TP53 mutations in functional corticotroph tumors are linked to invasion and worse clinical outcome.

Corticotroph macroadenomas are rare but difficult to manage intracranial neoplasms. Mutations in the two Cushing's disease mutational hotspots USP8 and USP48 are less frequent in corticotroph macroadenomas and invasive tumors. There is evidence that TP53 mutations are not as rare as previously thought in these tumors. The aim of this study was to determine the prevalence of TP53 mutations in corticotroph tumors, with emphasis on macroadenomas, and their possible association with clinical and tumor characteristics. To this end, the entire TP53 coding region was sequenced in 86 functional corticotroph tumors (61 USP8 wild type; 66 macroadenomas) and the clinical characteristics of patients with TP53 mutant tumors were compared with TP53/USP8 wild type and USP8 mutant tumors. We found pathogenic TP53 variants in 9 corticotroph tumors (all macroadenomas and USP8 wild type). TP53 mutant tumors represented 14% of all functional corticotroph macroadenomas and 24% of all invasive tumors, were significantly larger and invasive, and had higher Ki67 indices and Knosp grades compared to wild type tumors. Patients with TP53 mutant tumors had undergone more therapeutic interventions, including radiation and bilateral adrenalectomy. In conclusion, pathogenic TP53 variants are more frequent than expected, representing a relevant amount of functional corticotroph macroadenomas and invasive tumors. TP53 mutations associated with more aggressive tumor features and difficult to manage disease.

Inhibition of Heat Shock Factor 1 Enhances Repressive Molecular Mechanisms on the POMC Promoter.

BACKGROUND: Cushing's disease (CD) is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumours. They express high levels of heat shock protein 90 and heat shock factor 1 (HSF1) in comparison to the normal tissue counterpart, indicating activated cellular stress. AIMS: Our objectives were: (1) to correlate HSF1 expression with clinical features and hormonal/radiological findings of CD, and (2) to investigate the effects of HSF1 inhibition as a target for CD treatment. PATIENTS/METHODS: We examined the expression of total and pSer326HSF1 (marker for its transcriptional activation) by Western blot on eight human CD tumours and compared to the HSF1 status of normal pituitary. We screened a cohort of 45 patients with CD for HSF1 by immunohistochemistry and correlated the HSF1 immunoreactivity score with the available clinical data. We evaluated the effects of HSF1 silencing with RNA interference and the HSF1 inhibitor KRIBB11 in AtT-20 cells and four primary cultures of human corticotroph tumours. RESULTS: We show that HSF1 protein is highly expressed and transcriptionally active in CD tumours in comparison to normal pituitary. The immunoreactivity score for HSF1 did not correlate with the typical clinical features of the disease. HSF1 inhibition reduced proopiomelanocortin (Pomc) transcription in AtT-20 cells. The HSF1 inhibitor KRIBB11 suppressed ACTH synthesis from 75% of human CD tumours in primary cell culture. This inhibitory action on Pomc transcription was mediated by increased glucocorticoid receptor and suppressed Nurr77/Nurr1 and AP-1 transcriptional activities. CONCLUSIONS: These data show that HSF1 regulates POMC transcription. Pharmacological targeting of HSF1 may be a promising treatment option for the control of excess ACTH secretion in CD.

Aggressive and Malignant Prolactinomas.

Prolactin-secreting tumors (prolactinomas) represent the most common pituitary tumor type, accounting for 47-66% of functional pituitary tumors. Prolactinomas are usually benign and controllable tumors as they express abundant levels of dopamine type 2 receptor (D2), and can be treated with dopaminergic drugs, effectively reducing prolactin levels and tumor volume. However, a proportion of prolactinomas exhibit aggressive features (including invasiveness, relevant growth despite adequate dopamine agonist treatment, and recurrence potential) and few may exhibit metastasizing potential (carcinomas). In this context, the clinical, pathological, and molecular definitions of malignant and aggressive prolactinomas remain to be clearly defined, as primary prolactin-secreting carcinomas are similar to aggressive adenomas until the presence of metastases is detected. Indeed, standard molecular and histological analyses do not reflect differences between carcinomas and adenomas at a first glance and have limitations in prediction of the aggressive progression of prolactinomas, wherein the causes underlying the aggressive behavior remain unknown. Herein we present a comprehensive, multidisciplinary review of the most relevant epidemiological, clinical, pathological, genetic, biochemical, and molecular aspects of aggressive and malignant prolactinomas.

The Liege Acromegaly Survey (LAS): a new software tool for the study of acromegaly.

Acromegaly is a chronic rare disease associated with negative pathological effects on multiple systems and organs. We designed a new informatics tool to study data from patients with acromegaly, the Liege Acromegaly Survey (LAS). This relational database permits the inclusion of anonymous historical and prospective data on patients and includes pathophysiology, clinical features, responses to therapy and long term outcomes of acromegaly. We deployed the LAS in a validation study at a single center in order to study the characteristics of patients with acromegaly diagnosed at our center from 1970-2011. A total of 290 patients with acromegaly were included (147 males and 143 females). There was a linear relationship between age at diagnosis and the date of diagnosis, indicating that older patients are being diagnosed with acromegaly more frequently. A majority presented with macroadenomas (77.5%) and the median diameter was 14 mm. Patients with macroadenomas were significantly younger than patients with microadenomas (P=0.01). GH values at diagnosis decreased with the age of the patients (P=0.01) and there was a correlation between GH values and tumor size at diagnosis (P=0.02). No correlation existed between insulin-like growth factor 1 (IGF-1) levels and tumor characteristics. The prevalence of diabetes was 21.4% in this population and 41.0% had hypertension. The presence of hypertension and diabetes were significantly associated with one another (P<0.001). There was a linear relation between initial GH and IGF-1 levels at diagnosis and those obtained during SSA analog treatment and the lowest GH and IGF-1 values following SSA therapy were obtained in older patients (GH: P<0.001; IGF-1: P<0.001). The LAS is a new relational database that is feasible to use in the clinical research setting and permits ready pooling of anonymous patient data from multiple study sites to undertake robust statistical analyses of clinical and therapeutic characteristics.

Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds.

Familial isolated pituitary adenoma (FIPA) occurs in families and is unrelated to multiple endocrine neoplasia type 1 and Carney complex. Mutations in AIP account only for 15-25% of FIPA families. CDKN1B mutations cause MEN4 in which affected patients can suffer from pituitary adenomas. With this study, we wanted to assess whether mutations in CDKN1B occur among a large cohort of AIP mutation-negative FIPA kindreds. Eighty-eight AIP mutation-negative FIPA families were studied and 124 affected subjects underwent sequencing of CDKN1B. Functional analysis of putative CDKN1B mutations was performed using in silico and in vitro approaches. Germline CDKN1B analysis revealed two nucleotide changes: c.286A>C (p.K96Q) and c.356T>C (p.I119T). In vitro, the K96Q change decreased p27 affinity for Grb2 but did not segregate with pituitary adenoma in the FIPA kindred. The I119T substitution occurred in a female patient with acromegaly. p27(I119T) shows an abnormal migration pattern by SDS-PAGE. Three variants (p.S56T, p.T142T, and c.605+36C>T) are likely nonpathogenic because In vitro effects were not seen. In conclusion, two patients had germline sequence changes in CDKN1B, which led to functional alterations in the encoded p27 proteins in vitro. Such rare CDKN1B variants may contribute to the development of pituitary adenomas, but their low incidence and lack of clear segregation with affected patients make CDKN1B sequencing unlikely to be of use in routine genetic investigation of FIPA kindreds. However, further characterization of the role of CDKN1B in pituitary tumorigenesis in these and other cases could help clarify the clinicopathological profile of MEN4.

High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas.

BACKGROUND: Aryl hydrocarbon receptor interacting protein (AIP) mutations (AIPmut) cause aggressive pituitary adenomas in young patients, usually in the setting of familial isolated pituitary adenomas. The prevalence of AIPmut among sporadic pituitary adenoma patients appears to be low; studies have not addressed prevalence in the most clinically relevant population. Hence, we undertook an international, multicenter, prospective genetic, and clinical analysis at 21 tertiary referral endocrine departments. METHODS: We included 163 sporadic pituitary macroadenoma patients irrespective of clinical phenotype diagnosed at <30 years of age. RESULTS: Overall, 19/163 (11.7%) patients had germline AIPmut; a further nine patients had sequence changes of uncertain significance or polymorphisms. AIPmut were identified in 8/39 (20.5%) pediatric patients. Ten AIPmut were identified in 11/83 (13.3%) sporadic somatotropinoma patients, in 7/61 (11.5%) prolactinoma patients, and in 1/16 non-functioning pituitary adenoma patients. Large genetic deletions were not seen using multiplex ligation-dependent probe amplification. Familial screening was possible in the relatives of seven patients with AIPmut and carriers were found in six of the seven families. In total, pituitary adenomas were diagnosed in 2/21 AIPmut-screened carriers; both had asymptomatic microadenomas. CONCLUSION: Germline AIPmut occur in 11.7% of patients <30 years with sporadic pituitary macroadenomas and in 20.5% of pediatric patients. AIPmut mutation testing in this population should be considered in order to optimize clinical genetic investigation and management.

Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study.

CONTEXT: AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively. OBJECTIVE: The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas. DESIGN: This study was an international, multicenter, retrospective case collection/database analysis. SETTING: The study was conducted at 36 tertiary referral endocrine and clinical genetics departments. PATIENTS: Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls. RESULTS: The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy. CONCLUSIONS: AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.

Genetic factors in the development of pituitary adenomas.

Pituitary adenomas are one of the most frequent intracranial tumors. Usually, they are benign but are of great clinical significance because of tumor compression syndrome and hormone overproduction. The interest in this pathology is increasing, particularly after some recent reports on their prevalence that proved to be 3-5 times more than previously estimated. Pituitary tumors arise in a sporadic setting and rarely as part of hereditary genetic syndromes. Such rare hereditary conditions like MEN1, Carney complex and McCune-Albright syndrome give significant insight into pituitary tumorigenesis. Newer genes associated pituitary tumor development include CDKN1B (MEN4) and AIP, the latter of which is involved in the pathophysiology of 15% of FIPA kindreds. The number of genes involved in pituitary tumorigenesis is progressively increasing and the possible mechanisms of action include signal transduction pathways, cell cycle regulators, growth factors, chromosome instability and others. Nevertheless, in the majority of sporadic adenomas, the primary genetic defect remains unknown. Furthermore, there is not a well established relationship between the genotype and its influence on the protein expression, ligand-receptor interaction, tumor growth or hormone hyperproduction. Further studies should evaluate the clinical significance of genetic alterations and their implications for existing and new therapeutic options.

The epidemiology and genetics of pituitary adenomas.

According to data derived from autopsy and radiological imaging series, pituitary tumours occur very commonly in the general population; however, most of these tumours are incidental findings with no obvious clinical impact. The historical data on the prevalence of pituitary adenomas in the clinical setting are scant and point to such tumours being relatively rare. Recent studies have shown that the prevalence of clinically relevant pituitary adenomas is 3-5 times higher than previously reported, which adds impetus to research into the aetiology of these tumours. Although the majority of pituitary adenomas are sporadic, approximately 5% of all cases occur in a familial setting and over half of these are due to Multiple Endocrine Neoplasia Type 1 (MEN-1) and Carney's Complex (CNC) disorders. Since the late 1990 s, we have described non-MEN1/CNC familial pituitary tumours that include all tumour phenotypes as a condition termed Familial Isolated Pituitary Adenomas (FIPAs). The clinical characteristics of the FIPAs vary from those sporadic pituitary adenomas, as patients with FIPAs have a younger age at diagnosis and larger tumours. About 15% of the FIPA patients have mutations in the aryl hydrocarbon receptor-interacting protein gene (AIP), which indicates that the FIPA may have a diverse genetic pathophysiology.

[AIP mutations in familial and sporadic pituitary adenomas: local experience and review of the literature]. / Mutaciones de AIP en adenomas hipofisarios familiares y esporádicos: experiencia local y revisión de la literatura.

Clinically relevant pituitary adenomas occur 3-5 times more frequently than previously thought. The majority are isolated cases, but their presentation can be familial in the setting of known syndromes such as multiple endocrine neoplasia (MEN)-1 and Carney complex. When 2 or more cases of pituitary adenomas occur in the same family in the absence of the above-mentioned syndromes, a diagnosis of FIPA (familial isolated pituitary adenomas) is made, which accounts for 1-2% of all pituitary adenomas. Mutations of the gene AIP (aryl hydrocarbon receptor-interacting protein) may account for 15% of FIPA families (50% of familial acromegaly), and as such the genetic causes continue to be studied. Also mutations in AIP can be detected in sporadic adenomas among young populations (< 30 years of age). We describe the characteristics of FIPA, detailing the study of a spanish family, in this case AIP mutation negative. Also, the reported findings in sporadic adenomas in the young population are detailed, accompanied by the description of a 19- year old patient with an intronic AIP mutation. Multicenter studies have provided understanding of aspects such as mutations in AIP; however, further studies are necessary to identify other genes involved in FIPA and sporadic pituitary adenomas occurring at a young age.

Tumor ZAC1 expression is associated with the response to somatostatin analog therapy in patients with acromegaly.

Somatostatin analogs (SSA) with their potent antisecretory and antiproliferative effects are the main medical treatment option for patients with neuroendocrine tumors, such as gastroenteropancreatic and acromegaly-associated growth hormone secreting pituitary tumors. Although a good portion of acromegalic patients gets normalized after SSA treatment, strict hormonal control is not achieved in a sizeable proportion of these patients. The reasons for this incomplete response to SSA treatment are unclear. We have found that the tumor suppressor ZAC1 (LOT1/PLAGL1) is essential for the antiproliferative effect of SSA in pituitary tumor cells. The aim of the present retrospective cohort study was to determine whether ZAC1 immunoreactivity in archival somatotrophinoma tissue derived from 45 patients with acromegaly routinely pretreated with SSA before surgery, was associated with response to SSA (normalization of GH, IGF-I and presence of tumor shrinkage). All tumors displayed ZAC1 immunoreactivity [weak (+; n = 15), moderate (++; n = 16) and strong (+++; n = 14)]. A significant positive correlation was found between strong ZAC1 immunoreactivity and IGF-I normalization and presence of tumor shrinkage after SSA treatment, which was not affected by age at diagnosis, gender or duration of SSA treatment. These in vivo data combined with the antiproliferative properties of ZAC1/Zac1 provide evidence of a mechanistic role for this transcription factor on SSA induced tumor shrinkage and hormone normalization.

Expression of aryl hydrocarbon receptor (AHR) and AHR-interacting protein in pituitary adenomas: pathological and clinical implications.

Germline mutations of the aryl hydrocarbon receptor (AHR)-interacting protein (AIP) gene confer a predisposition to pituitary adenomas (PA), usually in the setting of familial isolated PA. To provide further insights into the possible role of AIP in pituitary tumour pathogenesis, the expression of AIP and AHR was determined by real-time RT-PCR and/or immunohistochemistry (IHC) in a large series of PA (n=103), including 17 with AIP mutations (AIP(mut)). Variable levels of AIP and AHR transcripts were detected in all PA, with a low AHR expression (P<0.0001 versus AIP). Cytoplasmic AIP and AHR were detected by IHC in 84.0 and 38.6% of PA respectively, and significantly correlated with each other (P=0.006). Nuclear AHR was detected in a minority of PA (19.7%). The highest AIP expression was observed in somatotrophinomas and non-secreting (NS) PA, and multivariate analysis in somatotrophinomas showed a significantly lower AIP immunostaining in invasive versus non-invasive cases (P=0.019). AIP expression was commonly low in other secreting PA. AIP immunostaining was abolished in a minority of AIP(mut) PA, with a frequent loss of cytoplasmic AHR and no evidence of nuclear AHR. In contrast, AIP overexpression in a subset of NS PA could be accompanied by nuclear AHR immunopositivity. We conclude that down-regulation of AIP and AHR may be involved in the aggressiveness of somatotrophinomas. Overall, IHC is a poorly sensitive tool for the screening of AIP mutations. Data obtained on AHR expression suggest that AHR signalling may be differentially affected according to PA phenotype.

Genetic, molecular and clinical features of familial isolated pituitary adenomas.

Pituitary adenomas occur in a familial setting in about 5% of all cases, and over half of these are due to multiple endocrine neoplasia type 1 (MEN1) and Carney's complex (CNC). Non-MEN1/CNC familial pituitary tumours of all tumour phenotypes, known as familial isolated pituitary adenomas (FIPA), were first described in the late 1990s. Clinical features of FIPA differ from those of sporadic pituitary adenomas, as patients with FIPA have a younger age at diagnosis and larger tumours. About 15% of patients with FIPA have mutations in the aryl hydrocarbon receptor-interacting protein gene (AIP), which indicates that FIPA may have a diverse genetic pathophysiology. This article describes the clinical features of FIPA, the tumour pathologies found in this setting and the genetic/molecular data that have recently been reported in FIPA.

Update on familial pituitary tumors: from multiple endocrine neoplasia type 1 to familial isolated pituitary adenoma.

BACKGROUND: Pituitary adenomas occur in a familial setting in about 5% of all cases and over half of these are due to multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). Since the late 1990s, we have described non-MEN1/CNC familial pituitary tumors that include all tumor phenotypes and have named this condition 'familial isolated pituitary adenoma' (FIPA). Clinical features of FIPA differ from those of sporadic pituitary adenomas in that patients with FIPA are often younger and have larger tumors at diagnosis. About 15% of FIPA patients have mutations in the aryl hydrocarbon receptor interacting protein gene (AIP), which indicates that FIPA may have a diverse genetic pathophysiology. We review the clinical features of FIPA, the tumor pathologies found in this setting and the genetic/molecular data that have been recently reported. CONCLUSIONS: Clinically relevant pituitary adenomas are more common than previously thought and occur in a familial setting in about 5% of cases overall. Therefore, specific questioning regarding family history of pituitary disease should be part of the workup of all patients with pituitary adenomas, not just those with acromegaly. FIPA is a useful clinical framework to study the features of pituitary adenomas that occur in a familial setting since it encompasses all tumor phenotypes and heterogeneous/homogeneous expression among affected family members.

Toll-like receptor-4 is expressed in meningiomas and mediates the antiproliferative action of paclitaxel.

Meningiomas are the second most common type of brain and CNS tumors by histology. Surgery and radiotherapy are main treatment options, but meningiomas may be impossible to adequately resect or may regrow after surgery. In spite of many experimental attempts, there is no generally accepted chemotherapeutic approach. We have studied in a series of meningiomas the expression of the Toll-like receptor 4 (TLR4), which apart from its major role as a key factor of the innate immune system, is believed to play a role in tumorigenesis. All meningiomas studied expressed TLR4 mRNA and protein at variable degree. Paclitaxel, a ligand of TLR4, exhibited a dose- and time-dependent growth suppression in both monolayer and spheroid meningioma cell cultures. The knockdown of TLR4 with siRNA in meningioma cell cultures abrogated the inhibitory effect of paclitaxel. The suppressive action of paclitaxel on meningioma cell growth was enhanced in the presence of fluvastatin or the mitogen-actvated protein kinase (ERK1/2) inhibitor PD98059. At least part of the growth suppressive effect was mediated by the induction of apoptosis in meningioma cells by paclitaxel alone or in combination with fluvastatin. In conclusion, our in vitro results suggest that paclitaxel alone or in combination with other inhibitors of cell growth (statins, MAPK inhibitors) could provide a potential tool for the treatment of TLR4 expressing meningiomas.

Current and future perspectives on recombinant growth hormone for the treatment of obesity.

The similarities between patients with untreated growth hormone (GH) deficiency and those with the cardiometabolic syndrome and the beneficial effects of recombinant human GH (rhGH) on body composition have led to the hypothesis that rhGH treatment may have utility in obesity. GH release is reduced in the setting of obesity, primarily due to hyperinsulinism and increased free fatty acid levels. We reviewed the outcomes of 23 clinical studies carried out between 1987 and 2006 that examined the effects of rhGH administration in the obese state. Typically, changes in overall body weight do not occur with rhGH therapy; however, assessment of body composition demonstrates reductions in visceral abdominal fat. Data on the effects of rhGH on lipid and carbohydrate metabolic profiles in obese patients are less clear-cut, with a subset of studies showing a beneficial effect and others a neutral effect. Given the increasing burden of obesity in the general population and the current paucity of effective therapies, it is useful to consider the data on rhGH and obesity from a clinical perspective to highlight potential treatment strategies that harness the somatotropic axis.

High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium.

CONTEXT: Prevalence data are important for assessing the burden of disease on the health care system; data on pituitary adenoma prevalence are very scarce. OBJECTIVE: The objective of the study was to measure the prevalence of clinically relevant pituitary adenomas in a well-defined population. DESIGN: This was a cross-sectional, intensive, case-finding study performed in three regions of the province of Liège, Belgium, to measure pituitary adenoma prevalence as of September 30, 2005. SETTING: The study was conducted in specialist and general medical practitioner patient populations, referral hospitals, and investigational centers. METHODS: Three demographically and geographically distinct districts of the province of Liège were delineated precisely using postal codes. Medical practitioners in these districts were recruited, and patients with pituitary adenomas under their care were identified. Diagnoses were confirmed after retrieval of clinical, hormonal, radiological, and pathological data; full demographic and therapeutic follow-up data were collected in all cases. RESULTS: Sixty-eight patients with clinically relevant pituitary adenomas were identified in a population of 71,972 individuals; the mean (+/- sd) prevalence was 94 +/- 19.3 cases per 100,000 population (95% confidence interval, 72.2 to 115.8). The group was 67.6% female and had a mean age at diagnosis of 40.3 yr; 42.6% had macroadenomas and 55.9% underwent surgery. Prolactinomas comprised 66% of the group, with the rest having nonsecreting tumors (14.7%), somatotropinomas (13.2%), or Cushing's disease (5.9%); 20.6% had hypopituitarism. CONCLUSION: The prevalence of pituitary adenomas in the study population (one case in 1064 individuals) was more than 3.5-5 times that previously reported. This increased prevalence may have important implications when prioritizing funding for research and treatment of pituitary adenomas.

Treatment of pituitary tumors: somatostatin.

Somatostatin is an important physiological regulator of neuroendocrine function across multiple biological systems, including the brain and the gastrointestinal tract. In the pituitary gland, somatostatin regulates the secretion of hormones such as growth hormone and thyroid-stimulating hormone in healthy and pathological states. The short half-life of somatostatin makes it unsuitable for clinical use in chronic diseases, which led to the development of long-acting somatostatin analogs for the treatment of acromegaly and thyroid-stimulating hormone-secreting adenomas, which were administered by intermittent injection twice or three times a day. More recently, depot versions have been developed that permit dosing once every month. This review assesses the efficacy of somatostatin analogs in the treatment of pituitary adenomas, including acromegaly, thyroid-stimulating hormone-secreting tumors, non-functioning adenomas, and Cushing's disease.