Acromegaly Research Articles

Potential biomarkers and lncRNA-mRNA regulatory networks in invasive growth hormone-secreting pituitary adenomas.

Growth hormone-secreting pituitary adenomas (GH-PAs) are common subtypes of functional PAs. Invasive GH-PAs play a key role in restricting poor outcomes. The transcriptional changes in GH-PAs were evaluated. In this study, the transcriptome analysis of six different GH-PA samples was performed. The functional roles, co-regulatory network, and chromosome location of differentially expressed (DE) genes in invasive GH-PAs were explored. Bioinformatic analysis revealed 101 DE mRNAs and 70 DE long non-coding RNAs (lncRNAs) between invasive and non-invasive GH-PAs. Functional enrichment analysis showed that epithelial cell differentiation and development pathways were suppressed in invasive GH-PAs, whereas the pathways of olfactory transduction, retinol metabolism, drug metabolism-cytochrome P450, and metabolism of xenobiotics by cytochrome P450 had an active trend. In the protein-protein interaction network, 11 main communities were characterized by cell- adhesion, -motility, and -cycle; transport process; phosphorus and hormone metabolic processes. The SGK1 gene was suggested to play a role in the invasiveness of GH-PAs. Furthermore, the up-regulated genes OR51B6, OR52E4, OR52E8, OR52E6, OR52N2, MAGEA6, MAGEC1, ST8SIA6-AS1, and the down-regulated genes GAD1-AS1 and SPINT1-AS1 were identified in the competing endogenous RNA network. The RT-qPCR results further supported the aberrant expression of those genes. Finally, the enrichment of DE genes in chromosome 11p15 and 12p13 regions were detected. Our findings provide a new perspective for studies evaluating the underlying mechanism of invasive GH-PAs.

Genetic and Epigenetic Causes of Pituitary Adenomas.

Pituitary adenomas (PAs) can be classified as non-secreting adenomas, somatotroph adenomas, corticotroph adenomas, lactotroph adenomas, and thyrotroph adenomas. Substantial advances have been made in our knowledge of the pathobiology of PAs. To obtain a comprehensive understanding of the molecular biological characteristics of different types of PAs, we reviewed the important advances that have been made involving genetic and epigenetic variation, comprising genetic mutations, chromosome number variations, DNA methylation, microRNA regulation, and transcription factor regulation. Classical tumor predisposition syndromes include multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4) syndromes, Carney complex, and X-LAG syndromes. PAs have also been described in association with succinate dehydrogenase-related familial PA, neurofibromatosis type 1, and von Hippel–Lindau, DICER1, and Lynch syndromes. Patients with aryl hydrocarbon receptor-interacting protein (AIP) mutations often present with pituitary gigantism, either in familial or sporadic adenomas. In contrast, guanine nucleotide-binding protein G(s) subunit alpha (GNAS) and G protein-coupled receptor 101 (GPR101) mutations can lead to excess growth hormone. Moreover, the deubiquitinase gene USP8, USP48, and BRAF mutations are associated with adrenocorticotropic hormone production. In this review, we describe the genetic and epigenetic landscape of PAs and summarize novel insights into the regulation of pituitary tumorigenesis.

A Challenge to Achieve Glycemic Control in a Patient with Diabetes Mellitus

Secondary diabetes mellitus (DM) is a known identity with multiple causes. Acromegaly, a state of growth hormone (GH) excess, is a rare but an established cause of DM. Dysglycemia is present in approximately 50% of patients of acromegaly with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) ranging from 6% to 45% and from 7% to 22%, respectively, and DM has been reported in 16%–56% of patients (Alexopoulou O, Bex M, Kamenicky P, Mvoula AB, Chanson P, Maiter D. Prevalence and risk factors of IGT and DM at diagnosis of acromegaly: A study in 148 patients. Pituitary 2014;17:81-9; Dal J, Feldt-Rasmussen U, Andersen M, Kristensen LØ, Laurberg P, Pedersen L, et al. Acromegaly incidence, prevalence, complications and long-term prognosis: A nationwide cohort study. Eur J Endocrinol 2016;175:181-90). Diabetes in these patients is usually severe and difficult to treat. Glycemic control in these patients is best achieved by treating the underlying GH excess. We report a 60-year-old female patient, case of somatotropinoma, who was referred to diabetic clinic in view of persistent hyperglycemia despite taking multiple antidiabetic medications along with high-dose basal-bolus insulin regimen. Patient had residual pituitary tumor with GH excess and clinically active disease. She was started with somatostatin analogs for the residual disease. Her blood sugar values improved dramatically with episodes of hypoglycemia in between. Patient was shifted to single oral hypoglycemic (OHA) along with low dose insulin. This case highlights the direct association between GH excess and its hyperglycemic effects. Following successful treatment of acromegaly with surgery, irradiation, or medical management, glucose tolerance improves; although complete resolution is rare, OHA/insulin requirement is dramatically reduced.

Integration of RNA-Seq and ATAC-Seq Identifies Key Genes and Chromatin Accessibility Changes in Growth Hormone-Secreting Pituitary Adenoma

Integration of RNA-Seq and ATAC-Seq Identifies Key Genes and Chromatin Accessibility Changes in Growth Hormone-Secreting Pituitary Adenoma

Investigation of Survivin Promoter-31 G/C Polymorphism and Survivin Levels in Acromegaly

Investigation of Survivin Promoter-31 G/C Polymorphism and Survivin Levels in Acromegaly

An introduction to “Gigantism and Acromegaly: Genetics, Diagnosis, and Treatment”

An introduction to “Gigantism and Acromegaly: Genetics, Diagnosis, and Treatment”

Kontrol Edilmesi Zor Yeni Tanı Diyabette Altta Yatan Başka Bir Hastalık Olabilir Mi?

High levels of growth hormone and insulin-like growth factor 1 contribute to tissue proliferation and hypertrophy in patients with acromegaly mostly due to growth hormone-secreting pituitary adenoma. Some phenotypic features of acromegaly that make us to consider in the differential diagnosis are excessive growth of the hands and feet and coarsening facial features. Growth hormone also induces lipolytic activities and insulin resistance, so patients with acromegaly often present with impaired glucose tolerance and type 2 diabetes mellitus. We wanted to share a case with treatment-resistant hyperglycemia which is the cause of presentation of acromegaly.

Old Wine in a New Bottle: Acromegaly Presenting as Diabetic Ketoacidosis

Acromegaly is a rare disease characterised by chronic excess of Growth Hormone (GH) levels. Insulin signalling is impaired, gluconeogenesis is excess and peripheral insulin resistance is increased in acromegaly causing hyperglycaemia and diabetes. Diabetic Ketoacidosis (DKA) is a rare but known complication of diabetes in acromegaly. Most cases of acromegaly come into light due to the classical soft tissue changes in the face and extremities. A high index of suspicion is required to diagnose this condition in early stage. Here, a case of 22-years-old male presented with DKA and on investigation was found to have acromegaly due to a GH secreting pituitary macroadenoma. This management and subsequent follow-up of the case along with review of literature is also done. Such a presentation of acromegaly was rare but rewarding.

Bone densitometry by radiofrequency echographic multi-spectrometry (REMS) in acromegaly patients.

Radiofrequency echographic multi-spectrometry (REMS) is a recently introduced non-ionising technology employed in the evaluation of osteoporosis. The aim of our study was to compare bone mineral density (BMD) in acromegaly patients and healthy controls by performing novel REMS densitometry. The second objective was to analyse the correlation between results of REMS and classical dual-energy X-ray absorptiometry (DXA) in acromegaly patients. We enrolled 33 patients with acromegaly (AG) and 24 controls (CG). The acromegaly patients were divided into two subgroups: well-controlled acromegaly (WCA) and surgery-cured acromegaly (SCA). REMS was performed in all participants, while DXA was performed only in the acromegaly group. IGF-I and GH levels were measured in acromegaly patients. Bone mineral density of the lumbar spine (LS) and the femoral neck (FN) obtained from REMS did not reveal significant differences between AG, CG, WCA, and SCA. Similarly, there were no significant differences in BMD measured by DXA at the LS and at the FN between WCA and SCA. Significant positive correlations between IGF-I concentrations and BMD obtained from both REMS and DXA were detected in the AG and WCA. In the AG and WCA, there were positive correlations between T-scores and LS BMD obtained from both methods. Radiofrequency echographic multi-spectrometry is a potential method in assessment of bone status in acromegaly. Further studies with participation of active disease patients are needed.

Serum Levels of Asprosin, a Novel Adipokine, Are Significantly Lowered in Patients with Acromegaly.

Background Asprosin is a novel identified adipokine secreted mainly by white adipose tissue, which is elevated in metabolic diseases such as diabetes and obesity. Acromegaly is a syndrome caused by pituitary growth hormone (GH) cell adenoma with excessive GH secretion. Serum adipocytokines levels may be involved in abnormal glycolipid metabolism in acromegaly patients. Objectives To investigate serum asprosin levels in acromegaly patients and its correlation with high GH levels and glucolipid metabolic parameters. Methods A retrospective case-control study was conducted and 68 acromegaly patients and 121 controls were included in this study. Clinical information and laboratory examinations were collected and serum asprosin levels were measured by commercial ELISA kits. Results Serum asprosin levels in acromegaly patients were significantly lower than controls (P < 0.001). Serum asprosin levels in patients with the course of acromegaly ≥5 years (compared with <5 years), high area under curve of growth hormone (GH-AUC) after 75 g oral glucose tolerance test (OGTT) (compared with low GH-AUC patients), and high IGF-1 SDS group (compared with low IGF-1 SDS group) were significantly reduced (all P < 0.05). Serum asprosin levels in acromegaly patients were negatively correlated with the course of acromegaly, IGF-1 SDS, nadir growth hormone value (GH-Nadir), and GH-AUC after OGTT. Multiple stepwise linear regression indicated that acromegaly was an independent influencing factor of serum asprosin levels. According to serum asprosin levels tertiles, the risk of acromegaly in the lowest group was 2.67 times higher than the highest group (OR ＝ 3.665, 95% CI 1.677 ∼ 8.007, P=0.001), and the increased risk of the lowest group still existed after adjusting for gender, age, BMI, and TC (Model 2). Conclusions Serum asprosin levels in acromegaly patients are lowered, which may be related to increased blood glucose and reduced body fat mass caused by long-term high GH levels exposure.

Prognostic Factors of Acromegalic Patients with Growth Hormone–Secreting Pituitary Adenoma After Transsphenoidal Surgery

Acromegaly is a rare, chronic disorder that mostly results from growth hormone (GH)-secreting pituitary adenoma. Transsphenoidal surgery is the first-line treatment of this adenoma. This study aimed to identify factors associated with remission outcome in patients with GH-secreting pituitary adenomas following transsphenoidal surgery. Patients with GH-secreting pituitary adenomas who underwent transsphenoidal surgery for tumor removal at Songklanagarind Hospital between January 2003 and December 2019 were retrospectively reviewed. The primary outcome was the remission of disease at the last follow-up using 2000 and 2010 consensus criteria. Using logistic regression analysis, various factors were analyzed for association with disease remission outcome. This study included 51 patients. The remission rate of GH-secreting pituitary microadenomas and macroadenomas following transsphenoidal surgery were 100% and 43.75%, respectively. Multivariate analysis showed that preoperative insulin-like growth factor 1 index ≥2.5 and Knosp classification grade 3-4 were significantly associated with nonremission outcome (P < 0.001 and P=0.012, respectively). Patients with both of these factors had poor outcomes and never achieved remission after treatment, while patients with neither of these factors had high remission rates (87.5%) following surgery. Four of 6 (66.7%) patients who underwent repeat surgery gained remission. Preoperative insulin-like growth factor 1 index ≥2.5 and Knosp classification grade 3-4 were important prognostic factors that determined remission outcome after treatment. Patients who have both of these poor prognostic factors should be aggressively treated with surgery, medication, and probably radiation to optimally control the disease.

Lifelong Excess in GH Elicits Sexually Dimorphic Effects on Skeletal Morphology and Bone Mechanical Properties.

Excess in growth hormone (GH) levels, seen in patients with acromegaly, is associated with increases in fractures. This happens despite wider bones and independent of bone mineral density. We used the bovine GH (bGH) transgenic mice, which show constitutive excess in GH and insulin-like growth factor 1 (IGF-1) in serum and tissues, to study how lifelong increases in GH and IGF-1 affect skeletal integrity. Additionally, we crossed the acid labile subunit (ALS) null (ALSKO) to the bGH mice to reduce serum IGF-1 levels. Our findings indicate sexually dimorphic effects of GH on cortical and trabecular bone. Male bGH mice showed enlarged cortical diameters, but with marrow cavity expansion and thin cortices as well as increased vascular porosity that were associated with reductions in diaphyseal strength and stiffness. In contrast, female bGH mice presented with significantly smaller-diameter diaphysis, with greater cortical bone thickness and with a slightly reduced tissue elastic modulus (by microindentation), ultimately resulting in overall stronger, stiffer bones. We found increases in C-terminal telopeptide of type 1 collagen and procollagen type 1N propeptide in serum, independent of circulating IGF-1 levels, indicating increased bone remodeling with excess GH. Sexual dimorphism in response to excess GH was also observed in the trabecular bone compartment, particularly at the femur distal metaphysis. Female bGH mice preserved their trabecular architecture during aging, whereas trabecular bone volume in male bGH mice significantly reduced and was associated with thinning of the trabeculae. We conclude that pathological excess in GH results in sexually dimorphic changes in bone architecture and gains in bone mass that affect whole-bone mechanical properties, as well as sex-specific differences in bone material properties. © 2022 American Society for Bone and Mineral Research (ASBMR).

Опыт использования пэгвисоманта в комбинированном лечении акромегалии

Опыт использования пэгвисоманта в комбинированном лечении акромегалии

Вклад аналогов соматостатина в реализацию пациенториентированного подхода к лечению акромегалии

Вклад аналогов соматостатина в реализацию пациенториентированного подхода к лечению акромегалии

Reference Ranges of Serum Insulin-Like Growth Factor-I and Insulin-Like Growth Factor Binding Protein-3: Results from a Multicenter Study in Healthy Korean Adults.

Insulin-like growth factor-I (IGF-I) plays a pivotal role in the diagnosis and treatment of growth hormone (GH) excess or deficiency. The GH study group of the Korean Endocrine Society aims to establish the Korean reference ranges of serum IGF-I and insulin-like growth factor binding protein-3 (IGFBP-3) and assess the relationship between IGF-I and IGFBP-3 and clinical parameters. Fasting serum was collected from healthy Korean adults at health promotion centers of five hospitals nationwide. Serum IGF-I and IGFBP-3 were measured via an immunoradiometric assay using a DSL kit (Diagnostic Systems Laboratories). Serum samples from 354 subjects (180 male, 174 female) were analyzed based on sex at 10-year intervals from 21 to 70 years. IGF-I levels were inversely correlated with age. After adjustment of age, the IGF-I/IGFBP-3 ratio was significantly negatively associated with blood pressure and free thyroxine and positively associated with weight, hemoglobin, creatinine, alanine transferase, fasting glucose, and thyroid stimulating hormone. Therefore, age- and sex-specific reference ranges of serum IGF-I and IGFBP-3 can be efficient in evaluating GH excess or deficiency in Korean population.

Growth hormone deficiency and excess alter the gut microbiome in adult male mice

The gut microbiome has been implicated in host metabolism, endocrinology, and pathophysiology. Furthermore, several studies have shown that gut bacteria impact host growth, partially mediated through the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis. Yet, no study to date has examined the specific role of GH on the gut microbiome. Our study thus characterized the adult gut microbial profile and intestinal phenotype in GH gene-disrupted (GH-/-) mice (a model of GH deficiency) and bovine GH transgenic (bGH) mice (a model of chronic, excess GH action) at 6 months of age. Both the GH-/- and bGH mice had altered microbial signatures, in opposing directions at the phylum and genus levels. For example, GH-/- mice had significantly reduced abundance in the Proteobacteria, Campylobacterota, and Actinobacteria phyla, whereas bGH mice exhibited a trending increase in those phyla compared with respective controls. Analysis of maturity of the microbial community demonstrated that lack of GH results in a significantly more immature microbiome while excess GH increases microbial maturity. Several common bacterial genera were shared, although in opposing directions, between the 2 mouse lines (e.g., decreased in GH-/- mice and increased in bGH mice), suggesting an association with GH. Similarly, metabolic pathways like acetate, butyrate, heme B, and folate biosynthesis were predicted to be impacted by GH. This study is the first to characterize the gut microbiome in mouse lines with altered GH action and indicates that GH may play a role in the growth of certain microbiota thus impacting microbial maturation and metabolic function.

HOMA-IR in acromegaly: a systematic review and meta-analysis.

This review is aimed at examining whether the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) is higher in Caucasian, adult, treatment-naïve patients with acromegaly (ACRO) than in the reference population independently of diabetes presence and to evaluate the impact of treatment [surgery and somatostatin analogues (SSAs)] on its assessment. We systematically reviewed in PubMed and Web of Science from July 1985 to December 2019, registered with the code number CRD42020148737. The inclusion criteria comprised studies conducted in Caucasian adult treatment-naïve patients with active ACRO in whom HOMA-IR or basal insulin and glucose were reported. Three reviewers screened eligible publications, extracted the outcomes, and assessed the risk of biases. Of 118 originally selected studies, 15 met the inclusion criteria. HOMA-IR was higher in ACRO than the reference population, with mean difference and (95% confidence intervals) of 2.04 (0.65-3.44), even in ACRO patients without diabetes, 1.89 (1.06-2.73). HOMA-IR significantly decreased after treatment with either surgery or SSAs - 2.53 (- 3.24- - 1.81) and - 2.30 (- 3.05- - 1.56); respectively. However, the reduction of HOMA-IR due to SSAs did not improve basal glucose. HOMA-IR in treatment-naïve ACRO patients is higher than in the reference population, even in patients without diabetes. This finding, confirms that insulin resistance is an early event in ACRO. Our results also suggest that HOMA-IR is not an adequate tool for assessing insulin resistance in those patients treated with SSAs.

Differential gene signature in adipose tissue depots of growth hormone transgenic mice.

Bovine growth hormone (bGH) transgenic mice mimic the clinical condition of acromegaly, having high circulating growth hormone (GH) levels. These mice are giant, have decreased adipose tissue (AT) mass, impaired glucose metabolism and a shortened lifespan. The detrimental effects of excess GH have been suggested, in part, to be a result of its depot-specific actions on AT. To investigate this relationship, we evaluated gene expression, biological mechanisms, cellular pathways and predicted microRNA (miRNA) in two AT depots (subcutaneous [Subq] and epididymal [Epi]) from bGH and littermate controls using RNA sequencing analysis. Two analyses on the differentially expressed genes (DEG) were performed: (i) comparison of the same AT depot between bGH and wild-type (WT) mice (genotype comparison) and (ii) comparison of Subq and Epi AT depots within the same genotype (depot comparison). For the genotype comparison, we found a higher number of significant DEG in the Subq AT depot of bGH mice compared to WT controls, corroborating previous reports that GH has a greater impact on the Subq depot. Furthermore, most of the DEG in bGH mice were not shared by WT mice, suggesting that excess GH induces the expression of genes not commonly present in AT. Through gene ontology and pathway analysis, the genotype comparison revealed that the DEG of the Subq depot of bGH mice relate to fatty acid oxidation, branched-chain amino acid degradation and the immune system. Additionally, the AT depot comparison showed that the immune cell activation and T-cell response appear up-regulated in the Subq compared to the Epi AT depot. The miRNA prediction also suggested a modulation of T-cell-related biological process in Subq. In summary, the present study provides a unique resource for understanding the specific differences in gene expression that are driven by both excess GH action and AT depot location.

Gamma Knife radiosurgery for acromegaly: Evaluating the role of the biological effective dose associated with endocrine remission in a series of 42 consecutive cases.

Stereotactic radiosurgery (SRS) is a valuable treatment option for persistent and/or recurrent acromegaly secondary to growth hormone (GH) secreting pituitary adenoma (PA). Here, we assess the role of biological effective dose (BED) received by PA treated with SRS in relation with endocrine remission. Forty-two patients (minimum 6months follow-up) were included. Mean marginal dose was 27.7 (median 28, 20-35), and mean BED received by tumour was 193.1Gy2.47 (median 199.7, 64.1-237.1). Based on the median values, we divided the patients in high tumour BED group (H-BEDtm, 199.7-237.1Gy2.47, n=12) and low BED one (L- BEDtm, 64.1-199.7Gy2.47 , n=10). The two groups did not differ by pretherapeutic IGF-1 levels (p=.1) or by the prescribed dose (p=.6). Mean follow-up period was 62.5months (median 60.5, 9-127). Probability of IGF-1 normalization was 65% at 3years and 72.4% at 4years, remaining stable until last follow-up. Twenty-two (52.4%) patients had complete endocrine remission in absence of any Somatostatin analogues. Actuarial rates were 33% at 3years and 57.4% at 7years, further remaining stable during follow-up course. In univariate analysis, only statistically significant parameter was pretherapeutic serum IGF-1 and IGF-1 index (p=.01). Five patients (5/26, 19.3%) without previous hypopituitarism developed new pituitary insufficiency. H-BEDtm was associated with higher rates of endocrine remission compared with L-BEDtm, with actuarial probability of 70.2% versus 48.2% at 9years, although this did not reach statistical significance (p>.05). Our study confirms that SRS by Gamma Knife is safe and effective for GH-secreting PA. Pretherapeutic serum levels of IGF-1 were only statistically significant parameter for endocrine remission.

Machine learning in predicting early remission in patients after surgical treatment of acromegaly: a multicenter study.

Accurate prediction of postoperative remission is beneficial for effective patient-physician communication in acromegalic patients. This study aims to train and validate machine learning prediction models for early endocrine remission of acromegalic patients. The training cohort included 833 patients with growth hormone (GH) secreting pituitary adenoma from 2010 to 2018. We trained a partial model (only using pre-operative variables) and a full model (using all variables) to predict off-medication endocrine remission at six-month follow-up after surgery using multiple algorithms. The models were validated in 99 prospectively collected patients from a second campus and 52 patients from a third institution. C-statistic and the accuracy of the best partial model was 0.803 (95% CI 0.757-0.849) and 72.5% (95% CI 67.6-77.5%), respectively. C-statistic and the accuracy of the best full model was 0.888 (95% CI 0.861-0.914) and 80.3% (95% CI 77.5-83.1%), respectively. The c-statistics (and accuracy) of using only Knosp grade, total resection, or postoperative day 1 GH level as the single predictor were lower than our partial model or full model (p < 0.001). C-statistics remained similar in the prospective cohort (partial model 0.798, and full model 0.903) and in the external cohort (partial model 0.771, and full model 0.871). A web-based application integrated with the trained models was published at https://deepvep.shinyapps.io/Acropred/ . We developed and validated interpretable and applicable machine learning models to predict early endocrine remission after surgical resection of a GH-secreting pituitary adenoma. Predication accuracy of the trained models were better than those using single variables.