormalities associated with this condition. In particular,Recent evidence suggests that correction of hypercortisolism in Cushing's syndrome (CS) may not lead to complete remission of the clinical abnormalities associated with this condition. In particular, elevated cardiovascular risk may persist in "cured" CS patients long-term after eucortisolism has been reached. This is believed to be related with the maintenance of visceral obesity and altered adipokine secretory pattern which perpetuate features of metabolic syndrome, including impaired glucose tolerance, hypertension, dyslipidemia, atherosclerosis and hypercoagulability. Nephrolithiasis and incomplete recovery of bone mineral density have also been described in "cured" CS patients. Moreover, previous exposure to excess cortisol may have irreversible effects on the structures of the central nervous system controlling cognitive function and mood. Thus, sustained deterioration of the cardiovascular system, bone remodelling and cognitive function may be associated with high morbidity and poor quality of life in CS patients in remission for many years. Although mortality in "cured" CS patients may not differ from that in the general population, data beyond 20 years follow-up are very scarce, so further studies evaluating larger cohorts for longer follow-up periods are needed to draw definitive conclusions on longevity. Life-long monitoring is mandatory in CS patients in order to control long term complications of previous cortisol excess and, possibly, normalize life expectancy.

• Genetic analysis in a patient presenting with meningioma and familial isolated pituitary adenoma (FIPA) reveals selective involvement of the R81X mutation of the AIP gene in the pathogenesis of the pituitary tumor.

  Authors: Federica Guaraldi, Valentina Corazzini, Gary L Gallia, Silvia Grottoli, Karen Stals, Nadezhda Dalantaeva, Lawrence A Frohman, Márta Korbonits, Roberto Salvatori

  Pituitary.

  Familial isolated pituitary adenoma (FIPA), defined as the occurrence of at least two cases of pituitary adenoma in a family that does not exhibit features of syndromic diseases, such as CarneyFamilial isolated pituitary adenoma (FIPA), defined as the occurrence of at least two cases of pituitary adenoma in a family that does not exhibit features of syndromic diseases, such as Carney complex or Multiple Endocrine Neoplasia type 1 or 4, is a rare autosomal dominant disease with low penetrance. About 20 % of the families with FIPA harbor inactivating mutation in aryl hydrocarbon receptor-interacting protein gene (AIP) associated with loss of heterozygosity of the same genetic locus (11q13) in the tumor. Rarely different types of extra-pituitary tumors have been described in the setting of AIP mutation-positive FIPA. We present the case of a patient who was diagnosed with acromegaly due to the AIP mutation c.241C>T (p.R81X) at the age of 34 years, and treated by transsphenoidal surgery. At the age of 43 years she was diagnosed with a meningioma, and at age 46 had recurrence of the somatotropinoma. Genetic studies demonstrated loss of the normal allele (by sequencing and microsatellite analysis) in DNA from the pituitary adenoma but not from the meningioma, suggesting a selective involvement of AIP mutation in the pathogenesis of the pituitary adenoma, and a casual association with the meningioma. Further investigations are required to define the exact role of AIP in non-pituitary tumorigenesis.

• Unusual cause of primary amenorrhea due to kissing internal carotid arteries.

  Authors: Mustafa Sahin, Alper Dilli, Basak Karbek, Ilknur Oztürk Unsal, Askın Gungunes, Nujen Colak, Bekir Uçan, Erman Cakal, Mustafa Ozbek, Tuncay Delibasi

  Pituitary.

• The trans-sphenoidal resection of pituitary adenomas in elderly patients and surgical risk.

  Authors: M Locatelli, G Bertani, G Carrabba, P Rampini, M Zavanone, M Caroli, E Sala, E Ferrante, S M Gaini, A Spada, G Mantovani, A Lania

  Pituitary.

  In western countries, the process of "ageing of the population" is increasingly forcing clinical medicine to find answers for pathologies affecting the elder segments of our community. In thisIn western countries, the process of "ageing of the population" is increasingly forcing clinical medicine to find answers for pathologies affecting the elder segments of our community. In this respect, pituitary adenomas often raise difficult questions on surgical indications, since little is known about postoperative morbidity and mortality in elderly patients. The transsphenoidal endonasal approach (TNS), which is considered the gold standard for surgical resection of the majority of functioning and non-functioning pituitary adenomas, is supposed to be a low morbidity and mortality procedure in adult patients. However, only a few contradicting data are available in the literature about elderly patients. In this paper we retrospectively analyze a cohort of 43 consecutive patients aged more than 65 years, operated on for pituitary adenomas at our Institution in the years 1998-2007. These patients were treated by transsphenoidal endonasal approach (TNS) for resection of non-functioning pituitary adenomas (n = 31), GH-secreting adenomas (n = 4) and ACTH-secreting adenomas (n = 8). Clinical records reported a macroadenoma with tumour-related mass symptoms in about 80 % of patients; single or multiple pituitary deficits were present in 44 % of patients. Regarding comorbidities, cardiac disease was the most frequently observed (86 %); assessment of anaesthesiological risk indicated a moderate to severe ASA score in most patients, 11 % showing a 4-5 score. On the basis of current criteria, our retrospective analysis revealed that cure was achieved in 54 % of patients. The outcome was similar to that observed in the general population of patients undergoing transphenoidal surgery in our centre, without differences in the rate of surgical and endocrinological cure, minor and major surgical complications and hospitalization duration. In particular, no significant anaesthesiological complications were observed and no patient developed either permanent diabetes insipidus or cerebrospinal fluid rhinorrhea. In conclusion, in specialized centres the surgical treatment of pituitary adenomas via the transsphenoidal route can be a safe and effective procedure even in elderly patients.

• Herniation of cerebellar tonsils in acromegaly: prevalence, pathogenesis and clinical impact.

  Authors: Renzo Manara, Giulia Bommarito, Silvia Rizzati, Chiara Briani, Alessandro Della Puppa, Valentina Citton, Eva Zanchetta, Fabio Zerbo, Mario Ermani, Chiara Martini, Franco Mantero, Nicola Sicolo, Pietro Maffei, Carla Scaroni

  Pituitary.

  Herniation of cerebellar tonsils (CTH) might occur in acromegaly patients and improve after acromegaly treatment. Our study investigated CTH prevalence in acromegaly, its relationship with clinical,Herniation of cerebellar tonsils (CTH) might occur in acromegaly patients and improve after acromegaly treatment. Our study investigated CTH prevalence in acromegaly, its relationship with clinical, laboratory and neuroimaging findings and its possible pathogenesis and clinical impact. 150 acromegaly patients (median-age 56 years, age-range 21-88, 83 females) underwent brain magnetic resonance imaging (MRI). Clinical data, laboratory and pituitary adenoma imaging findings were recorded. CTH, posterior cranial fossa area, tentorial angle, clivus, supraocciput and Twining's line length were measured in acromegaly patients and controls, who included MRI of 115 consecutive subjects with headache or transient neurological deficits (control group-1) and 24 symptomatic classic Chiari 1 malformation patients (control group-2). Acromegaly patients were interviewed for symptoms known to be related with CTH. 22/150 acromegaly patients (15 %) and 8/115 control group-1 subjects presented with CTH (p = 0.04). In acromegaly patients, CTH correlated positively with younger age and inversely with GH-receptor antagonist treatment. Control group-2 had a shorter clivus than CTH acromegaly patients (40.4 ± 3.2 mm vs 42.5 ± 3.3 mm, p < 0.05), while posterior fossa measures did not differ among acromegaly subgroups (with and without CTH) and control group-1. Headache and vision problems were more frequent in CTH acromegaly patients (p < 0.05); two acromegaly patients presented with imaging and neurological signs of syringomyelia. Despite no signs of posterior fossa underdevelopment or cranial constriction, CTH is more frequent in acromegaly patients and seems to contribute to some disabling neurological symptoms.

• Bronchial carcinoid tumors metastatic to the sella turcica and review of the literature.

  Authors: Olga Moshkin, Fabio Rotondo, Bernd W Scheithauer, Mark Soares, Claire Coire, Harley S Smyth, Miklos Goth, Eva Horvath, Kalman Kovacs

  Pituitary.

  We review here the literature on neuroendocrine neoplasms metastatic to the pituitary and present an example of the disease. Metastasis of bronchial carcinoid tumors to the sellar region are rare.We review here the literature on neuroendocrine neoplasms metastatic to the pituitary and present an example of the disease. Metastasis of bronchial carcinoid tumors to the sellar region are rare. Herein, we describe the case of a 63-year-old woman who presented with constant cough and headaches. She had previously been operated for carcinoid tumor of the lung. During the preoperative investigation, a CT scan of the head revealed a sellar mass. Six months after a left lower lobectomy, the sellar lesion was removed by transsphenoidal surgery. The two tumors were evaluated by histology, immunohistochemistry and electron microscopy. Both showed identical morphologic features, those of carcinoid tumor. Immunohistochemistry revealed immunoreactivity for the endocrine markers, synaptophysin and chromogranin, as well as CD-56, serotonin, bombesin and vascular endothelial growth factor. The sellar neoplasm showed nuclear immunopositivity for thyroid transcription factor-1, supporting the diagnosis of a metastatic bronchial carcinoid tumor. In conclusion, this is the first report of a serotonin- and bombesin-immunopositive atypical bronchial carcinoid tumor metastatic to the sella.

• Changes in acromegaly treatment over four decades in Spain: analysis of the Spanish Acromegaly Registry (REA).

  Authors: Gemma Sesmilo, Sonia Gaztambide, Eva Venegas, Antonio Picó, Carlos Del Pozo, Concepción Blanco, Elena Torres, Cristina Alvarez-Escolà, Carmen Fajardo, Rogelio García, Rosa Cámara, Ignacio Bernabeu, Alfonso Soto, Carles Villabona, Alicia Serraclara, Irene Halperin, Victoria Alcázar, Elisabet Palomera, Susan M Webb

  Pituitary.

  Since 1997 there is an online National Registry of acromegalic patients in Spain (REA). We aimed to study changes in acromegaly treatment and outcomes over the last four decades in Spain. In REASince 1997 there is an online National Registry of acromegalic patients in Spain (REA). We aimed to study changes in acromegaly treatment and outcomes over the last four decades in Spain. In REA clinical and biochemical data are collected at diagnosis and updated every one to 2 years. We analyzed the first treatment received and the different treatments administered according to decade of diagnosis of acromegaly: prior to 1980, 1980-1989, 1990-1999 and 2000-2009. Surgical cure rates according to pretreatment with long-acting somatostatin receptor ligands (SRLs) were also analyzed. 1,658 patients were included of which 698 had accurate follow-up data. Treatment of acromegaly changed over time. Surgery was the main treatment option (83.8 %) and medical treatment was widely used (74.7 %) both maintained over decades, while radiation therapy declined (62.8, 61.6, 42.2 and 11.9 % over decades, p < 0.001). First treatment type also changed: surgery was the first line option up until the last decade in which medical treatment was preferred (p < 0.001). Radiotherapy was barely used as first treatment. Treatment combinations changed over time (p < 0.001). The most common treatment combination (surgery plus medical therapy), was received by 24.4, 16.4, 25.3 and 56.5 % of patients over decades. Medical treatment alone was performed in 7.3, 6, 7.2 and 14.7 % over decades. Type of medical treatment also changed, SRLs becoming the first medical treatment modality in the last decades, whereas dopamine agonist use declined (p < 0.001). Surgical cure rates improved over decades (21, 21, 36 and 38 %, p = 0.002) and were not influenced by SRL pre-surgical use. Acromegaly treatment has changed in Spain in the last four decades. Surgery has been the main treatment option for decades; however, medical therapy has replaced surgery as first line in the last decade and radiotherapy rates have clearly declined. SRLs are the most used medical treatment.

• Acromegalic gigantism, physicians and body snatching. Past or present?

  Authors: Wouter W de Herder

  Pituitary.

  The skeletons of 2 famous acromegalic giants: Charles Byrne (1761-1783) and Henri Cot = Joseph Dusorc (1883-1912) and the embalmed body of the famous acromegalic giant Édouard Beaupré (1881-1904) allThe skeletons of 2 famous acromegalic giants: Charles Byrne (1761-1783) and Henri Cot = Joseph Dusorc (1883-1912) and the embalmed body of the famous acromegalic giant Édouard Beaupré (1881-1904) all ended up in the medical collections of museums despite the fact that these patients had never donated or even refused to donate their corpses, nor had their relatives given permission. The corpse of the acromegalic giant John Aasen (1890-1938) was voluntarily donated to a physician annex collector of trivia from acromegalic giants. The autopsy on the acromegalic giant John Turner (1874-1911) was performed during his funeral ceremony without the relatives being informed. Only recently, the acromegalic giant Alexander Sizonenko (1959-2012) was made a financial offer during his life in exchange for his body after his death. The case-histories of these 6 patients and also the circumstances that led to the (in-) voluntary donation of their bodies are reviewed.

• Reliability of the diagnostic tests for Cushing's syndrome performed in a tertiary referral center.

  Authors: Mutlu Günes, Ozlem Celik, Pinar Kadioglu

  Pituitary.

  The study aimed to retrospectively evaluate the reliability of the diagnostic and location tests in Cushing's Syndrome (CS). Eighty-seven patients diagnosed with CS between 1995 and 2007 byThe study aimed to retrospectively evaluate the reliability of the diagnostic and location tests in Cushing's Syndrome (CS). Eighty-seven patients diagnosed with CS between 1995 and 2007 by Endocrinology Metabolism Department of Cerrahpasa Medical School were included in the study. The control group consisted of 91 patients who presented to the outpatient clinic because of obesity. The diagnostic tests were as follows: 1 mg dexamethasone suppression test (DST), 24-h urinary free cortisol (UFC), midnight cortisol level (MCL), ACTH level and overnight 8 mg DST. The sensitivity and specificity of UFC were 81 and 66 % respectively for the cut-off point of 50 μg/day, whereas they were 64 and 76 % respectively for the cut-off point of 100 μg/day. For the cut-off value of 1.8/μg/dL for MCL and 1 mDST, the sensitivity rates were 100 and 98 %, while the specificity rates were 88 and 33 %, respectively. Among the location tests, the sensitivity and specificity of ACTH under 10 pg/mL for adrenal CS were 92 and 94 % respectively. The sensitivity and specificity of ACTH higher than 30 pg/mL for ACTH-dependent CS were 69 and 100 % respectively. The sensitivity rates of 8 mg DST for 50 and 60 % suppressions were 83 and 79 % respectively, whereas the specificity rates were 75 and 88 % respectively. 1 mg DST (cut-off <1.8 μg/dL) and UFC (50 μg/24 h) are appropriate tests for screening CS. Overnight 8 mg DST with 60 % suppression for Cushing's Disease (CD) and ACTH levels <10 pg/mL for adrenal CS, ACTH levels >30 pg/mL for ACTH dependency were identified as the best tests for the differential diagnosis of the subtypes.

• Hypothalamic pituitary complications in Kabuki syndrome.

  Authors: Naoko Ito, Kenji Ihara, Yasushi Tsutsumi, Noriko Miyake, Naomichi Matsumoto, Toshiro Hara

  Pituitary.

  Kabuki syndrome is characterized by distinctive facial features, multiple anomalies and mental retardation. In this syndrome, structural CNS abnormalities are commonly observed, but congenitalKabuki syndrome is characterized by distinctive facial features, multiple anomalies and mental retardation. In this syndrome, structural CNS abnormalities are commonly observed, but congenital abnormalities in the pituitary gland or hypothalamus have rarely been reported. We searched the published medical literature on the complications in hypothalamic pituitary axis in this syndrome. As a result, only nine patients with Kabuki syndrome had been reported to have complications in hypothalamic pituitary axis in previous papers. Among the nine reported patients and one presented case in this report, GH deficiency was the most frequent complication and found in six patients. Precocious puberty and central diabetes insipidus (DI) was identified in two cases, respectively, and ACTH deficiency was found in one. One case had combination of GH deficiency and central DI. Three of the 10 patients demonstrated abnormal pituitary findings in MRI study. Two of the six patients with GH deficiency were accompanied with premature thelarche. This review highlights that patients with Kabuki syndrome could present various clinical manifestations due to abnormalities in hypothalamic pituitary axis.

• Pegvisomant and cabergoline combination therapy in acromegaly.

  Authors: I Bernabeu, C Alvarez-Escolá, A E Paniagua, T Lucas, I Pavón, J M Cabezas-Agrícola, F F Casanueva, M Marazuela

  Pituitary.

  Combination with cabergoline may offer additional benefits to acromegalic patients on pegvisomant monotherapy. We evaluated the safety and efficacy profile of this combination and investigated theCombination with cabergoline may offer additional benefits to acromegalic patients on pegvisomant monotherapy. We evaluated the safety and efficacy profile of this combination and investigated the determinants of response. An observational, retrospective, cross-sectional study. Fourteen acromegalic patients (9 females), who were partially resistant to somatostatin analogs and on pegvisomant monotherapy. Cabergoline was added because of the presence of persistent mildly increased IGF-I. The mean follow-up time was 18.3 ± 10.4 months. The efficacy and safety profile was assessed. The influence of clinical and biochemical characteristics on treatment efficacy was studied. IGF-I levels returned to normal in 4 patients (28%) at the end of the study. In addition, some decline in IGF-I levels was observed in a further 5 patients. The % IGF-I decreased from 158 ± 64% to 124 ± 44% (p = 0.001). The average change in IGF-I was -18 ± 27% (range -67 to +24%). Lower baseline IGF-I (p = 0.007), female gender (p = 0.013), lower body weight (p = 0.031), and higher prolactin (PRL) levels (p = 0.007) were associated with a better response to combination therapy. There were no significant severe adverse events. Significant tumour shrinkage was observed in 1 patient. Combination therapy with pegvisomant and cabergoline could provide better control of IGF-I in some patients with acromegaly. Baseline IGF-I levels, female gender, body weight, and PRL levels affect the response to this combination therapy.

• Erratum to: A review of guidelines for use of growth hormone in pediatric and transition patients.

  Authors: David M Cook, Susan R Rose

  Pituitary.

• Lymphocytic hypophysitis in a patient presenting with sequential episodes of optic neuritis.

  Authors: Garrett K Zoeller, Ronald J Benveniste, F A Farhadi, Jocelyn H Bruce

  Pituitary. 15(1):101-5.

  A 41-year-old man presented with left optic neuritis (ON) without evidence of other autoimmune disease or hormonal imbalance. MRI showed enlargement of the left optic nerve but no sellar lesion. TheA 41-year-old man presented with left optic neuritis (ON) without evidence of other autoimmune disease or hormonal imbalance. MRI showed enlargement of the left optic nerve but no sellar lesion. The patient recovered after steroid therapy but later developed right ON and required treatment again. Follow-up MRI revealed an ill-defined, enlarging sellar lesion with enhancement extending into the right cavernous sinus, and the patient developed symptoms of fatigue and loss of libido. Hormonal studies revealed hypogonadism and hypocortisolism. All laboratory investigation for autoimmune and infectious diseases remained negative. A transsphenoidal biopsy of the lesion revealed lymphocytic hypophysitis. The concomitant development of lymphocytic hypophysitis and optic neuritis suggests a common and likely autoimmune etiology. Visual loss in patients with LYH can sometimes be due to ON rather than compression of the optic apparatus, with significant implications for treatment strategies.

• Involvement of genes related to inflammation and cell cycle in Idiopathic Short Stature.

  Authors: Letizia Trovato, Flavia Prodam, Giulia Genoni, Francesca De Rienzo, Gillian E Walker, Stefania Moia, Stefania Riccomagno, Simonetta Bellone, Gianni Bona

  Pituitary.

  Idiopathic Short Stature (ISS) defines a condition in which height is <-2SD compared to the mean of a reference population where systemic, endocrinological, nutritional or chromosomal disorders haveIdiopathic Short Stature (ISS) defines a condition in which height is <-2SD compared to the mean of a reference population where systemic, endocrinological, nutritional or chromosomal disorders have not been identified and diagnosis is based on exclusion of any known causes of short stature. JAK/STAT pathway is triggered by GH binding to the GH receptor and promotes cellular growth through transcription of GH-responsive genes. In order to identify "candidate genes" differently expressed in ISS subjects with respect to control ones, we analyzed the expression of 84 genes related to JAK/STAT pathway by RT(2) Profiler PCR array approach in a total of 10 subjects. Then, we validated the observed data by Real Time PCR and ELISA assays in a major number of subjects. We found two genes that were differently expressed in ISS subjects with respect to the control group: CXCL9 and FCGR1A/CD64, both significantly up-regulated (fold change 2.17 and 1.70, respectively) and belonging to family of IFN-γ-inducible factors. Further, ISS subjects showed an increased gene expression of IFN-γ and IFI16, higher serum levels of IFN-γ but similar levels of CXCL9 when compared to healthy subjects. In addition, we showed a pubertal modulation of CXCL9 levels. These data suggest that inflammatory and regulatory factors of the cell cycle may be involved in the ISS condition, introducing a new perspective to its etiology.

• Failure of temozolomide and conventional doses of pegvisomant to attain biochemical control in a severe case of acromegaly.

  Authors: Emilie Morin, France Berthelet, John Weisnagel, Martin Bidlingmaier, Omar Serri

  Pituitary. 15(1):97-100.

  It has been suggested that treatment with adequate dose titration of pegvisomant, a GH antagonist, up to a maximum of 40 mg daily, can achieve IGF-1 normalisation in virtually all patients withIt has been suggested that treatment with adequate dose titration of pegvisomant, a GH antagonist, up to a maximum of 40 mg daily, can achieve IGF-1 normalisation in virtually all patients with acromegaly. On the other hand, temozolomide (TMZ), an alkylating cytostatic agent, has been reported to reduce pituitary tumour size and hormone hypersecretion in a small number of aggressive pituitary macroadenomas. In this paper we report the case of a patient resistant to very high doses of pegvisomant used in combination with somatostatin analogs (SSA) and to TMZ therapy. The patient, initially a 22 year-old man with an invasive GH-secreting pituitary macroadenoma (IGF-1, 371% upper limit of normal), had active acromegaly despite a repeat transsphenoidal surgery followed by radiotherapy and SSA (octreotide 800 μg sc daily) (IGF-1, 262% ULN). In combination with SSA, pegvisomant was started at 20 mg daily and doses were titrated up to 60 mg daily. IGF-1 was moderately reduced and stabilized at 200% ULN after 1 year of treatment. Serum pegvisomant level was 30,500 ng/l, the denaturalized GHBP concentration 1,120 pM and the endogenous GH level was 220 μg/l. Pegvisomant was stopped and TMZ therapy was given for 5 cycles. However, the patient reported an increase of acromegaly symptoms and the serum IGF-1 was raised to the same level prior to pegvisomant therapy. Consequently, pegvisomant was tried again with doses up to 100 mg daily finally resulting in normalisation of serum IGF-1 level and improvement of acromegaly symptoms and patient well-being. We conclude that in some patients with severe acromegaly refractory to multimodal therapy, biochemical control may be difficult to attain with conventional doses of pegvisomant or TMZ therapy.

• Primary pituitary lymphoma in immunocompetent patient: diagnostic problems and prolonged follow-up.

  Authors: Carmen A Carrasco, David Rojas-Z, Renato Chiorino, Gilberto González

  Pituitary. 15(1):93-6.

  Primary pituitary lymphoma in immunocompetent patients is a rare disease and has been described in less than 20 cases. Moreover, low-grade lymphomas constitute only 3% of all primary central nervousPrimary pituitary lymphoma in immunocompetent patients is a rare disease and has been described in less than 20 cases. Moreover, low-grade lymphomas constitute only 3% of all primary central nervous system lymphoma. The objective of this report is to report a low-grade primary pituitary lymphoma, diagnostic problems and to give more evidence about the evolution of this rare disease. A 49 y.o. woman was referred to our clinic with symptoms of hypopituitarism. A diagnostic work-up showed mild anemia, an erythrocyte sedimentation rate of 122 mm/h and a negative Elisa test for HIV. Panhypopituitarism was confirmed and the MRI showed a 20 mm sellar and suprasellar enhancing mass with a thickening of the pituitary stalk, chiasmal compression and bitemporal hemianopsia. She underwent transsphenoidal resection only 10 months later for non medical reasons. During this period she was clinically asymptomatic on hormonal replacement therapy. A new MRI showed regression of the suprasellar extension and invasion to the left cavernous sinus. A firm and infiltrative mass was found during transsphenoidal surgery, and only partial resection was performed. Biopsy showed a low-grade lymphoplasmacytic lymphoma. Staging was negative for other localizations. She was given chemotherapy and localized radiotherapy. Four years after surgery, the sellar MRI showed a 10 mm residual sellar mass with the persistence of a cavernous sinus invasion and she is considered to be in remission. The neurosurgeon and clinician should consider primary pituitary lymphoma as a potential cause of a sellar mass, especially in the presence of diabetes insipidus and an enhancing invasive mass. Neurosurgical biopsy is crucial for a correct diagnosis and prognosis could be better than classic CNS primary lymphomas.

• Hypopituitarism following brain injury: when does it occur and how best to test?

  Authors: Valentina Gasco, Flavia Prodam, Loredana Pagano, Silvia Grottoli, Sara Belcastro, Paolo Marzullo, Guglielmo Beccuti, Ezio Ghigo, Gianluca Aimaretti

  Pituitary. 15(1):20-4.

  Aim of this review is to highlight how and when Traumatic Brain Injury (TBI) as well as Subarachnoid Haemorrhage (SAH) and primary Brain Tumours (pBT) of the Central Nervous System (CNS) can induceAim of this review is to highlight how and when Traumatic Brain Injury (TBI) as well as Subarachnoid Haemorrhage (SAH) and primary Brain Tumours (pBT) of the Central Nervous System (CNS) can induce hypopituitarism, an under-diagnosed clinical problem. Moreover, this review aims to clarify, on the basis of the recent evidences, how these patients have to be tested for pituitary-function. Both retrospective and prospective studies recommended that patients with more severe form of Brain Injuries (BI) and in particular, those with fractures of the base of the skull or early diabetes insipidus, have to be closely monitored for signs and symptoms of endocrine dysfunction. Further studies will be crucial to raise awareness and remind physicians on the prevalence of hypopituitarism in patients with BI and to elucidate any incremental benefits these patients may receive from hormone replacement.

• Cabergoline reduces cell viability in non functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion.

  Authors: Teresa Gagliano, Carlo Filieri, Mariella Minoia, Mattia Buratto, Federico Tagliati, Maria Rosaria Ambrosio, Marcello Lapparelli, Matteo Zoli, Giorgio Frank, Ettore Degli Uberti, Maria Chiara Zatelli

  Pituitary.

  Dopamine (DA) therapy of non-functioning pituitary adenomas (NFA) can result in tumor stabilization and shrinkage. However, the mechanism of action is still unknown. Previous evidence showed that DADopamine (DA) therapy of non-functioning pituitary adenomas (NFA) can result in tumor stabilization and shrinkage. However, the mechanism of action is still unknown. Previous evidence showed that DA can inhibit pituitary vascular endothelial growth factor expression (VEGF), that may be involved in pituitary tumor growth. The aim of our study was to clarify whether VEGF secretion modulation might mediate the effects of DA agonists on cell proliferation in human NFA. We assessed DA receptor subtype 2 (DR2) expression in 20 NFA primary cultures, where we also investigated the effects of a selective DR2 agonist, cabergoline (Cab), on VEGF secretion and on cell viability. All NFA samples expressed α-subunit and DR2 was expressed in 11 samples. In DR2 expressing tumors, Cab significantly reduced cell viability (-25%; P < 0.05) and VEGF secretion (-20%; P < 0.05). These effects were counteracted by treatment with the DA antagonist sulpiride. Cab antiproliferative effects were blocked by VEGF. Our data demonstrate that Cab, via DR2, inhibits cell viability also by reducing VEGF secretion in a selected group of NFA, supporting that DA agonists can be useful in the medical therapy of DR2 expressing NFA.

• Three years prospective investigation of pituitary functions following subarachnoid haemorrhage.

  Authors: Z Karaca, F Tanriverdi, A T Dagli, A Selcuklu, F F Casanueva, K Unluhizarci, F Kelestimur

  Pituitary.

  Subarachnoid haemorrhage (SAH) is known to be related to pituitary dysfuntion in retrospective and short-term prospective studies. We aimed to investigate pituitary functions in patients with SAH inSubarachnoid haemorrhage (SAH) is known to be related to pituitary dysfuntion in retrospective and short-term prospective studies. We aimed to investigate pituitary functions in patients with SAH in longer follow-up periods to demonstrate if pituitary hormone deficiencies recover, persist or new hormone deficiencies occur. Twenty patients with SAH, who were followed up for 3 years, were included in the present study. Patients were evaluated with basal hormone levels and glucagon stimulation test (GST). Serum basal cortisol and adrenocorticotropic hormone (ACTH) levels were found to be significantly elevated at 3rd year of SAH compared to 1st year. Other basal hormone levels at 3rd year did not show a significant change from the levels found at 1st year. One of the patients had ACTH deficiency at 1st year of SAH and recovered at 3rd year. Growth hormone (GH) deficiency, according to GST, was diagnosed in 4 patients. One patient with GH deficiency at first year was still deficient, 3 of them recovered and 3 patients were found to have new-onset GH deficiency 3 years after SAH. SAH is associated with anterior pituitary dysfunction and GH is the most frequently found deficient hormone in the patients. Although one year after SAH seems to be an appropriate time for the evaluation of pituitary functions, further follow-up may be required at least in some cases due to recovered and new-onset hormone deficiencies at 3rd year of SAH.

• Tumors invading the cavernous sinus that cause internal carotid artery compression are rarely pituitary adenomas.

  Authors: Mark E Molitch, Laura Cowen, Raymond Stadiem, Alexander Uihlein, Michelle Naidich, Eric Russell

  Pituitary.

  There is a clinical impression that when tumors invade the cavernous sinus, compression of the internal carotid artery is rare with pituitary adenomas and more common with other types of lesions butThere is a clinical impression that when tumors invade the cavernous sinus, compression of the internal carotid artery is rare with pituitary adenomas and more common with other types of lesions but there are no actual data to support this impression. To confirm the impression that the finding of internal carotid artery compression by tumors invading the cavernous sinus is inconsistent with a diagnosis of a pituitary adenoma, we performed a retrospective analysis of MRI scans performed between 2000 and July 2009. An initial search of the radiology database was performed using the terms "invasive mass cavernous MRI" and subsequent refinement narrowed the evaluation to 141 patients with cavernous sinus invasion by sellar/parasellar tumors for whom there were clinical/pathological data to determine tumor type. 83 of the 141 patients with cavernous sinus invasion had carotid artery encasement; 58 were pituitary adenomas and 25 were other types of lesions. Eight of these 83 scans revealed compression of the internal carotid lumen, with only one being a pituitary adenoma and seven being other types of lesions. Therefore, only 1/58 (1.7%) of pituitary adenomas and 7/25 (28%) of non-pituitary adenoma lesions that encased the internal carotid artery caused compression of the artery (P = 0.0007). A mass lesion that invades the cavernous sinus and encases the internal carotid artery is very unlikely, therefore, to be a pituitary adenoma if it compresses the lumen of the internal carotid artery.

• Gamma knife stereotactic radiosurgery for drug resistant or intolerant invasive prolactinomas.

  Authors: Xiaomin Liu, Hideyuki Kano, Douglas Kondziolka, Kyung-Jae Park, Aditya Iyer, Samuel Shin, Ajay Niranjan, John C Flickinger, L Dade Lunsford

  Pituitary.

  We evaluated the efficacy of Gamma knife stereotactic radiosurgery (GKSR) as an adjunctive management modality for patients with drug resistant or intolerant cavernous sinus invasive prolactinomas.We evaluated the efficacy of Gamma knife stereotactic radiosurgery (GKSR) as an adjunctive management modality for patients with drug resistant or intolerant cavernous sinus invasive prolactinomas. Twenty-two patients with cavernous sinus invasive prolactinoma underwent GKSR between 1994 and 2009. Thirteen patients were dopamine agonist (DA) resistant. Six patients were intolerant to DA. Three patients chose GKSR as their initial treatment modality in hopes they might avoid life long suppression medication. The median tumor volume was 3.0 cm(3) (range 0.3-11.6). The marginal tumor dose (median = 15 Gy, range 12-25 Gy) prescribed was based on the dose delivered to the optic apparatus. The median follow-up interval was 36 months (range, 12-185). Endocrine normalization was defined as a normal serum prolactin level off DA (cure) or on DA. Endocrine improvement was defined as a decreased but still elevated serum prolactin level. Endocrine deterioration was defined as an increased serum prolactin level. Endocrine normalization was achieved in six (27.3%) patients. Twelve (54.5%) patients had endocrine improvement. Four patients (18.2%) developed delayed increased prolactin. Imaging-defined local tumor control was achieved in 19 (86.4%) patients, 12 of whom had tumor regression. Three patients had a delayed tumor progression and required additional management. One patient developed a new pituitary axis deficiency after GKSR. Invasive prolactinomas continue to pose management challenges. GKSR is a non invasive adjunctive option that may reduce prolactin levels in patients who are resistant to or intolerant of suppression medication. In a minority of cases, patients may no longer require long term suppression therapy.

Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.