GH-secreting Pituitary Adenomas Research Articles

Curious Cases: Acromegaly and Schizophrenia: An Incidental Association?

Acromegaly associated to schizophrenia was first reported ~60 years ago, and so far, it is unclear whether this association is causal or not. Our aim was to report new cases with both clinical entities and to discuss the potential pathophysiological mechanisms of this association. Three new cases and data from literature are reviewed. We report 2 males and 1 female diagnosed with schizophrenia and treated for several years with antipsychotics who developed acromegaly due to a growth hormone (GH)-secreting pituitary macroadenoma. In all cases, the diagnosis of schizophrenia preceded acromegaly with mean disease duration of ~12 years. Antipsychotic therapy was different in every patient. Two patients underwent transsphenoidal surgery. Histopathological study showed mixed GH- and prolactin-secreting adenoma in 1 patient and pure GH-secreting adenoma in the other patient. Several pathophysiological mechanisms related to alterations in dopaminergic neurotransmission due to psychiatric disease itself or its pharmacological treatment are proposed and discussed as likely linkage between schizophrenia and acromegaly. These case reports suggest that schizophrenia and/or its antipsychotic therapy in the long term might be in relation with the development of GH-secreting pituitary adenomas.

Clinical applications of somatostatin analogs for growth hormone-secreting pituitary adenomas

Excessive growth hormone (GH) is usually secreted by GH-secreting pituitary adenomas and causes gigantism in juveniles or acromegaly in adults. The clinical complications involving cardiovascular, respiratory, and metabolic systems lead to elevated morbidity in acromegaly. Control of serum GH and insulin-like growth factor (IGF) 1 hypersecretion by surgery or pharmacotherapy can decrease morbidity. Current pharmacotherapy includes somatostatin analogs (SAs) and GH receptor antagonist; the former consists of lanreotide Autogel (ATG) and octreotide long-acting release (LAR), and the latter refers to pegvisomant. As primary medical therapy, lanreotide ATG and octreotide LAR can be supplied in a long-lasting formulation to achieve biochemical control of GH and IGF-1 by subcutaneous injection every 4–6 weeks. Lanreotide ATG and octreotide LAR provide an effective medical treatment, whether as a primary or secondary therapy, for the treatment of GH-secreting pituitary adenoma; however, to maximize benefits with the least cost, several points should be emphasized before the application of SAs. A comprehensive assessment, especially of the observation of clinical predictors and preselection of SA treatment, should be completed in advance. A treatment process lasting at least 3 months should be implemented to achieve a long-term stable blood concentration. More satisfactory surgical outcomes for noninvasive macroadenomas treated with presurgical SA may be achieved, although controversy of such adjuvant therapy exists. Combination of SA and pegvisomant or cabergoline shows advantages in some specific cases. Thus, an individual treatment program should be established for each patient under a full evaluation of the risks and benefits.

Using growth hormone levels to detect macroadenoma in patients with acromegaly.

BackgroundThe aim of this study was to assess the clinical differences between acromegalic patients with microadenoma and patients with macroadenoma, and to evaluate the predictive value of growth hormone (GH) levels for early detection of macroadenoma.MethodsWe performed a retrospective analysis of 215 patients diagnosed with a GH-secreting pituitary adenoma. The patients were divided into two groups: the microadenoma group and the macroadenoma group, and the clinical parameters were compared between these two groups. The most sensitive and specific GH values for predicting macroadenoma were selected using receiver operating characteristic (ROC) curves.ResultsCompared with the microadenoma group, the macroadenoma group had a significantly younger age, higher body mass index, higher prevalence of hyperprolactinemia and hypogonadism, and a lower proportion of positive suppression to octreotide. However, there were no significant differences in the gender or in the prevalence of diabetes between the two groups. The tumor diameter was positively correlated with all GH values during the oral glucose tolerance test (OGTT). All GH values were significantly higher in the macroadenoma group than the microadenoma group. Cut-off values for GH levels at 0, 30, 60, 90, and 120 minutes for optimal discrimination between macroadenoma and microadenoma were 5.6, 5.7, 6.3, 6.0, and 5.8 ng/mL, respectively. ROC curve analysis revealed that the GH value at 30 minutes had the highest area under the curve.ConclusionThe GH level of 5.7 ng/mL or higher at 30 minutes during OGTT could provide sufficient information to detect macroadenoma at the time of diagnosis.

Gigantism caused by growth hormone secreting pituitary adenoma.

Gigantism indicates excessive secretion of growth hormones (GH) during childhood when open epiphyseal growth plates allow for excessive linear growth. Case one involved a 14.7-year-old boy presented with extreme tall stature. His random serum GH level was 38.4 ng/mL, and failure of GH suppression was noted during an oral glucose tolerance test (OGTT; nadir serum GH, 22.7 ng/mL). Magnetic resonance imaging (MRI) of the brain revealed a 12-mm-sized pituitary adenoma. Transsphenoidal surgery was performed and a pituitary adenoma displaying positive immunohistochemical staining for GH was reported. Pituitary MRI scan was performed 4 months after surgery and showed recurrence/residual tumor. Medical treatment with a long-acting somatostatin analogue for six months was unsuccessful. As a result, secondary surgery was performed. Three months after reoperation, the GH level was 0.2 ng/mL and insulin-like growth factor 1 was 205 ng/mL. Case two involved a 14.9-year-old boy, who was referred to our department for his tall stature. His basal GH level was 9.3 ng/mL, and failure of GH suppression was reported during OGTT (nadir GH, 9.0 ng/mL). Pituitary MRI showed a 6-mm-sized pituitary adenoma. Surgery was done and histopathological examination demonstrated a pituitary adenoma with positive staining for GH. Three months after surgery, the GH level was 0.2 ng/mL and nadir GH during OGTT was less than 0.1 ng/mL. Pituitary MRI scans showed no residual tumor. We present two cases of gigantism caused by a GH-secreting pituitary adenoma with clinical and microscopic findings.

The expression profile of Dopamine D2 receptor, MGMT and VEGF in different histological subtypes of pituitary adenomas: a study of 197 cases and indications for the medical therapy

To study the expression of D2R, MGMT and VEGF for clinical significance in pituitary adenomas, and to predict the potential curative medical therapy of dopamine agonists, temozolomide and bevacizumab on pituitary adenomas. Immunohistochemistry and western blot were performed to detect the expression of expression of D2R, MGMT and VEGF in pituitary adenoma tissue samples. The ratio of high expression of D2R, MGMT or VEGF in different subtypes of PA was compared by the use of chi-squared tests. The relationships between D2R, MGMT and VEGF expression were assessed by the Spearman rank correlation test. The association between their expression and clinical parameters was analyzed using a chi-squared test, or Fisher's exact probability test when appropriate. The data showed that in 197 different histological subtypes of pituitary adenomas (PAs), 64.9% of them were D2R high expression, 86.3% were MGMT low expression and 58.9% were VEGF high expression. D2R high expression existed more frequently in PRL- and GH- secreting PAs. MGMT low expression existed in all PA subtypes. VEGF high expression existed more frequently in PRL, ACTH, FSH secreting and non-functioning PAs. The data of western blot also support the results. Spearman's rank correlation analysis showed that expression of MGMT was positively associated with D2R (r = 0.154, P = 0.031) and VEGF (r = 0.161, P = 0.024) in PAs, but no correlation was showed between D2R and VEGF expression (r = −0.025, P = 0.725 > 0.05). The association between their expression and clinical parameters was analyzed using a chi-squared test, or Fisher's exact probability test when appropriate, but the result showed no significant association. PRL-and GH-secreting PAs exist high expression of D2R, responding to dopamine agonists; Most PAs exist low expression of MGMT and high expression of VEGF, TMZ or bevacizumab treatment could be applied under the premise of indications.

Cavernous sinus invasion and effect of immunohistochemical features over remission in growth hormone secreting pituitary adenomas

We examined the cavernous sinus invasion and tumor biological markers that influence the remission rate. Cavernous sinus (CS) invasion was evaluated radiologically. Tumor biological markers consisting of the tumor cell growth parameter Ki-67 and the cancer cell vasculature marker of vascular endothelial growth factor (VEGF) were evaluated. We examined 28 immunohistochemically proven GH secreting pituitary adenoma patients who had been operated via endoscopic transsphenoidal surgery at Department of Neurosurgery, Kocaeli University Hospital between 2003 and 2008. Pathology preparations were stained with Ki-67 and VEGF. We evaluated remission at the postoperative 6th week. The basal GH level, nadir GH level and IGF-1 levels were evaluated to determine remission. Remission was achieved in 6 of 18 patients (33%) who had cavernous sinus invasion. Remission was achieved in 7 of 10 patients (70%) who did not have cavernous sinus invasion. There was no correlation between the Ki-67 proliferation index and cavernous sinus invasion (p=0.593). There was a positive correlation between VEGF expression and cavernous sinus invasion (p=0.03). The remission rate found less in the cavernous sinus invasion group. No association was found between Ki 67 proliferation index and cavernous sinus invasion. We found that a positive correlation between VEGF expression and cavernous sinus invasion. VEGF expression can therefore indirectly affect remission via cavernous sinus invasion.

Diagnostic features and outcome of surgical therapy of acromegalic patients: experience of the last three decades.

Transsphenoidal (TNS) surgery remains the primary therapeutic option for GH-secreting pituitary adenomas. The aims of this study were to verify the impact of TNS surgery on treatment of acromegaly before and after identification by a dedicated neurosurgical team and to enumerate diagnostic features of the disease described over three decades. 41 patients (group A) who underwent TNS surgery by a dedicated neurosurgical team (2000-2008) and 126 patients (group B) operated on by surgeons not specialized in pituitary surgery (1979-1999) were retrospectively analyzed. No significant differences were observed between the two groups in terms of delay of diagnosis, mean basal GH levels and GH nadir values, prevalence of hypopituitarism and hypertension. IGF-I SDS were significantly higher, while prevalence of IGT/diabetes was significantly lower in group B than in group A. Overall remission rate after surgery was 58.5% for group A (75% in microadenomas and 48% in macroadenomas, P=NS) and 37% for group B (P<0.05 vs group A; for microadenomas, 34% vs 75% of group A, P<0.05, for macroadenomas, 36% vs 48% of group A, P=NS). The mean delay of diagnosis was 4.9 and 5.9 years in group A and B, respectively. Our data confirm that a dedicated neurosurgical team is needed in order to improve remission rates in acromegalic patients. No changes in biochemical, clinical and neuroradiological presentation of disease were observed over the last three decades. As the high prevalence of macroadenomas negatively influences surgical cure, earlier diagnosis should be considered as mandatory to achieve a better outcome.

Ectopic acromegaly due to a GH-secreting pituitary adenoma in the sphenoid sinus: a case report and review of the literature

BackgroundIn more than 98% of cases, acromegaly is due to a GH-secreting pituitary adenoma. The term “ectopic acromegaly” includes neuroendocrine tumors secreting GH releasing hormone (GHRH), usually located in the lungs, thymus and endocrine pancreas. Considerably less frequent are cases of ectopic acromegaly due to GH-secreting tumors located out of the pituitary fossa; except for one isolated case of a well-documented GH-secreting lymphoma, the majority of these lesions are located in the sphenoid sinus.Case presentationWe present the case of a 45 year old woman with acromegaly whose MRI showed an empty sella without evidence of a pituitary adenoma but revealed a large mass within the sphenoid sinus. She underwent transsphenoidal surgery and the excised sphenoid sinus mass, proved to be a GH-secreting adenoma; the sellar floor was intact and no other lesions were found in the pituitary fossa. She required postoperative treatment with somatostatin analogs and cabergoline for clinical and biochemical control.ConclusionsThis case highlights the importance of carefully evaluating the structures surrounding the sellar area when a pituitary adenoma is not found with currently available imaging techniques. The finding of an intact sellar floor and duramater lead us to conclude that the patient’s tumor originated de novo from embryological pituitary remnants. Upon a careful review of the literature and a critical evaluation of our case we found neither clinical nor biochemical features that would distinguish an ectopic from the more common eutopically located somatotrophinoma.

Acromégalie et grossesse : six nouvelles observations

Pregnancies in acromegalic women are rare. Data from the literature indicate absence of congenital malformation in newborns, an increase of pituitary adenoma volume rarely clinically symptomatic, an increased risk of gestational diabetes and gravid hypertension in women with non-controlled GH/IGF-1hypersecretion before gestation. The changes of somatotroph function are rarely described. Report of six new pregnancies in five women with acromegaly. Before pregnancy three women had incomplete surgical resection of GH-secreting pituitary adenoma, all were treated with somatostatin analogues, and the medical treatment was withdrawal at the diagnosis of gestation. We studied clinical (blood pressure, headaches, visual field), biological (blood glucose concentration) signs, GH and IGF-1levels were measured during each trimester of pregnancy as well as in post-partum and were compared with pregestational values, MRI of the pituitary performed during the second trimester and in the post-partum were compared with MRI examen before pregnancy. All those pregnancies were normal without gestational diabetes, gravid hypertension and pituitary tumor syndrome. Clinical signs of acromegaly improved in 50% of the patients, and IGF-1decreased (22%) in comparison of pregestational value without significant change in GH levels. No newborn had congenital malformation. Pregnancies in those women with acromegaly are uneventful without obstetrical or foetal complication, but a maternal follow-up is necessary in order to diagnose gravid hypertension and gestational diabetes. On the other hand, a clinical monitoring of pituitary tumor syndrome is necessary in women with non-operated GH-secreting macroadenoma before pregnancy. During the first trimester of gestation, an improvement of acromegalic signs can be due to a decrease of IGF-1levels related to hepatic GH-resistance state secondary to physiological secretion of estrogens during gestation.

Improvement of insulin resistance following transsphenoidal surgery in patients with acromegaly: correlation with serum IGF-I levels.

The aim of this study was to determine the correlation between the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis and glucose intolerance in acromegaly during the early postoperative period. The study included 20 patients with acromegaly caused by GH-secreting pituitary adenoma who received transsphenoidal surgery in our hospital. Glucose tolerance was evaluated with oral glucose tolerance tests (OGTTs) performed during pre- and early postoperative periods (9 [7-18] days after surgery). Homeostasis model assessment of insulin resistance (HOMA-IR) and insulinogenic index (IGI) were calculated, and correlation analyses were performed between these values and the GH-IGF-I axis. Patients were divided according to postoperative changes of the axis, and glucose tolerance was compared between the groups. In preoperative OGTTs, nine patients had impaired glucose tolerance and two had diabetes mellitus patterns. Postoperatively, significant reduction was observed both in fasting plasma glucose levels (p<0.01) and in HOMA-IR (p<0.01), whereas IGI showed no significant change. HOMA-IR was significantly correlated with serum IGF-I levels both before (r=0.83, p<0.01) and after (r=0.57, p<0.01) surgery, although it was not correlated with serum GH levels. Patients who achieved more than 50% postoperative reduction in serum IGF-I levels showed significant improvement in OGTTs results (p<0.05). In patients with acromegaly, serum IGF-I levels, but not GH levels, were significantly correlated with insulin resistance. Early postoperative improvement of glucose tolerance is observed in patients who achieved postoperative reduction in serum IGF-I levels.

Monitoring for potential residual disease activity by serum insulin-like growth factor 1 and soluble Klotho in patients with acromegaly after pituitary surgery: Is there an impact of the genomic deletion of exon 3 in the growth hormone receptor (d3-GHR) gene on “safe” GH cut-off values?

BackgroundAcromegaly is an illness usually defined by excessively high growth hormone (GH) and insulin like growth factor 1 (IGF-1) levels, the latter mainly reflecting GH action on the liver. IGF-1, also known as somatomedin C, mediates several actions of GH. The diagnosis and management of acromegaly is relatively straight forward, but long-term follow-up of patients can be difficult, as elevated IGF-1 levels can occur in the presence of apparently normalised GH levels and late recurrence of acromegaly may arise despite previous suppression on oral glucose tolerance testing. Data suggest this applies especially to patients in whom the GH receptor lacks exon 3. In such patients, GH may not always be a useful marker of disease, and traditional GH cut-offs may be misleading. Recent data suggest that soluble Klotho (sKlotho), besides and in addition to IGF-1, may help monitor the activity of GH-producing adenomas (presumably reflecting GH action on the kidneys) and may be a useful supplementary tool. MethodsGHR genotyping was performed in 112 patients with acromegaly. IGF-1 and sKlotho levels were measured in the sera of patients before and after transsphenoidal surgery, with emphasis on patients judged inconclusively cured by surgery or with small residual tumour masses shortly after surgery. Patients were assessed for recurrence of acromegaly with GH levels (random or nadir during an oGTT). ResultsOf the 48 patients who underwent surgery between 2000 and 2009 and who had well-documented longer term follow-up at our institution, 29 had no biochemical evidence of residual disease activity after transsphenoidal surgery (marked reduction in IGF-1 and sKlotho levels, GH suppressible to <1ng/ml) and were classified as in remission. 2 of these patients developed recurrent symptoms of acromegaly during follow-up with increasing levels of IGF-1 and sKlotho, and both patients were carriers of the d3-GHR genotype. ConclusionsAcromegalic patients with the d3-GHR polymorphism might be – for a given low postsurgical GH level – at higher risk for recurrence and may require a lower GH nadir during oGTT to be classified as in remission. Soluble Klotho could be useful in the follow-up of acromegalic patients. The question arises whether sKlotho not only reflects the activity of GH-secreting pituitary adenomas but whether Klotho (ectodomain clipping?) could also mediate selected actions of GH.

Place of Preoperative Treatment of Acromegaly with Somatostatin Analog on Surgical Outcome: A Systematic Review and Meta-Analysis

ContextTranssphenoidal neurosurgery is the accepted first-line treatment of acromegaly in the majority of patients. Previous studies addressing preoperative somatostatin analog (SSA) treatment and subsequent surgical cure rates are conflicting, reporting either benefits or no significant differences.ObjectiveThe aim of this study, based on a meta-analysis of all published reports, was to investigate whether treatment with SSA before surgery improves the surgical outcome of acromegaly.Data SourcesAll studies of preoperative treatment of acromegaly with SSA were systematically reviewed up to December 2011. We searched the Medline, Embase, Cochrane and Google Scholar electronic databases. Study Selection: The primary endpoint was the biochemical postoperative cure rate. We identified 286 studies, out of which 10 studies (3.49%) fulfilling the eligibility criteria were selected for analysis; five retrospective studies with a control group, two prospective non-randomized trials, and three prospective controlled trials. The meta-analysis was conducted using the random-effects model.Data ExtractionData were extracted from published reports by two independent observers. Data Synthesis: A borderline effect was detected in the analysis of all of the trials with control groups, with a pooled odds ratio (OR) for biochemical cure with SSA treatment of 1.62 (95% CI, 0.93–2.82). In the analysis of the three prospective controlled trials, a statistically significant effect was idenfified OR: 3.62 (95% CI, 1.88–6.96).ConclusionsPreoperative treatment with SSA og GH-secreting pituitary adenomas shows a significant improvement on surgical results. This meta-analysis suggests that in centers without optimal results all patients with a GH-secreting pituitary macroadenoma should be treated with a long-acting SSA prior to surgical treatment.

Atypical McCune--Albright syndrome associated with GH secreting pituitary adenoma

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Visual Field Improvement After Pituitary Tumor Surgery in Patients With McCune–Albright Syndrome

McCune-Albright syndrome (MAS) is a rare, sporadic congenital disorder, in which optic neuropathy may cause devastating visual consequences. Pituitary adenoma with overproduction of growth hormone (GH) is present in approximately two-thirds of MAS patients, and its role in the pathogenesis of MAS-associated optic neuropathy has not been studied. Three MAS patients with GH-secreting pituitary adenoma and optic chiasm compression diagnosed between January 2008 and November 2010 were included in this case series. Transsphenoidal pituitary resection was performed in all 3 patients. Neuro-ophthalmologic evaluation was performed at presentation and every 6 months during follow-up. Of the 3 patients, 2 were female and 1 was male; their ages ranged from 17 to 27 years. Visual acuity ranged from 20/20 to 20/200 before surgery and all had visual field loss. The patients were followed up for 6-18 months with substantial improvement in their visual fields. GH-secreting pituitary adenoma may contribute to optic nerve damage, at least partially, in MAS patients. Pituitary surgery may be important for visual recovery in some MAS patients in whom there is compression of the optic chiasm.

Routine Intensive Care Unit–Level Care After Elective Craniotomy: Time to Rethink

Transsphenoid surgery is the treatment of choice for growth hormone (GH)-producing pituitary adenomas. The measures that may predict postoperative remission need to be elucidated.Transsphenoid surgery was performed in 163 patients by a single neurosurgeon from 1992 until 2010. Thirty-three patients were lost to follow-up, and the results of the remaining 130 are presented here.A total of 81.5% of patients obtained a first postoperative day GH level less than 5 μg/L, whereas 60.5% achieved a value less than 2.5 μg/L. A total of 56.9% had achieved both a GH less than 2.5 μg/L and normal insulin-like growth factor I (IGF-I) on delayed follow-up and could be regarded as in remission. Duration of symptoms before surgery, age, preoperative GH, and IGF-I levels did not significantly influence a patient's remission. Analysis showed that cavernous sinus extension and larger tumor size were associated with decreased remission rate, whereas sellar floor invasion or suprasellar extension did not significantly influence remission.The results of our study show that transsphenoid surgery is an optimal treatment modality for GH-secreting pituitary adenoma. Suprasellar or sellar floor invasion, and preoperative GH or IGF-I do not necessarily predict poor outcomes. Large tumor size and cavernous sinus extension contribute to greater recurrence rates.

MTOR is Frequently Active in GH-Secreting Pituitary Adenomas without Influencing their Morphopathological Features

Initiating factors and mechanisms of tumor formation are poorly understood in nonfamilial pituitary adenomas. Alteration of intracellular pathways is an underlying event in numerous neoplasms. Among them, excessive activation of mammalian target of rapamycin (mTOR) pathway and its two main regulators, Akt and Erk, has been detected frequently in solid tumors. This study tests the activation of mTOR pathway in pituitary adenomas and its influence on their morphopathological features. Fifty-three pituitary adenomas were fresh frozen after surgery and analyzed by western blotting using phospho-specific antibodies. The impact of Akt and Erk activation on mTOR pathway was assessed in five primary cultures derived from the excised adenomas using selective kinase inhibitors. Statistical correlations of size, volume, Ki-67 %, Knosp's grading, and somatostatin receptor (SSTR) expression with the activation of mentioned kinases was performed. GHomas showed the highest frequency (71 %) and level of mTOR pathway activity comparing to other adenomas (33 %). No significant correlation was found between mTOR activation and any of the morphopathological features in the studied samples. mTOR kinase phosphorylation was independent of Erk and Akt in primary cultures. Erk activity was significant in all types of adenomas but was the highest in control samples. Its phosphorylation correlated inversely with the Knosp's grading in nonfunctional pituitary adenomas and directly with somatostatin receptor subtype 2 A expression in GHomas. Presented data point to the noteworthy mTOR activity in GHomas. However, the lack of correlation with morphopathological features, its independence of Erk and Akt phosphorylation, and high level of Erk activity in control pituitary necessitate further research for clarifying the role of these pathways in pituitary adenomas.

Prevalence and incidence of pituitary adenomas: a population based study in Malta

Epidemiological data is important to correctly quantify the extent of disease and needed health care resources. The aim of the study was to establish the prevalence and incidence of pituitary adenomas (PAs) in the same well defined population, with in-depth analysis of the various subtypes. The design involved a retrospective cross-sectional analysis of PA patients diagnosed prior to 31 July 2011 for prevalence estimates and those diagnosed between July 2000 and July 2011 for incidence estimation. A thorough search for patients with PAs was carried out in central hospital registries including outpatients departments, surgical registries, radiological department and specialty clinic databases. Prevalence rates/100,000 and Standardised incidence ratios (SIR)/100,000/year were worked out. The respective prevalence rates and SIR for PAs overall were 75.7/100,000, and 4.27/100,000/year, for Prolactinomas 35.0/100,000 and 2.05/100,000/year, for nonfunctioning PA 25.9/100,000 and 1.79/100,000/year and for GH-secreting PAs 12.5/100,000 and 0.31/100,000/year. The overall prevalence for macroadenomas was 32.8/100,000 and SIR was 1.49/100,000/year. The prevalence rate in males for PAs overall was 46.3/100,000 and SIR was 2.08/100,000/year and in females 104.8/100,000 and SIR was 6.58/100,000/year. Females had a lower proportion of macroadenomas than males (29.5 vs. 75.0%; P < 0.001) and macroadenomas tended to present at a later age compared to microadenomas (48 vs. 34.5; P < 0.001). The highest SIR was reached in the 30-39 age group at 7.42/100,000/year. Our data confirm the considerable disease burden that PAs bear on health care resources. Males and females have similar prevalence and SIR rates for macroadenomas but there is a significant increase in SIR in females of child bearing age compared to males. These observations may have important implications in terms of the economic burden and need for early intervention.

Surgical and Endocrinological Outcomes in the Treatment of Growth Hormone-Secreting Pituitary Adenomas According to the Shift of Surgical Paradigm

Extensive data exist regarding the success rates and long-term outcomes of transsphenoidal adenomectomy (TSA) of growth hormone (GH)-secreting pituitary tumors; however, few data exist regarding the extent of adenomectomy. To evaluate surgical outcomes for the treatment of GH-secreting pituitary adenomas with regard to the extent of adenomectomy. A retrospective study of 282 patients with GH-secreting pituitary tumors who underwent TSA. Three surgical paradigms (1, 2, and 3) were applied, all of which differed in extent of adenomectomy. All participants were evaluated with oral glucose tolerance tests (OGTTs) at 6-month intervals for 1.5 years and combined pituitary function tests at 1.5-year intervals after TSA. All surgeries were conducted by a single neurosurgeon at a single medical center. Biochemical remission was defined with insulinlike growth factor 1 and OGTT results. The overall surgical remission rates were 89%, 87%, 64%, 70%, and 50% (nadir GH <1 ng/mL on OGTTs: 96%, 95%, 73%, 84%, and 56%) for modified Hardy classifications I, II, IIIA, IIIB, and IV, respectively. The remission rates for modified Hardy classification I-IIIB improved to 42%, 68%, and 84% after application of surgical paradigms 1, 2, and 3, respectively (P = .002). Aggressive surgical resection did not worsen hypopituitarism. Among the 42 patients with modified Hardy classification IV, 24 (57%) achieved remission without recurrence after applying the aggressive paradigm 3 surgery. An aggressive surgical approach may be critical to managing GH-secreting pituitary adenomas and does not increase the risk of postoperative hypopituitarism. ACTH, corticotropinCPFT, combined pituitary function testCV, coefficient of variationGH, growth hormoneOGTT, oral glucose tolerance testPRL, prolactinTSA, transsphenoidal adenomectomyTSH, thyroid-stimulating hormone.

Effects of AMPK activation and combined treatment with AMPK activators and somatostatin on hormone secretion and cell growth in cultured GH-secreting pituitary tumor cells

We investigated the effects of the AMPK activator AICAR as compared to somatostatin-14 on cell viability and GH secretion in human GH-secreting pituitary adenomas in vitro and in rat GH3 cells.Overnight treatment with AICAR increased phospho-(threonine-172) AMPK levels (activated AMPK) in cultured human adenomas.As to the effects on cell viability, four adenomas out of 15 were responsive to AICAR (0.4mM) and five adenomas were responsive to SS-14 (100nM). One adenoma was responsive to both somatostatin and AICAR. The effects of cotreatment with SS-14 and AICAR were investigated in eight adenomas. In two adenomas, the effects of AICAR+SS-14 did not exceed the effect of AICAR. In two adenomas which were not responsive to either AICAR or SS-14, the cotreatment was able to reduce cell viability versus control. Two adenomas were not responsive to any treatment.As to the effects on GH secretion, nine adenomas out of 15 were responsive to AICAR. Twelve adenomas were responsive to SS-14. Eight adenomas were responsive to both AICAR and SS-14. Cotreatment exceeded the effect of single treatments in 4 out of 10 adenomas.In GH3 cells, AICAR reduced the activity of p70S6 kinase, which plays an important role in cell growth. SS-14 did not affect significantly AMPK phosphorylation and p70S6K activity but it was able to enhance the inhibitory effect of AICAR on phospho-S6 levels. Moreover, AICAR and SS-14 reduced ERK phosphorylation with a different time course. The combined treatment reduced phospho-ERK levels at any time point.

SAGE analysis highlights the putative role of underexpression of ribosomal proteins in GH-secreting pituitary adenomas

Although the molecular pathogenesis of pituitary adenomas has been assessed by several different techniques, it still remains partially unclear. Ribosomal proteins (RPs) have been recently related to human tumorigenesis, but they have not yet been evaluated in pituitary tumorigenesis. The aim of this study was to introduce serial analysis of gene expression (SAGE), a high-throughput method, in pituitary research in order to compare differential gene expression. Two SAGE cDNA libraries were constructed, one using a pool of mRNA obtained from five GH-secreting pituitary tumors and another from three normal pituitaries. Genes differentially expressed between the libraries were further validated by real-time PCR in 22 GH-secreting pituitary tumors and in 15 normal pituitaries. Computer-generated genomic analysis tools identified 13,722 and 14,993 exclusive genes in normal and adenoma libraries respectively. Both shared 6497 genes, 2188 were underexpressed and 4309 overexpressed in tumoral library. In adenoma library, 33 genes encoding RPs were underexpressed. Among these, RPSA, RPS3, RPS14, and RPS29 were validated by real-time PCR. We report the first SAGE library from normal pituitary tissue and GH-secreting pituitary tumor, which provide quantitative assessment of cellular transcriptome. We also validated some downregulated genes encoding RPs. Altogether, the present data suggest that the underexpression of the studied RP genes possibly collaborates directly or indirectly with other genes to modify cell cycle arrest, DNA repair, and apoptosis, leading to an environment that might have a putative role in the tumorigenesis, introducing new perspectives for further studies on molecular genesis of somatotrophinomas.