Acromegaly Research Articles

Next-generation sequencing of microRNAs reveals a unique expression pattern in different types of pituitary adenomas.

Pituitary adenomas (PAs) are considered the most common intracranial tumor to cause serious morbidity because of dysregulated pituitary hormone secretions. Aberrant expression of microRNAs (miRNAs) is correlated with the development and function of the pituitary gland as well as the tumorigenesis of hypothalamic-pituitary axis-related pituitary tumors. In this study, we showed the differential expression patterns of miRNAs in NFPAs (nonfunctioning pituitary adenomas), GHPAs (growth hormone-secreting pituitary adenomas) and PRLPAs (prolactin-secreting pituitary adenomas) compared to those in three normal pituitary glands using the HiSeq 2000 sequencing system (Illumina). We validated miRNA expression using real-time quantitative polymerase chain reaction (RT-qPCR) analyses of samples from 73 patients (13 GHPAs, 42 NFPAs, and 18 PRLPAs) and 6 normal pituitary gland. We observed that miR-34c-3p was significantly downregulated in our PRLPA samples (p < 0.01), along with miR-34b-5p, miR-378 and miR-338-5p (all p < 0.05). In NFPAs, miR-493-5p was downregulated, and miR-181b-5p was significantly upregulated (p < 0.01). In GHPAs, miR-184 was significantly upregulated (p < 0.05). We observed that the tumor suppressive miR-124-3p was downregulated in both NFPAs and GHPAs. Taken together, we showed distinctive miRNA expression patterns in these three PAs, and these miRNA signatures in PA may have therapeutic potential as novel biomarkers for each type of PA.

Executive functioning and quality of life in acromegaly.

IntroductionActive acromegaly is a rare chronic endocrine disorder caused by excessive growth hormone (GH). Clinical studies suggest that cognitive performance is impaired in acromegaly – particularly executive function as well as short- and long-term memory. This study compared the quality of life (QoL) and executive functioning in acromegaly patients vs healthy controls.Materials and methodsThis was an observational case–control study on 38 subjects divided into 19 acromegaly patients and 19 matched controls. The groups were evaluated for QoL, attention, and executive function. All subjects completed Acromegaly Quality of Life Questionnaire (AcroQoL), Trail Making Test (parts A and B), Stroop, and phonemic fluency tests.ResultsAcromegaly patients had an AcroQoL global score that was significantly lower than controls. There were significant differences between the acromegaly group and the control group in terms of the physical effects (P=0.001) and appearance (P<0.001) but not for personal relationships (P=0.421). Acromegaly patients performed worse in the trail making test part B. They provided significantly fewer words than healthy subjects in phonemic fluency testing. Although patients performed generally worse than controls, no significant differences were noted in the trail making test part A, Stroop test, and the constrained phonemic fluency.ConclusionAcromegaly patients display worse executive functioning than healthy controls and have a decreased QoL.

Pseudoacromegaly.

Individuals with acromegaloid physical appearance or tall stature may be referred to endocrinologists to exclude growth hormone (GH) excess. While some of these subjects could be healthy individuals with normal variants of growth or physical traits, others will have acromegaly or pituitary gigantism, which are, in general, straightforward diagnoses upon assessment of the GH/IGF-1 axis. However, some patients with physical features resembling acromegaly - usually affecting the face and extremities -, or gigantism - accelerated growth/tall stature - will have no abnormalities in the GH axis. This scenario is termed pseudoacromegaly, and its correct diagnosis can be challenging due to the rarity and variability of these conditions, as well as due to significant overlap in their characteristics. In this review we aim to provide a comprehensive overview of pseudoacromegaly conditions, highlighting their similarities and differences with acromegaly and pituitary gigantism, to aid physicians with the diagnosis of patients with pseudoacromegaly.

Growth hormone and chronic kidney disease.

Elevated circulating levels of growth hormone (GH) and/or increased expression of the GH receptor in the kidney are associated with the development of nephropathy in type1 diabetes and acromegaly. Conditions of GH excess are characterized by hyperfiltration, glomerular hypertrophy, glomerulosclerosis and albuminuria, whereas states of decreased GH secretion or action are protected against glomerulopathy. The direct role of GH's action on glomerular cells, particularly podocytes, has been the focus of recent studies. In this review, the emerging role of GH on the biological function of podocytes and its implications in the pathogenesis of diabetic and chronic kidney disease will be discussed. Elevated GH levels impair glomerular permselectivity by altering the expression of podocyte slit-diaphragm proteins. GH stimulates the epithelial-mesenchymal transition of podocytes and decreases podocyte count. GH also induces the expression of prosclerotic molecules transforming growth factor beta, and TGFBIp. Our understanding of the cellular and molecular effects of GH in the pathogenesis of renal complications of diabetes and acromegaly has significantly progressed in recent years. These observations open up new possibilities in the prevention and treatment of diabetic nephropathy.

Circulating miR-103a-3p and miR-660-5p are associated with bone parameters in patients with controlled acromegaly.

BackgroundBiochemical control of GH/IGF-I excess in acromegaly (ACRO) is associated with persistent impairment of trabecular microstructure leading to increased risk of vertebral fractures. Circulating miRNAs modulate the activity of osteoblasts and osteoclasts, and may be potential biomarkers of osteoporosis.AimsIdentify differentially expressed miRNAs in the serum of patients with controlled ACRO vs controls and correlate miRNA levels with both biochemical and structural bone parameters.Patients and methodsTwenty-seven patients with controlled ACRO (11 males, 16 females; mean age, 48 ± 5 years; BMI, 28 ± 4 kg/m2) and 27 age-, gender- and BMI-matched controls were recruited. Areal BMD at lumbar spine and femur, and trabecular bone score were assessed; volumetric BMD was measured by quantitative computed tomography QCT-Pro (Mindways). Twenty miRNAs, chosen by their putative role in bone, were quantified in serum using real-time qPCR.ResultsIn ACRO patients, miR-103a-3p and miR-191-5p were found overexpressed, whereas miR-660-5p was underexpressed (P < 0.001). miR-103a-3p levels were negatively associated with both trabecular vBMD at trochanter and serum osteoprotegerin concentrations (P < 0.05) and positively with vitamin D concentrations (P < 0.01) and total cross-sectional area of the femoral neck (P < 0.05). miR-660-5p levels were correlated with both trabecular vBMD at trochanter and OPG concentrations (P < 0.05), but were negatively associated with vitamin D levels (P < 0.05). A negative correlation between miR-103-a-3p and miR-660-5p was found in both groups (P < 0.001).ConclusionsCirculating miR-103a-3p and miR-660-5p are differentially expressed in controlled ACRO patients and associated with bone structural parameters. miRNAs may be one of the mechanisms involved in the pathogenesis of bone disease and could be used as biomarkers in ACRO patients.

Insulin resistance and pseudoacromegaly: A case report

Patients with acromegaly have soft tissue overgrowth that induced characteristic clinical presentation. A growth hormone-secreting adenoma of the anterior pituitary gland is the most common cause of acromegaly. Metabolic and somatic features of acromegaly caused by high serum concentrations of insulin-like growth factor-I (IGF-I) and excess growth hormone (GH) production. we present a case of ‘pseudoacromegaly’ with an acromegaloid features, suppressed IGF-I levels and marked elevation of serum insulin. Endocrinologists should consider this diagnosis when assessing patients with clinical features of acromegaly and insulin resistance, in the absence of elevated levels of GH and IGF-I.

Influence of the IGFBP3-202A/C Gene Polymorphism on Clinical Features and Surgery Outcome in Acromegalic Patients.

Purpose: Excess growth hormone (GH) secretion in acromegaly patients results in increased levels of IGF-1 expression, which causes the clinical manifestations of acromegaly. IGF-1 levels are attenuated by IGFBP3, and a polymorphism in the promoter of IGFBP3 is known to affect the circulating level of IGFBP3 protein. The aim of the study was to evaluate the association of the IGFBP3 gene polymorphism with clinical features and surgery outcomes in acromegaly. We also investigate the difference in IGFBP3 polymorphism between acromegaly and general population.Methods: The study included 102 acromegalic patients and 142 sex- and age-matched healthy controls. The genotyping of IGFBP3 was carried out using the MassARRAY method. Patients were followed up for 4–12 months to estimate the neurosurgical effects. Clinical data were obtained from the medical records.Results: The CC genotype, which is associated with decreased IGFBP3 levels, was less common in acromegaly patients than among the healthy controls; although, this correlation was not significant (P = 0.056). There was no association of the IGFBP3 gene polymorphism with glucose, lipid, phosphorus, blood urea nitrogen, creatinine or uric acid levels. Additionally, there was no association between tumor size, texture, or hemorrhage/cyst, except there was a trend that more patients with the C allele (P = 0.054) needed additional treatment post-operation than did patients carrying the A allele (OR 1.985, 95% CI 0.983–4.008). Moreover, higher IGF-1 values after treatment were observed in patients carrying the C allele (P = 0.012 and P = 0.014 according to the additive model and dominant model, respectively).Conclusion: Polymorphisms in IGFBP3 may not influence metabolic parameters or pituitary tumor characteristics in acromegalic patients, but they may be associated with the hormone levels and surgery effects.

Incidence rate and risk factors of early repolarization in patients with growth hormone-secreting pituitary adenoma: a cohort study.

PurposeTo investigate the incidence and risk factors for early repolarization (ER) in patients with growth hormone (GH)-secreting pituitary adenomas.MethodsFrom August 2014 to August 2016, patients with GH-secreting pituitary adenomas and non-functioning pituitary adenomas admitted to the First Affiliated Hospital, Sun Yat-sen University, were prospectively enrolled. Logistic regression analysis was used to investigate risk factors for ER development.ResultsA total of 118 patients with GH-secreting pituitary adenomas (41 with concomitant ER) and 103 patients with non-functioning pituitary adenomas were included. Compared with the non-functioning adenoma group GH and IGF-1 levels, left ventricular mass index (LVMI), and incidence of ER were significantly higher in the GH-secreting pituitary adenoma group (all P<0.05). LVMI was an independent risk factor for ER. Bivariate correlation analysis showed that course of disease, GH, IGF-1, and diabetes were correlated with LVMI. Course of disease and IGF-1 were directly correlated with LVMI. Two-year follow-up of patients who underwent transsphenoidal resection showed that incidence of ER was significantly decreased in patients with normal GH and IGF-1 levels.ConclusionCompared with non-functioning pituitary adenoma patients, patients with GH-secreting pituitary adenomas have a significantly higher incidence of ER. Elevation of serum GH and IGF-1 had positive correlations with cardiac muscle cell hypertrophy and increased LVMI.

Surgical Results and Predictors of Initial and Delayed Remission for Growth Hormone-Secreting Pituitary Adenomas Using the 2010 Consensus Criteria in 162 Patients from a Single Center

The factors associated with initial and delayed remission after growth hormone (GH)-secreting pituitary adenoma excision have not been completely elucidated. We recruited 185 consecutive patients who had undergone resection of GH-secreting pituitary adenomas from January 2013 to December 2014 and assessed their tumor characteristics and surgical outcomes. The criteria for initial or delayed remission (using the 2010 consensus criteria) were normalized insulin-like growth factor 1 (IGF-1) levels, GH levels <0.4 μg/L with an oral glucose tolerance test, and/or random GH levels <1.0 μg/L at or after the postoperative 3-month (PO3M) follow-up, without adjuvant therapy. Remission was achieved in 92 of 162 patients (56.8%) after surgery alone and was associated with a lower Knosp grade of 0-2 and lower postoperative day 1 GH level on multivariate regression analysis. A baseline IGF-1 index (IGF-1 level/upper limit of normal) of <2.835 predicted for initial remission at the PO3M follow-up (positive predictive value, 95.3%; negative predictive value, 36.6%; P < 0.001). The PO3M IGF-1 index was significantly lower in the delayed remission group than in the nonremission group. Furthermore, the former had had fewer invasive tumors (1.23 ± 0.21 vs. 1.77 ± 0.37 [9.52% vs. 76.47%]; P < 0.001). A PO3M IGF-1 index of <1.485 predicted for delayed remission during subsequent follow-up (positive predictive value, 84.6%; negative predictive value, 92.3%; P < 0.001). A lower Knosp grade of 0-2 and lower postoperative day 1 GH level were independent predictors of surgical remission. The baseline IGF-1 and PO3M IGF-1 indexes might predict for initial and delayed remission, respectively.

Sleep apnea and cardiovascular complications of the acromegaly. Response to the medical treatment.

Acromegaly is a rare disease characterized by high levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). The excess of GH leads to the development of different manifestations in different organs, from subtle signs in the bones and soft tissues to the development of respiratory and cardiac insufficiency. In the cardiovascular system, the GH/IGF-1 axis exerts its influence on three major aspects: myocyte growth and structure, cardiac contractility and vascular function. In this article, we review the different cardiovascular and respiratory complications as well as the effects of the different treatments on these complications. Cardiovascular complications that occur in acromegaly are known as "acromegalic cardiomyopathy," and include ventricular hypertrophy, impaired diastolic and systolic function, valve diseases, coronary artery disease, and arrhythmias. Acromegaly is also associated with relevant complications of the respiratory system, mainly sleep apnea and respiratory insufficiency. Regarding treatment, there are different therapeutic strategies. Surgery is the first-choice treatment, but in general, half of patients will require adjuvant treatments, such as medical treatment (somatostatin analogues, dopamine agonists and GH receptor antagonists) or radiotherapy. The treatment can improve some complications of acromegaly, such as left ventricular hypertrophy, hypertension, or obstructive sleep apnea. On the other hand, when strict control of the disease is achieved, a reduction in mortality and cardiovascular morbidity is assured, reaching rates similar to those of the general population.

Growth Hormone and Metabolic Homeostasis

Pituitary growth hormone (GH) is a peptide hormone predominantly secreted by somatotrophs in the anterior pituitary under the tight control of the hypothalamic–pituitary axis and GH secretagogues. GH elicits its effects directly on target organs and cells interacting with GH receptors and through stimulation of insulin-like growth factor 1 production. GH plays critical roles in regulating somatic growth and the metabolism of carbohydrates, lipids, and protein. GH increases insulin secretion and glucose uptake. Conversely, a GH deficient state is characterised by enhanced insulin sensitivity. Diabetogenic actions of GH are evident in conditions of GH excess, such as acromegaly or poorly controlled Type 1 diabetes mellitus. In patients with GH deficiency, administration of GH resulted in impaired glucose tolerance and insulin sensitivity. Owing to its multiple and complex effects, the regulation of GH secretion and its function in normal health and metabolic diseases is a major research interest in the field of molecular endocrinology. This review provides an overview of the effects of GH on glucose, lipid, and protein metabolism, insulin resistance, and metabolic homeostasis.

Carney Complex.

Carney complex is a rare, autosomal dominant, multiple endocrine neoplasia and lentiginosis syndrome, caused in most patients by defects in the PRKAR1A gene, which encodes the regulatory subunit type 1α of protein kinase A. Inactivating defects of PRKAR1A lead to aberrant cyclic-AMP-protein kinase A signaling. Patients may develop multiple skin abnormalities and a variety of endocrine and non-endocrine tumors. Endocrine manifestations include primary pigmented nodular adrenocortical disease, that may cause Cushing syndrome, growth-hormone secreting pituitary adenoma or pituitary somatotropic hyperplasia which can result in acromegaly, as well as gonadal and thyroid tumors. Non-endocrine tumors associated with Carney complex include myxomas of the heart, breast, and other sites, psamommatous melanotic schwannomas, breast ductal adenomas, osteochondromyxomas, and a predisposition to a number of malignancies from adrenal to pancreatic and liver cancer.

Delayed Remission of Growth Hormone-Secreting Pituitary Adenoma After Transsphenoidal Adenectomy

To investigate the clinical characteristics of delayed remission (DR) of growth hormone (GH)-secreting pituitary adenoma after transsphenoidal adenectomy and inform follow-up treatments. We retrospectively reviewed 87 patients who had undergone transsphenoidal surgery for acromegaly. Demographic, radiological, and endocrinological data were reviewed before, immediately after, 3 months after, and in the long term (2.4 ± 1.1 years) after surgery. The definition of DR was that patients did not achieve GH remission immediately, 3 months, or later after surgery, but did so in the long term without any additional postoperative treatment. Fifty-one patients (58.6%) achieved long-term GH remission. There were 24 (27.6%) DR patients immediately postoperatively and 9 (10.3%) DR patients 3 months postoperatively. On average, the 24 DR patients achieved remission at 10.2 (range, 3-32) months. Immediate postoperative random and nadir GH after an oral glucose load were significantly lower in the DR group than in the nonremission group (2.73 ± 3.17 and 2.03 ± 2.59 vs. 8.05 ± 10.35 and 5.55 ± 5.91 μg/L, respectively). Three-month postoperative nadir GH was significantly lower in the DR group than in the nonremission group (1.63 ± 2.82 vs. 3.48 ± 4.25 μg/L, P= 0.007). Immediate postoperative random GHeffectively predicted long-term remission (Spearman's ρ= 0.513, area under the curve= 0.905 > 0.90). However, the best predictor of long-term remission was 3-month postoperative nadir GH (Spearman's ρ= 0.728, area under the curve= 0.944 > 0.90), with 76.5% sensitivity and 97.2% specificity. For certain groups of patients likely to achieve DR, additional treatments should not be performed early after surgery. Prolonged follow-up and close observation could help determine the therapeutic effect of surgery and guide postoperative treatments.

High ketones due to excess growth hormone

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

Surgery cost saving in acromegaly in Brazil

Surgery cost saving in acromegaly in Brazil

Acromegalic Cardiomyopathy: An Overview of Risk Factors, Clinical Manifestations, and Therapeutic Options.

Acromegaly is a rare endocrine disorder that carries a significant burden of cardiovascular morbidity and mortality. Abnormalities of the growth hormone/insulin-like growth factor-1 axis in acromegaly lead to the characteristic cardiovascular manifestations of this disease. One hallmark feature of the disease is acromegalic cardiomyopathy, a syndrome of progressive cardiac dysfunction characterized by left ventricular hypertrophy, diastolic dysfunction, and combined systolic and diastolic dysfunction in the very advanced stage. In this article, we review the current concepts regarding the pathophysiology of acromegalic cardiomyopathy and discuss the various risk factors for its development. We also explore the question of whether the alterations in cardiac function are reversible with successful biochemical control of growth hormone excess either medically or surgically.

Endocrine Remission after Pituitary Stereotactic Radiosurgery: Differences in Rates of Response for Matched Cohorts of Cushing’s Disease and Acromegaly Patients

To compare and describe the time to endocrine remission and new hypopituitarism among patients with growth hormone (GH) and adrenocorticotropic hormone (ACTH) secreting pituitary adenomas after radiosurgery after controlling for several known prognostic factors. An institutional review board approved, institutional retrospective analysis of patients with GH- and ACTH-secreting pituitary adenomas was performed, with matching based on patient gender, age at radiosurgery, time interval between the last resection and radiosurgery, use of previous radiotherapy, whole sella treatment, suprasellar extension, cavernous sinus invasion, and margin dose. Endocrine remission was defined, off of suppressive medications, as a normal serum IGF-1 (GH-secreting) or a normal 24-hour urine free-cortisol (ACTH-secreting). Endocrine remission and the incidence of new hypopituitarism after single fraction radiosurgery were described and compared between groups. Two-hundred and forty-two (242) patients were evaluated, 121 with GH-secreting tumors and 121 with ACTH-secreting tumors. A total of 75% of patients had cavernous sinus invasion and 10% had suprasellar extension at the time of radiosurgery. The median radiosurgical marginal dose was 25 Gy to the 50% isodose line between each group. After multivariable adjustment, factors associated with increased time to endocrine remission included patient age (HR 1.016, p = 0.023), cavernous sinus invasion (HR 1.793, p = 0.004), and patients with acromegaly (HR 2.912, p < 0.001). The incidence of a new hypopituitarism developing after SRS was 29% and did not appreciably differ by adenoma subtype (p = 0.180). After radiosurgery, patients with ACTH-secreting tumors achieve endocrine remission sooner than those with GH-secreting tumors. These results provide insight into the relative tumor biology and post-radiosurgical disease course that will serve to further improve clinical outcomes and patient management in the future.

Serial overnight growth hormone profiling in diagnosing growth hormone excess in McCune Albright Syndrome

Serial overnight growth hormone profiling in diagnosing growth hormone excess in McCune Albright Syndrome

A Zebrafish Acromegaly Model Elevates DNA Damage and Impairs DNA Repair Pathways.

Acromegaly is a pathological condition due to excess growth hormone (GH) secretion. Acromegaly patients exhibit a deterioration of health and many associated complications, such as cardiovascular issues, arthritis, kidney diseases, muscular weakness, and colon cancer. Since these complications are generalized throughout the body, we investigated the effect of GH excess on cellular integrity. Here, we established stable acromegaly model zebrafish lines that overexpress tilapia GH and the red fluorescence protein (RFP) reporter gene for tracking GH gene expression throughout generations, and performed RNA-Seq data analysis from different organs. Intriguingly, heatmap and Expression2Kinases (X2K) analysis revealed the enrichment of DNA damage markers in various organs. Moreover, H2A.X immunostaining analysis in acromegaly zebrafish larvae and the adult acromegaly model brain and muscle showed a robust increase in the number of DNA-damaged cells. Using Gene Set Enrichment Analysis (GSEA), we found that the acromegaly zebrafish model had impaired DNA repair pathways in the liver, such as double-strand break (DSB), homologous recombination repair (HRR), non-homologous end joining (NHEJ), nucleotide excision repair (NER), and translesion synthesis (TLS). Interestingly, the impairment of DNA repair was even more prominent in acromegaly model than in aged zebrafish (three years old). Thus, our study demonstrates that affection of cellular integrity is characteristic of acromegaly.

Biochemical following-up of treated acromegaly. Limitations of the current determinations of IGF-I and perspective.

Acromegaly is a rare disease caused by excess growth hormone (GH) secretion leading to an insulin-like growth factor-1 (IGF-I) which is the major mediator of GH action. Biochemical diagnosis of GH excess is accomplished by the combined measurement of baseline serum IGF-I concentration and the response of GH on an oral glucose tolerance test (OGTT). Several drawbacks regarding the interpretation of biochemical tests that include measurement of GH have been widely described in the literature, including different protocols for obtaining serum samples, great differences in the results obtained by different immunoassays, different cut-off points used to differentiate the normal status of the hypersecretion of GH. Clinical guidelines related to the diagnosis and management of patients with acromegaly state that "normal" IGF-I concentrations, (within an established age- and sex- reference range), excludes the diagnosis of active acromegaly, and mean disease control in patients who have received treatment. But many factors may exert influence over IGF-I measurement or interpretation and limit its value as a biological marker of disease activity. Major drawbacks of IGF-I measurements derive both from its own physiology, to the divergences in results obtained from different biochemical methods used for their quantification, to the heterogeneous ways of expressing the results obtained and to the lack of uniformity of the cut-offs to define treatment effectiveness. All these issues make it difficult to compare the results obtained by different authors. We will focus on the issues regarding the measurement and interpretation of IGF-I concentrations in the management of acromegaly patients.