Acromegaly Research Articles

Could predict the postoperative rosnance the acromegaly cure?

Could predict the postoperative rosnance the acromegaly cure?

Hyper Secretion of GH: Pituitary Gigantism

Gigantism refers to a condition characterized by extreme physical size and stature. By definition, this originates during infancy, childhood or adolescence, when epiphyseal growth plates remain open. Although the term gigantism may be applied to a number of non-hormonally mediated overgrowth conditions in children, it is often used to specifically denote growth hormone(GH) excess. GH excess during childhood and adolescence is extremely rare, with the total number of reported cases thus far numbering only in the hundreds. Herein we present such a case.

Phosphoproteome profiling revealed abnormally phosphorylated AMPK and ATF2 involved in glucose metabolism and tumorigenesis of GH-PAs.

Protein phosphorylation plays a key role in tumorigenesis and progression. However, little is known about the phosphoproteome profiles of growth hormone-secreting pituitary adenomas (GH-PAs). The aim of this study was to identify critical biomarkers and signaling pathways that might play important roles in GH-PAs and may, therefore, represent potential therapeutic targets. The differential phosphoprotein expression patterns involved in GH-PAs were investigated by nano-LC-MS/MS in a group of samples. The phosphoprotein expression data were analyzed by bioinformatics. The expression levels of the candidate phosphorylated AMPK (ser496) and ATF2 (ser112) were validated by Western blot analysis in another group of samples. A total of 1213 phosphorylated protein sites corresponding to 667 proteins were significantly different between GH-PAs and healthy pituitary glands. Among these phosphorylated sites, 871 exhibited lower levels of phosphorylation in GH-PAs. Moreover, 140 novel phosphosites corresponding to 93 proteins were differentially phosphorylated between GH-PAs and healthy pituitary glands, 101 of which showed decreased phosphorylation in GH-PAs. The majority of differentially expressed phosphorylated proteins were significantly enriched in glycolysis and the AMPK signaling pathway in GH-PAs. The AMPK signaling pathway was demonstrated to be inhibited in GH-PAs by pathway activity analysis (z score = - 2.324). Notably, the phosphorylated levels of AMPK (ser496) and ATF2 (ser112) were significantly lower in GH-PAs than in healthy pituitary glands. These findings suggest that decreased phosphorylation of the AMPK/ATF2 pathway may be critical for glucose metabolism and tumorigenesis in GH-PAs.

Screening for germline KCNQ1 and KCNE2 mutations in a set of somatotropinoma patients.

ObjectiveRecently, mutations in KCNQ1, a potassium channel gene usually linked to long QT syndrome, were reported to cause maternally inherited gingival fibromatosis and growth hormone deficiency (GHD). Expression of the mutated KCNQ1 with the auxiliary potassium channel subunit KCNE2 was shown to reduce pituitary hormone secretion in functional experiments. Here, we investigated if germline mutations in KCNQ1 and KCNE2 were present in patients with somatotropinomas, which represent a model of growth hormone excess.Design and methods KCNQ1 and KCNE2 were screened for germline mutations in 53 patients with acromegaly by Sanger sequencing. Effects of the variants were predicted by in silico tools.ResultsOnly deep intronic and synonymous polymorphisms were detected in KCNQ1. These findings were likely insignificant based on in silico predictions and the variants’ frequencies in the general population. In KCNE2, a heterozygous c.22A>G, p.(Thr8Ala) mutation with unknown significance was found in three patients. It was present in the database controls with a frequency of 0.0038.ConclusionsKCNQ1 or KCNE2 mutations do not appear to account for somatotropinoma formation, although larger patient series are needed to validate the findings.

Abstract #843 What to Expect When She is Expecting: Acromegaly in Pregnancy

Abstract #843 What to Expect When She is Expecting: Acromegaly in Pregnancy

Expression of the long non-coding RNA H19 and MALAT-1 in growth hormone-secreting pituitary adenomas and its relationship to tumor behavior

Aggressive growth hormone-secreting pituitary adenomas (GHPAs) represent an important clinical problem in patients with acromegaly. Surgical therapy, although often the mainstay of treatment for GHPAs, is less effective in aggressive GHPAs due to their invasive and destructive growth patterns, and their proclivity for infrasellar invasion. LncRNAs are important players in cancer development and emerging in various fundamental biological processes. In the present study, qRT-PCR was performed to examine the expression of lncRNA H19 and MALAT-1 in invasive and non-invasive GHPAs. Our results revealed that the expression of lncRNA H19 was remarkably higher in invasive GHPAs, however, there was no significant differences between the expression of lncRNA MALAT-1 in invasive GHPAs and non-invasive GHPAs, suggesting that lncRNA H19 may play an important role in GHPA invasion. LncRNA H19 might be a target for the study of GHPAs invasion, and a potential index for the diagnosis or prognosis of GHPAs.

A rare challenging case of co-existent craniopharyngioma, acromegaly and squamous cell lung cancer.

SummaryCo-existence of craniopharyngioma and acromegaly has been very rarely reported. A 65-year-old man presented with visual deterioration, fatigue and frontal headaches. Magnetic resonance imaging revealed a suprasellar heterogeneous, mainly cystic, 1.9 × 2 × 1.9 cm mass compressing the optic chiasm and expanding to the third ventricle; the findings were consistent with a craniopharyngioma. Pituitary hormone profile showed hypogonadotropic hypogonadism, mildly elevated prolactin, increased insulin-like growth factor 1 (IGF-1) and normal thyroid function and cortisol reserve. The patient had transsphenoidal surgery and pathology of the specimen was diagnostic of adamantinomatous craniopharyngioma. Post-operatively, he had diabetes insipidus, hypogonadotropic hypogonadism and adrenocorticotropic hormone and thyroid-stimulating hormone deficiency. Despite the hypopituitarism, his IGF-1 levels remained elevated and subsequent oral glucose tolerance test did not show complete growth hormone (GH) suppression. Further review of the pre-operative imaging revealed a 12 × 4 mm pituitary adenoma close to the right carotid artery and no signs of pituitary hyperplasia. At that time, he was also diagnosed with squamous cell carcinoma of the left upper lung lobe finally managed with radical radiotherapy. Treatment with long-acting somatostatin analogue was initiated leading to biochemical control of the acromegaly. Latest imaging has shown no evidence of craniopharyngioma regrowth and stable adenoma. This is a unique case report of co-existence of craniopharyngioma, acromegaly and squamous lung cell carcinoma that highlights diagnostic and management challenges. Potential effects of the GH hypersecretion on the co-existent tumours of this patient are also briefly discussed.Learning points:Although an extremely rare clinical scenario, craniopharyngioma and acromegaly can co-exist; aetiopathogenic link between these two conditions is unlikely.Meticulous review of unexpected biochemical findings is vital for correct diagnosis of dual pituitary pathology.The potential adverse impact of GH excess due to acromegaly in a patient with craniopharyngioma (and other neoplasm) mandates adequate biochemical control of the GH hypersecretion.

Three-dimensional speckle tracking echocardiography-derived left atrial deformation analysis in acromegaly (Results from the MAGYAR-Path Study).

Acromegaly is a chronic and disfiguring hormonal disease caused by a benign growth hormone-secreting pituitary adenoma in most of the cases. The objective of this study was to investigate three-dimensional (3D) speckle tracking echocardiography (3DSTE)-derived left atrial (LA) volumetric and functional properties in patients with acromegaly. It was also examined whether the activity of acromegaly is associated with further alterations in these LA parameters. A total of 23 patients with acromegaly were involved in this study. Due to inadequate image quality, 4 patients were excluded from the 3DSTE analysis. The mean age of the remaining acromegalic subjects was 58.5±13.1years (7males). The control group consisted of 21 age- and gender-matched healthy subjects (mean age 51.8±10.3years, 10males). Maximum (44.8±12.7mL vs 78.7±25.4mL, P<.05), minimum (24.1±9.0mL vs 44.5±15.5mL, P<.05), and preatrial contraction (35.5±11.2mL vs 66.0±22.8mL, P<.05) LA volumes were significantly different between all acromegaly patients compared with controls. Increased peak global and mean segmental radial and 3D strains and decreased LA circumferential strain (CS) could be detected in all acromegaly patients as compared to healthy subjects. Significant correlation could be detected between insulin-like growth factor 1 (IGF-1) index and peak superior LA-CS (r=.49, P=.05) in acromegaly. Acromegaly is associated with increased LA volumes and changes in LA functional properties.

Polyostotic Fibrous Dysplasia With and Without McCune-Albright Syndrome-Clinical Features in a Nordic Pediatric Cohort.

Fibrous dysplasia (FD) presents as skeletal lesions in which normal bone is replaced by abnormal fibrous tissue due to mosaic GNAS mutation. McCune-Albright syndrome (MAS) refers to FD combined with skin (café-au-lait) and endocrine manifestations. This study describes the clinical childhood manifestations of polyostotic FD and MAS in a Nordic cohort. We retrospectively reviewed a cohort of pediatric patients (n = 16) with polyostotic FD with or without MAS diagnosed and followed in two Nordic Pediatric tertiary clinics between 1996 and 2017. Half of the 16 patients with polyostotic FD presented with MAS. All patients with MAS (n = 8) had café-au-lait spots, and either gonadotropin-independent precocious puberty (PP) (girls; n = 5) or abnormal testicle structure (boys, n = 3). None manifested hyperthyroidism or growth hormone excess. Mild hypophosphatemia was common (11/16), but none had signs of hypophosphatemic rickets. Craniofacial bone involvement was found in 12 patients (75%); in 5 of these, skeletal lesions were limited to craniofacial area. One child with craniofacial disease had lost vision due to optic nerve damage. Eleven (69%) patients had sustained a fracture at FD lesion, over half of them requiring surgical fixation of the fracture, most commonly in the proximal femur. The first symptoms leading to FD/MAS diagnosis included skull/facial asymmetry (n = 4), PP (n = 3), abnormal gait (n = 3), pathologic fracture (n = 3), wide-spread café-au-lait spots (n = 1), headache (n = 1), and vision loss (n = 1). Polyostotic FD and MAS remain diagnostic and therapeutic challenges because of the broad clinical spectrum. Recurrent fractures, pain, and even vision loss may impair the quality of life in children with FD.

Leptin Level in Newly Diagnosed Iraqi Acromegaly Patients

Acromegaly is a serious endocrine disease resulting from an increase of growth hormone in the blood. Excessive growth hormone secretion may be caused by an adenoma of the pituitary. This study was designed to assess the effect of serum leptin concentration on acromegaly patients with both gender and its relation with some biochemical analysis. The study conducted 96 subjects (48 acromegaly patients and 48 controls) aged between (30-70) years who were attending the National Diabetic Center/ Al-Mustansirya University and AlYarmuk Teaching Hospital. Fasting blood sugar, lipid profile, growth hormone, insulin like growth factor-1, and serum leptin concentrations were measured for each individual. The results explained a significant increased in body mass index, triacylglycerol and low density lipoprotein cholesterol, (P&lt;0.05) in acromegaly patients when compared with control group. Fasting blood sugar, serum growth hormone and serum insulin like growth factor-1 concentrations explained a highly significant increased, (P&lt;0.01). While serum leptin concentration was significantly decreased. Fasting blood sugar, triacylglycerol, low density lipoprotein, serum growth hormone, serum insulin like growth factor-1, and serum leptin concentrations showed a significant increased in female patients when compared with male acromegaly patients, (P&lt;0.05). This study showed that higher serum leptin levels with higher concentrations of triacylglycerol and low density lipoprotein cholesterol might play a vital function in the progress of acromegaly disease. Also, high serum leptin levels observed in female acromegaly patients when compared with male acromegaly patients, the present study suggested the role of leptin hormone as one of the biomarkers affecting in acromegaly patients..

Oro-dental pathologies in acromegaly.

Oro-dental pathologies (ODP) such as enlargement of the tongue, mandibular prognathism, and spaced teeth are characteristic features of acromegaly. Their frequency of occurrence during the course of the disease is largely unresolved. Purpose of this study was to assess ODP and oro-dental treatments in patients with acromegaly with regard to the length of the diagnostic process, tumor histology, and quality of life (QoL). Single-center retrospective survey study using questionnaires on dental symptoms, diagnostic process, and treatment in patients with acromegaly operated on a growth hormone-secreting pituitary adenoma. The association between ODP and QoL was assessed using the Short-Form 36 (SF-36) Health Survey. 145/314 patients completed the questionnaires. 80.7% were affected by any ODP, most frequently enlargement of the tongue (57.9%), spaced teeth (42.8%), mandibular growth (24.1%), and mandibular prognathism (22.1%). ODP were significantly more frequent in patients with sparsely vs. densely granulated adenomas (p = 0.045). Early diagnosis within 2 years was associated with significantly fewer ODP than later diagnosis (68.5 vs. 87.2%, p = 0.009). Treatments included dental crowns (16.6%), dental bridges (12.4%), dental implants (9.7%), dental prostheses (3.4%), orthodontal (i.e., braces, 6.9%), and surgical correction of the teeth (2.1%). Physical QoL was significantly lower in patients with ODP than in those without (p = 0.014). In our large series of patients, four of five patients were affected by ODP at any time during the course of the disease. The results highlight the importance of early identification and treatment of oro-dental problems in patients with acromegaly as hallmarks of the disease.

Nature Reviews Endocrinology: Acromegaly

Acromegaly is a rare disease most often caused by the prolonged secretion of excess growth hormone from a pituitary adenoma. The disease is associated with multiple significant comorbidities and increased mortality. The delay to diagnosis is often long. This may be because of low disease awareness among health care professionals, the insidious onset of differentiating features, and because patients are likely to present with complaints typical of other conditions more frequently seen in primary care. Early identification of acromegaly facilitates prompt treatment initiation and may minimize the permanent effects of excess growth hormone. The primary treatment for many patients will be pituitary surgery, although not all patients will be eligible for surgery or achieve a surgical cure

Genomic Alterations and Complex Subclonal Architecture in Sporadic GH-Secreting Pituitary Adenomas.

The molecular pathogenesis of growth hormone-secreting pituitary adenomas is not fully understood. Cytogenetic alterations might serve as alternative driver events in GNAS mutation-negative somatotroph tumors. We performed cytogenetic profiling of pituitary adenomas obtained from 39 patients with acromegaly and four patients with sporadic gigantism by using array comparative genomic hybridization analysis. We explored intratumor DNA copy-number heterogeneity in two tumor samples by using DNA fluorescence in situ hybridization (FISH). Based on copy-number profiles, we found two groups of adenomas: a low-copy-number alteration (CNA) group (<12% of genomic disruption, 63% of tumors) and a high-CNA group (24% to 45% of genomic disruption, 37% of tumors). Arm-level CNAs were the most common abnormalities. GNAS mutation-positive adenomas belonged exclusively to the low-CNA group, whereas a subgroup of GNAS mutation-negative adenomas had a high degree of genomic disruption. We detected chromothripsis-related CNA profiles in two adenoma samples from an AIP mutation-positive patient with acromegaly and a patient with sporadic gigantism. RNA sequencing of these two samples identified 17 fusion transcripts, most of which resulted from chromothripsis-related chromosomal rearrangements. DNA FISH analysis of these samples demonstrated a subclonal architecture with up to six distinct cell populations in each tumor. Somatotroph pituitary adenomas display substantial intertumor and intratumor DNA copy-number heterogeneity, as revealed by variable CNA profiles and complex subclonal architecture. The extensive cytogenetic burden in a subgroup of GNAS mutation-negative somatotroph adenomas points to an alternative tumorigenic pathway linked to genomic instability.

Risk category system to identify pituitary adenoma patients with AIP mutations

BackgroundPredictive tools to identify patients at risk for gene mutations related to pituitary adenomas are very helpful in clinical practice. We therefore aimed to develop and validate a reliable risk...

Presurgical treatment with somatostatin analogues in growth hormone-secreting pituitary adenomas: A long-term single-center experience

ObjectiveAcromegalic patients with macro- or giant adenomas often had poor prognosis after surgery. Somatostatin analogues (SSAs) show high effectiveness in both tumor shrinkage and serum GH reduction. But the role of SSAs in pre-surgical treatment and the management among macro- and giant adenomas remains controversial. Patients and MethodsA total of 100 acromegalic patients with macro- or giant adenomas that underwent surgery in our institution between January 2010 and December 2016 were enrolled in the current retrospective study. The relationships between several potential parameters and surgical outcomes were further analyzed. ResultsThe overall long-term remission rate was 45% accompanied by gross total resection (GTR) rate of 44%. GTR (adjusted OR = 16.346; p = .001) and nadir GH level on OGTT 7 days after surgery (GH-7, adjusted OR = 0.660, p = .039) showed predictive significance for remission after surgery. Tumor size and invasiveness as well as cavernous sinus invasion were risk factors for residual tumor. For invasive macro- or giant adenomas, 6 of 15 patients achieved long-term remission with SSA pre-treatment whereas none of the 18 patients without any preoperative treatment was endocrine controlled. ConclusionsAcromegalic patients did not gain more benefits from SSAs pretreatment. But, pre-treatment with SSA could be recommended to patients with invasive macro- or giant adenomas for significant improvement in long-term remission. GTR and GH-7 could be significant predictors in postoperative management of macro- or giant adenomas.

Postoperative Diabetes Insipidus and Hyponatremia in Children after Transsphenoidal Surgery for Adrenocorticotropin Hormone and Growth Hormone Secreting Adenomas

To define the incidence and risk factors of postoperative sodium alterations in pediatric patients undergoing transsphenoidal surgery (TSS) for adrenocorticotropic hormone and growth hormone secreting pituitary adenomas. We retrospectively reviewed 160 patients ≤18 years of age who had TSS for pituitary adenomas at our institution from 1999 to 2017. Variables included daily serum sodium through postoperative day 10, urine specific gravity, and medications administered. We examined associations between sex, repeat surgery, manipulation of the posterior pituitary (PP), tumor invasion into the PP, tumor type and size, cerebrospinal fluid (CSF) leak, lumbar drain insertion, body mass index, puberty, and development of diabetes insipidus (DI) or syndrome of inappropriate antidiuretic hormone secretion (SIADH). Mean age was 12.9 ± 3.4 years (female = 81). Patients had adrenocorticotropic hormone (150/160) and growth hormone (10/160) producing adenomas. Forty-two (26%) patients developed DI. Among the 37 of 160 who required desmopressin acutely, 13 of 37 required it long term. Risk of long-term need for desmopressin was significantly higher in patients who had CSF leak 9 of 48 (P = .003), lumbar drain 6 of 30 (P = .019), manipulation 11 of 50 (P < .001), or invasion 4 of 15 (P = .022) of the PP. Sixty patients developed hyponatremia, 19 because of SIADH, 39 to hypotonic fluids and 2 to cerebral salt wasting syndrome. Patients with SIADH were placed on fluid restriction; 1 received salt tablets. Among 160 children who underwent TSS for pituitary adenomas, the incidence of DI and SIADH after TSS was 26% and 14%, respectively. Combined risk factors for DI and/or SIADH include female sex, manipulation of and/or tumor invasion into the PP, and CSF leak or lumbar drain. ClinicalTrials.gov: NCT00001595 and NCT00060541.

The comprehensive impact on human body induced by resolution of growth hormone excess.

Chronic excess of growth hormone (GH) often leads to systemic complications. The reversibility of these complications after GH resolution is not fully understood. To investigate when and to what extent will the comorbidities be ameliorated. We conducted a prospective study comprising 24 patients with acromegaly, who achieved remission after transsphenoidal surgery. The dynamic changes of endocrine, cardiovascular, respiratory, sleep, bone and morphology parameters were evaluated at enrollment and 1 week, 1 month, 3 months, 6 months and 12 months after surgery. Random GH dropped by 98.4% at the first day postoperatively. IGF-I index dropped by 50% and 64% at 1 week and 1 month respectively and remained unchanged onwards. Glucose metabolism improved significantly at 1 week and stabilized at 1 month. Testosterone in male patients recovered to normal range since 1 month. Systolic blood pressures dropped markedly at 3 months while diastolic blood pressures fell mildly at later visits. Abnormal lung function showed no improvement. The decrease of bone formation and resorption markers occurred at 1 week and 3 months, respectively. At 1 month, the tongue area declined while the airway volume increased significantly, accompanied with improved obstructive sleep apnea syndrome. Extremities, lips and nasal ala became smaller since 1 week. Liver, kidney and spleen volumes declined by 6.4, 15.9, 9.2%, respectively at 1 month. The volumes of pancreas and adrenal showed no change. The rapid resolution of excessive GH led to the reversible changes of systemic comorbidities in a time-dependent and organ-specific manner.

Effects of active acromegaly on bone mRNA and microRNA expression patterns.

To evaluate the response of bone to chronic long-term growth hormone (GH) and insulin-like growth factor-1 (IGF1) excess by measuring the expression of selected mRNA and microRNA (miR) in bone tissue samples of patients with active acromegaly. Case-control study. Bone tissue samples were obtained during transsphenoidal adenomectomy from the sphenoid bone (sella turcica) from 14 patients with clinically and biochemically confirmed acromegaly and 10 patients with clinically non-functioning pituitary adenoma (NFPA) matched by sex and age. Expression of genes involved in the regulation of bone remodeling was studied using quantitative polymerase chain reaction (qPCR). Of the genes involved in osteoblast and osteoclast activity, only alkaline phosphatase (ALP) mRNA was 50% downregulated in patients with acromegaly. GH excess caused increased expression of the Wnt signaling antagonists (DKK1) and agonists (WNT10B) and changes in the levels of miR involved in mesenchymal stem cell commitment to chondrocytes (miR-199a-5p) or adipocytes (miR-27-5p, miR-125b-5p, miR-34a-5p, miR-188-3p) P < 0.05; q < 0.1. Relevant compensatory mechanisms were found through the changes in miR involved in osteoblastogenesis (miR-210-5p, miR-135a-5p, miR-211, miR-23a-3p, miR-204-5p), but the expression of TWIST1 was 50% downregulated and RUNX2 was unchanged. Acromegaly had minimal effects on tested mRNAs specific to osteoblast or osteoclast function except for downregulated ALP expression. The expressions of miR known to be involved in mesenchymal stem cell commitment and downregulated TWIST1 expression suggest acromegaly has a negative effect on osteoblastogenesis.

Management of Pituitary Adenomas: Mononostril Endoscopic Transsphenoidal Surgery.

Introduction:The endoscopic transsphenoidal approach for pituitary adenomas and other sellar lesions is quickly becoming the procedure of choice in their surgical management. The most common approach is binostril three-hand technique which requires a large exposure and subjects both nasal cavities to potential trauma. To reduce nasal morbidity, we employ a mononostril two-hand technique with the help of the endoscope holder. In this research, we review our series to determine efficacy of this approach in the management of pituitary adenomas.Methods:We performed a retrospective analysis of our initial series of 64 consecutive patients with pituitary adenomas operated by the same surgical team from 2008 till 2014 using a mononostril endoscopic approach. After categorizing the lesions into microadenomas, noninvasive macroadenomas, and invasive macroadenomas, we reviewed the radiological and biochemical outcomes of the surgeries after 3 months, 12 months, and 18 months. We also assessed recurrences and complications. Extent of resection was divided into gross total resection, near total resection (>90% resection), and partial resection for the remaining.Results:Our results show resection rates comparable to most series in the literature, with a gross total resection of 87% in non-invasive macroadenomas, and surgical disease control in 75% of invasive nonfunctioning adenomas. The remission rate in Cushing’s disease was 81%, where it achieved up to 58% surgical remission in growth hormone secreting pituitary adenomas (including the invasive adenomas). The complication rate was very low.Conclusion:We conclude that the mononostril endoscopic approach is well suited for most pituitary tumor operations and carries comparable remission and resection rates to most endoscopic series with minimal complications and nasal morbidity.

The Association of Acromegaly and Visfatin

The Association of Acromegaly and Visfatin