Acromegaly Research Articles

Acromegaly and ultrasound: how, when and why?

Acromegaly is a rare disease caused by an excess of growth hormone and insulin-like growth factor 1. It is usually diagnosed because of typical signs such as macroglossia, acral enlargement, jaw prognathism and malocclusion. Systemic complications are a major cause of morbidity and mortality in acromegaly, and many patients remain undiagnosed for several years. Increased ultrasound (US) application in the general population, and including among acromegaly patients, has revealed many suggestive features which, taken together with clinical suspicion, could induce suspicion of this disease. This review describes main US features in acromegaly. Echocardiography shows a typical cardiomyopathy, characterized by left ventricular hypertrophy, diastolic and systolic dysfunction, aortic and mitral regurgitation, and increased aortic root diameters. US preclinical markers of atherosclerosis, such as intima media thickness (IMT), seem also to be impaired. Visceromegaly and increased organ stiffness are other features of acromegaly, including enlarged prostate, kidneys, liver, and thyroid. In addition, other US findings are: renal cysts, micronephrolithiasis, impairment of renal haemodynamic parameters, gallstones and gallbladder polyps, hepatic steatosis, thyroid nodules, multinodular goiter, and polycystic ovaries. Musculoskeletal US findings are increased cartilage thickness, impaired density and elasticity of bones, nerve enlargement, carpal and cubital tunnel syndrome, and trigger finger. Acromegaly patients frequently present systemic complications and a diagnostic delay. US features of acromegaly are not specific, but could potentially have a key role in early detection of the disease in the presence of typical clinical features.

Two Synchronous Pituitary Adenomas Causing Cushing Disease and Acromegaly

To report the first case of 2 synchronous pituitary adenomas, 1 corticotroph and 1 somatotroph, with distinct molecular lineages confirmed by differential hormone and S-100 protein expression. A case report followed by a literature review are presented. A 68-year-old woman presented for evaluation of resistant hypertension. Biochemical testing demonstrated adrenocorticotropic hormone (ACTH)-dependent hypercortisolemia and growth hormone (GH) excess. Pituitary magnetic resonance imaging (MRI) revealed a 2 cm left sellar lesion consistent with a pituitary macroadenoma. The patient therefore underwent transsphenoidal surgery for a presumed cosecreting ACTH and GH macroadenoma. Tumor immunohistochemical staining (IHC) was positive for ACTH, but negative for GH. Postoperative biochemical testing confirmed remission from Cushing disease, but the insulin-like growth factor 1 (IGF-1) level remained elevated. Postoperative MRI demonstrated a small right sellar lesion that, in retrospect, had been present on the preoperative MRI. Resection of the right lesion confirmed a GH-secreting adenoma with negative ACTH staining. After the second surgery, the IGF-1 level normalized and blood pressure improved. Further pathologic examination of both surgical specimens demonstrated differential expression of S-100 protein, a folliculostellate cell marker. Reverse transcription polymerase chain reaction of messenger ribonucleic acid from the left sellar lesion was positive for ACTH and negative for GH, confirming the IHC results. Germline mutations in genes known to be associated with pituitary adenoma syndromes (MEN1, CDC73, CDKN1A, CDKN1B, CDKN2B, CDKN2C, and AIP) were not detected. Although the pathogenesis of synchronous pituitary adenomas has not been fully elucidated, this case report suggests that they can have distinct molecular lineages.

Pituitary magnetic resonance imaging predictive role in the therapeutic response of growth hormone-secreting pituitary adenomas.

Growth hormone (GH)-secreting pituitary adenomas, responsible for the development of acromegaly, are the second most frequent type of secreting pituitary adenomas and are characterized by very variable T2-weighted signal intensity on pituitary magnetic resonance imaging (MRI). Previous data have demonstrated a correlation between T2-weighted tumor signal intensity and response to therapy with conventional somatostatin analogs (SSA) in patients with acromegaly. The aim of the current retrospective study was to investigate the correlation between the T2-weighted tumor signal on pituitary MRI and both biochemical and radiological response to first-line SSA therapy. Twenty-two naive patients with acromegaly were eligible for the study (14 females and 8 males, mean age ± SD: 58.8±15.74). A biochemical evaluation (GH and IGF-I levels) and an MRI assessment (volume and signal intensity analysis of adenoma) were conducted in each patient at diagnosis and after 12 months of SSA therapy. On diagnostic pituitary MRI, 16 (72.7%) adenomas were T2- hypointense and 6 (27.2%) T2-hyperintense. After 12 months of SSA therapy, IGF-I levels decreased by more than 50% from baseline in 62.5% of patients with T2-hypointense and 33.3% of patients with T2- hyperintense tumor signal, respectively (P=0.03). Moreover, GH levels decreased by more than 80% from baseline in 81.3% and 33.3% of patients with T2-hypointense and T2-hyperintense tumor signal (P=0.02). A significant tumor volume reduction (≥20%) was observed in 75% of the T2-hypointense and 33.3% of the T2-hyperintense adenomas (P=0.001). In naive patients with acromegaly, first-line SSA therapy is associated with a better biochemical response and greater tumor shrinkage in T2-hypointense compared to T2-hyperintense adenomas. Therefore, T2-weighted sequences of pituitary MRI can help to classify GH-secreting pituitary adenomas into a T2-hypointense and T2-hyperintense type and, therefore, to identify patients who can better respond to first-line SSA therapy.

Metabolic profiling reveals distinct metabolic alterations in different subtypes of pituitary adenomas and confers therapeutic targets

BackgroundPituitary adenomas are common brain tumors. Although transsphenoidal surgery are able to achieve extensive tumor removal, the rate of recurrence ranges from 5 to 20% depending on the different subtype. Further understanding of these tumors is needed to develop novel strategies to improve the prognosis of patients. But their metabolic characteristics are largely unknown.MethodsWe used metabolomic, transcriptomic, and proteomic approaches to systematically investigate eight subtypes of pituitary adenomas and normal pituitary glands. By blocking IDH2, we investigate IDH2 play an inhibitory role in GH tumor cell growth and tumor secretion.ResultsWe found that all of the pituitary adenomas displayed downregulated glucose metabolism and glycolysis compared to normal tissues. Together with the differences in amino acids and fatty acids, we categorized these tumors into three clusters. We then re-established the reprogrammed metabolic flux in pituitary adenomas based on multiomic analyses. Take growth hormone-secreting pituitary adenomas as an example, we revealed that IDH2 is a key player in the reprogrammed metabolism of such tumors. By blocking IDH2, we confirmed that IDH2 is a potential target for the inhibition of tumor cell growth and tumor secretion.ConclusionsOur study first uncovered the metabolic landscape of pituitary adenomas and demonstrated a possible way to inhibit tumor growth by regulating aberrant metabolism.

Reproducibility and Utility of OGTT in Acromegaly

Reproducibility and Utility of OGTT in Acromegaly

Acromegaly in a Hog Badger (Arctonyx collaris)

Our understanding of pathological conditions is usually centered on human and domesticated species. Thus, a vast array of pathologies within vertebrates are unknown, especially those that occur in exotics and those that lack external characters, such as conditions that affect the skeleton. Exotics represent a majority of the vertebrates housed in zoos and other wildlife centers, and in the larger picture of conservation, represent the best way to determine potential health threats and cures for endangered and threatened species in the wild. Here we describe a case of acromegaly, a rare condition of excess growth hormone, in a hog badger (Arctonyx collaris) based on Computed Tomography (CT). This is the first documented occurrence of this condition in non-human or non-domesticated mammals, and the first occurrence within Mustelidae. The recognition of this rare condition within a badger suggests that acromegaly may be more widespread within mammals than previously thought, and has implications for diagnosis of other exotics within zoos.

Exosomal hsa-miR-21-5p derived from growth hormone-secreting pituitary adenoma promotes abnormal bone formation in acromegaly

Growth hormone-secreting pituitary adenoma (GHPA), a benign endocrine tumor located in the base of the skull, results in acromegaly. In addition to the mass effect of the tumor itself in the sellar region, GHPA can lead to the overgrowth of almost every organ. Previous findings indicated that the processes underlying acromegaly were partly attributable to hyperactivity of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis. However, the mechanisms driving this syndrome remains largely unknown. Additionally, the roles of GHPA-derived exosomes, which contain functional microRNAs and proteins that manipulate target cell proliferation and differentiation in distal extremities, are also unknown. In this study, we demonstrated that GHPA exosomes promote bone formation in vitro and trabecula number in vivo. The mechanism of increased trabecula formation may be attributable to GHPA exosome-induced osteoblast proliferation via increased cell viability and DNA replication. We further discovered that exosomal hsa-miR-21-5p plays a distinct role from the GH/IGF-1 axis in these processes. Accordingly, the results of this study provide a novel mechanism whereby GHPA influences distal extremities and a new perspective for treating GHPA.

Treatment of Growth Hormone Excess is Associated with Improvement in Abnormal Cardiac Phenotypes

IntroductionCardiovascular disease is the leading cause of mortality in patients with growth hormone (GH) hypersecretion, termed acromegaly. The traditional manifestation of GH excess is cardiac hypertrophy, but a dilated phenotype with clinical heart failure exists. Prior studies have suggested that treatment of GH excess may lead to an improvement in early stage dysfunction, but have shown no benefit in dilated cardiomyopathy or advanced disease.HypothesisCorrection of GH excess in acromegaly will result in improvement in both a hypertrophic and dilated (DCM) cardiac phenotype, even in more advanced disease.MethodsA retrospective analysis was performed on all patients diagnosed with and treated for acromegaly at a single institution. Patients with abnormalities on baseline transthoracic echocardiogram were evaluated (n=50). Abnormalities were defined as an elevated left ventricular mass index, elevated left ventricular diastolic diameter, or reduced ejection fraction. Detailed histories were extracted, including age of diagnosis, treatment modality, IGF-1 levels, cardiovascular medications, and clinical outcomes. Where available, we compared pretreatment imaging to most recent findings to quantify changes in cardiac function.ResultsThe study cohort consisted of 21 patients (42%) with dilated cardiomyopathy, 25 patients (50%) with hypertrophic phenotype and 4 patients (8%) with ischemic cardiomyopathy. Hypertension (61%), diabetes mellitus (36%) and obstructive sleep apnea (48%) were the most common comorbidities. Successful treatment of acromegaly resulted in a clinically-relevant improvement in mean LV ejection fraction in the DCM cohort from 38% to 49% (p = 0.05) and mean LV diastolic diameter from 66 to 60 mm (p = 0.20). Additionally, an improvement in LV mass index was seen in the hypertrophic phenotype from 117 to 104 g/m2 (p = 0.05). Heart rate, QRS and QTC intervals were statistically unchanged.ConclusionsContrary to prior research, treatment of human growth hormone excess resulted in an improvement in dilated as well as hypertrophic phenotypes, though not necessarily independent of guideline-directed medical therapy. This highlights the importance of effective treatment of GH excess states in reducing the prevalent cardiovascular morbidity and mortality in patients with acromegaly. Cardiovascular disease is the leading cause of mortality in patients with growth hormone (GH) hypersecretion, termed acromegaly. The traditional manifestation of GH excess is cardiac hypertrophy, but a dilated phenotype with clinical heart failure exists. Prior studies have suggested that treatment of GH excess may lead to an improvement in early stage dysfunction, but have shown no benefit in dilated cardiomyopathy or advanced disease. Correction of GH excess in acromegaly will result in improvement in both a hypertrophic and dilated (DCM) cardiac phenotype, even in more advanced disease. A retrospective analysis was performed on all patients diagnosed with and treated for acromegaly at a single institution. Patients with abnormalities on baseline transthoracic echocardiogram were evaluated (n=50). Abnormalities were defined as an elevated left ventricular mass index, elevated left ventricular diastolic diameter, or reduced ejection fraction. Detailed histories were extracted, including age of diagnosis, treatment modality, IGF-1 levels, cardiovascular medications, and clinical outcomes. Where available, we compared pretreatment imaging to most recent findings to quantify changes in cardiac function. The study cohort consisted of 21 patients (42%) with dilated cardiomyopathy, 25 patients (50%) with hypertrophic phenotype and 4 patients (8%) with ischemic cardiomyopathy. Hypertension (61%), diabetes mellitus (36%) and obstructive sleep apnea (48%) were the most common comorbidities. Successful treatment of acromegaly resulted in a clinically-relevant improvement in mean LV ejection fraction in the DCM cohort from 38% to 49% (p = 0.05) and mean LV diastolic diameter from 66 to 60 mm (p = 0.20). Additionally, an improvement in LV mass index was seen in the hypertrophic phenotype from 117 to 104 g/m2 (p = 0.05). Heart rate, QRS and QTC intervals were statistically unchanged. Contrary to prior research, treatment of human growth hormone excess resulted in an improvement in dilated as well as hypertrophic phenotypes, though not necessarily independent of guideline-directed medical therapy. This highlights the importance of effective treatment of GH excess states in reducing the prevalent cardiovascular morbidity and mortality in patients with acromegaly.

MANAGEMENT OF ENDOCRINE DISEASE: Bone disorders associated with acromegaly: mechanisms and treatment.

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) exert physiological actions on the skeleton throughout life, by stimulating longitudinal bone growth in children, the acquisition of bone mass during adolescence and the maintenance of skeletal architecture in adults. When GH and IGF-I are secreted in excess, bone remodeling is enhanced leading to deterioration of bone microstructure and impairment of bone strength. Indeed, acromegaly causes skeletal fragility, and vertebral fractures are reported in a remarkable number of subjects exposed to GH and IGF-I excess. The management of skeletal fragility in acromegaly is a challenge, since the awareness of this complication is low, the prediction of fracture risk is difficult to ascertain, the risk of fractures remains after the control of acromegaly and the effectiveness of bone-active drugs is unknown. This review is an update on bone disorders associated with acromegaly and provides a perspective of possible therapeutic approaches based on emerging pathophysiological and clinical information.

Current perspectives on the impact of clinical disease and biochemical control on comorbidities and quality of life in acromegaly.

Acromegaly is a rare chronic, systemic disorder caused by excessive growth hormone (GH) secretion from a somatotroph pituitary adenoma. GH hypersecretion leads to overproduction of insulin-like growth factor-1 (IGF-1), which contributes to the somatic overgrowth, physical disfigurement, onset of multiple systemic comorbidities, reduced quality of life (QoL) and premature mortality of uncontrolled patients. Somatostatin receptor ligands, dopamine agonists and a GH receptor antagonist are currently available for medical therapy of acromegaly. The main aim of treatment is biochemical normalisation, defined as age-normalised serum IGF-1 values and random GH levels <1.0μg/L. However, there is an increasing evidence suggesting that achieving biochemical control does not always decrease the burden of disease-related comorbidities and/or improve patients' QoL. This lack of correlation between biochemical and clinical control can be due to both disease duration (late diagnosis) or to the peculiarity of a given comorbidity. Herein we conducted ad hoc literature searches in order to find the most recent and relevant reports on biochemical and clinical disease control during medical treatment of acromegaly. Particularly, we analyse and describe the relationship between biochemical, as well as clinical disease control in patients with acromegaly receiving medical therapy, with a focus on comorbidities and QoL. In conclusion, we found that current literature data seem to indicate that clinical disease control (besides biochemical control), encompassing clinical signs and symptoms, comorbidities and QoL, emerge as a primary focus of acromegaly patient management.

The Endothelium in Acromegaly.

Growth hormone (GH) and insulin like growth factor-1 (IGF-1) excess induce well-known deleterious effects on the cardiovascular system, especially after long-term exposition. Acromegaly, a condition of chronic GH and IGF-1 hypersecretion, is frequently associated to cardiovascular complications, although recent studies have shown a reduction in the prevalence of these comorbidities in well-controlled patients and a mortality risk similar to normal aging population. Many factors could contribute to the increased cardiovascular risk of acromegaly patients. Among these factors, the endothelium plays a key role in the pathogenesis of atherosclerotic plaques and could be considered an early marker of atherosclerosis and cardiovascular dysfunction. In this review we examined the relationship between GH/IGF-1 excess and the endothelium, from basic studies to clinical evidence. Many studies involving various arterial districts (microvascular arteries of retina, kidney and brain, and major vessels as carotid and aorta) showed that GH/IGF-1 excess promotes endothelial dysfunction via several different mechanisms. Increased endothelial proliferation, dysfunction of endothelial progenitor cells, increased oxidative stress, and compromised oxidative defenses are the main factors that are associated with endothelial dysfunction. In the general population, these alterations are associated with the development of atherosclerosis with an increased incidence of coronary artery disease and cerebrovascular complications. However, in acromegaly this is still a debated issue, despite the presence of many pro-atherogenic factors and comorbidities, such as hypertension, diabetes, sleep apnoea, and metabolic syndrome. Preclinical markers of atherosclerosis as arterial intima media thickness, pulse wave velocity and flow mediated dilation seem to be impaired in acromegaly and partly mediated by the endothelium dysfunction. In conclusion, the pathophysiology of endothelial dysfunction in the condition of GH and IGF-1 excess remains a crucial area of investigation to fully dissect the association of acromegaly with cardiovascular disease complications.

Influence of Variables on Hormone Profile in Endoscopic Transsphenoidal Surgery for Pituitary Adenomas

Objective: to evaluate the hormone profiles of patients with pituitary adenomas operated on in Hospital das Clínicas, UniversidadeFederal de Goiás (HC-UFG), correlating them with the variables age, sex, and Knosp grade. Method: This is a retrospective quantitativestudy of medical records, including a total population of 20 patients diagnosed with pituitary adenomas operated on using the pureendoscopic endonasal transsphenoidal approach. The hormone profiles of the three types of pituitary adenoma prevalent in this institutionwere analyzed: nonfunctioning macroadenoma, growth hormone-secreting pituitary adenoma (acromegaly), and adrenocorticotropichormone-secreting pituitary adenoma (Cushing’s disease). Pre and postoperative hormone values were statistically paired with thevariables selected. Results: The global levels of the specific hormones of each disease decreased after surgery. However, no statisticalsignificance was found between the variables selected in this study and the pre and postoperative hormone values. Conclusion:The main surgical goal, the specific hormones decrease, was achieved in all the surgeries performed. Analyzing the relationshipbetween the variables and the hormone profiles, we conclude that age, sex, and Knosp grade did not influence the results obtained.

Higher Growth Hormone Levels are Associated with Erectile Dysfunction in Male Patients With Acromegaly

Objective: To investigate in vivo correlates of erectile dysfunction (ED) in male patients with acromegaly. Methods: Fifty-one male patients with acromegaly were assessed by the International Index of Erectile Function-5 and Acromegaly Quality of Life (Acro-QoL) questionnaires. The measurement of serum nitric oxide (NO) were performed in patients and age-matched nonacromegalic controls. Results: Among 51 patients analyzed, 32 (62.7%) had ED. Patients with ED showed lower Acro-QoL scores regarding global (69.8 ± 17.7 versus 79.4 ± 11.2; P = .035) and personal relationship dimensions (59.6 ± 22.1 versus 76.8 ± 17.6; P = .012) than non-ED patients. ED patients were older (44.5 ± 11.2 years versus 33.2 ± 8.5 years; P = .04) and showed higher growth hormone (GH) levels (15.5 μg/L [interquartile range of 9.5 to 34.5 μg/L] versus 5.9 μg/L [interquartile range of 3.4 to 13.9 μg/L]; P = .001) compared to non-ED patients. The cutoff values for identifying ED were 7.9 μg/L for random GH and 5.3 μg/L for GH nadir after oral administration of 75 g of glucose. There was no significant difference in total testosterone levels between the two groups (6.36 ± 4.24 nmol/L versus 9.54 ± 5.50 nmol/L; P = .299). The NO levels in patients with acromegaly were significantly lower than those in nonacromegalic controls (8.77 ± 1.78 μmol/L versus 19.19 ± 5.02 μmol/L, respectively; P = .049). Furthermore, the NO levels were even lower in ED patients than those in non-ED patients (5.14 ± 0.98 μmol/L versus 12.09 ± 3.44 μmol/L; P = .027). Conclusion: Our study showed that ED is prevalent in male acromegalic patients and may be associated with systemic endothelial dysfunction induced by excessive GH. Further studies investigating the mechanism of GH and ED are required. Abbreviations: Acro-QoL = Acromegaly Quality of Life; ED = erectile dysfunction; FSH = follicle-stimulating hormone; GH = growth hormone; IGF-1 = insulin-like growth factor 1; IIEF-5 = international index of erection function-5; LH = luteinizing hormone; MRI = magnetic resonance imaging; NO = nitric oxide; OGTT = oral glucose tolerance test; QoL = quality of life; ROC = receiver operating characteristic.

Can the sFLC assay help on the optimization of the use of 24h urines in patients with monoclonal gammapathies?

Acromegaly is typically caused by a growth hormone–secreting pituitary adenoma, driving excess secretion of insulin-like growth factor 1. Acromegaly may result in a variety of cardiovascular, respiratory, endocrine, metabolic, musculoskeletal, and neoplastic comorbidities. Early diagnosis and adequate treatment are essential to mitigate excess mortality associated with acromegaly.PubMed searches were conducted using the keywords growth hormone, acromegaly, pituitary adenoma, diagnosis, treatment, pituitary surgery, medical therapy, and radiation therapy (between 1981 and 2021).The diagnosis of acromegaly is confirmed on biochemical grounds, including elevated serum insulin-like growth factor 1 and lack of growth hormone suppression after glucose administration. Pituitary magnetic resonance imaging is advised in patients with acromegaly to identify an underlying pituitary adenoma.Transsphenoidal pituitary surgery is generally first-line therapy for patients with acromegaly. However, patients with larger and invasive tumors (macroadenomas) are often not in remission postoperatively. Medical therapies, including somatostatin receptor ligands, cabergoline, and pegvisomant, can be recommended to patients with persistent disease after surgery. Select patients may also be candidates for preoperative medical therapy. In addition, primary medical therapy has a role for patients without mass effect on the optic chiasm who are unlikely to be cured by surgery. Clinical, endocrine, imaging, histologic, and molecular markers may help predict the response to medical therapy; however, confirmation in prospective studies is needed. Radiation therapy is usually a third-line option and is increasingly administered by a variety of stereotactic techniques. An improved understanding of the pathogenesis of acromegaly may ultimately lead to the design of novel, efficacious therapies for this serious condition.

Acromegaly in a 29-year-old woman: restored fertility after surgery and radiosurgery

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

Acromegaly complications at the time of diagnosis

Acromegaly complications at the time of diagnosis

Cardiac resynchronization therapy improves heart failure in one patient with acromegaly-induced cardiomyopathy: a case report

BackgroundCongestive heart failure is rarely observed in patients with acromegaly. Excessive growth hormone secretion and elevation of insulin-like growth factor 1 contribute to pathological changes in myocyte growth and structure, cardiac contractility, vascular function, and in later stage may progress to cardiac dysfunction. Early recognition of the condition is paramount, though the insidious progression of the disease commonly results in late diagnosis. Current standard regimens of pharmacological therapy, surgical treatment, radiotherapy are designed to normalize serum levels of both insulin-like growth factor 1 and growth hormone. In patients with late-stage heart failure due to acromegalic cardiomyopathy, cardiac resynchronization therapy might be a desirable treatment to help cardiac synchronization, improve symptoms, and eventually reduce hospital admissions together with mortality rates.Case presentationWe describe a case of a 49-year-old man with a history of acromegaly who presented to our hospital with a diagnosis of decompensated systolic heart failure. Serial electrocardiograms showed wide (160–200 ms) QRS duration with left bundle branch block. Echocardiography showed severe left ventricular dysfunction that simultaneously achieved a left ventricular ejection fraction of 16%. Surgical indication was rarely assessed by neurosurgeons. Given that the stereotactic radiosurgery together with pharmacotherapy produced infinitesimal effects, cardiac resynchronization therapy was performed. Owing to biventricular synchronization and holding back reverse remodeling, the patient’s symptoms were successfully alleviated, and he was discharged from the hospital.ConclusionsCongestive heart failure is a rare complication in acromegaly-induced cardiomyopathy (occurs in only 3% of patients). Early diagnosis and treatment with curative drugs more than cardiovascular implantable electronic devices might lead to better surgical outcomes in this group of patients.

MON-433 The Spectrum Of Growth Hormone Excess In Carney Complex: Characterizing A Common Finding In A Rare Syndrome

Objective: Carney complex (CNC) is a familial lentiginosis and multiple endocrine neoplasia syndrome, caused by PRKAR1A gene mutations in 70% of patients. Involvement of the pituitary somatotrophs may lead to growth hormone (GH) excess; however, little is published about the progress and management of these patients. Objective: To describe the relative frequency of GH excess in a large cohort of patients with CNC, and to identify the characteristics and the natural history of the disorder. Methods: Via retrospective chart review, we identified 135 patients who have been diagnosed with CNC and had at least one clinical and biochemical evaluation of GH secretion at the Clinical Center, NIH, from 1995-2018. GH secretion was considered abnormal if any of the following criteria occurred: elevated IGF1 (according to sex and age- or Tanner-stage reference range), lack of suppression to Oral Glucose Tolerance Test (GH >2ng/mL for samples collected before 1/1/1999, or GH >1ng/mL for samples collected afterwards), increase of GH by > 50% after TRH stimulation test, and mean GH level > 4.5 ng/mL during serial GH sampling. Results: Fifty-five subjects (40.7%) had at least one abnormal result in the diagnostic tests for GH secretion. Twenty-eight subjects (20.7%) had at least 2 abnormal diagnostic tests, and fit the diagnosis of GH excess. The mean age at diagnosis was 26.7 yo (range:5.8-61.2), which was similar with the age at the latest follow up of the remaining patients (p=NS). The presence of PRKAR1A gene mutation was not associated with the presence of GH dysregulation (p= 0.63). Of the patients with dysregulation of GH secretion, 75% had abnormal pituitary MRI at any time of their evaluation: 23.5% before biochemical diagnosis, 41% at the time of the first biochemical finding and 9.8% after biochemical diagnosis. Of the patients with normal GH results, 45% had abnormal findings in the pituitary MRI, including enlargement of the gland or pituitary lesions, which was lower than the GH excess cohort (p=0.001) however clinically significant. Management of the patients differed according to their biochemical findings and clinical symptoms. Of the patients with GH excess and available follow up, 15 patients (55.5%) required more definite treatment: 7/15 were treated with somatostatin analogues and 8/15 underwent transsphenoidal resection of a pituitary adenoma, while the remaining retained mild GH excess despite no intervention. Conclusion: Dysregulation of GH secretion is a common finding in CNC. The spectrum of the disorder ranges from isolated structural abnormalities identified at imaging studies, mild dysregulation of growth hormone secretion, and clinically significant GH excess. The diagnosis of growth hormone excess and the selection of patients requiring any intervention is of outmost importance given the potential implication of GH excess in tumor progression and subsequent comorbidities.

SUN-LB074 Racial Distribution, Presentation and Outcome in Acromegaly and Cushing's Disease: A Tertiary Referral Center Study in 220 Patients

Background: Transsphenoidal surgery (TSS) is the primary therapy for acromegaly (ACM) and Cushing’s disease (CD) with superior outcomes at high-volume centers. According to the U.S. Central Brain Tumor Registry, African Americans (AA) have higher incidence of pituitary adenomas than non-Hispanic white (W) patients, but race-specific data in ACM and CD are not available. Our aims are to evaluate racial distribution, presentation, and long-term outcomes of adult patients who underwent TSS for these conditions at our pituitary center by a single dedicated neurosurgeon. Methods: We reviewed all cases of TSS operated between 1994-2016 and compared presentation and postoperative events (biochemical remission, recurrence, reoperation, radiation, and death) across racial demographic groups. For patients living in Metropolitan Atlanta, we used U.S. Census data to compare patient racial distribution to the demographics. Results The ACM group consisted of 112 patients (54 men and 58 women), of whom 87 were W and 13 AA. Age and gender were similar in AA and W. Main reasons for referral were physical changes (23% AA vs 44% W), headaches (38% AA vs 17% W), and pituitary incidentaloma (31% AA vs 14% W). AA had higher rates of diabetes (54% vs 16%, p 0.005) and hypertension (69% vs 42% p 0.08), lower mean IGF-1 levels (662±324 ng/ml vs 823±321 ng/ml, p 0.06), and lower median GH levels (8.6. vs 45 ng/ml p 0.002). Mean tumor diameter and cavernous sinus invasion were similar. Biochemical remission at 3 months (46% AA and 55% W) and event-free survival during follow-up (median 3.8 years) were similar in AA and W. Normal IGF-1 at last follow-up was achieved by 92% AA and 80%W after multimodality therapy. The CD group consisted of 108 patients (15 men and 93 women) of whom 70 were W and 24 AA. Age, gender, and prevalence of diabetes and hypertension were similar in AA and W. Mean urinary cortisol and ACTH levels were similar. Mean tumor diameter was similar but AA had more macroadenomas (33% AA vs 14% W). During follow-up (median 4.3 years), event-free survival was similar although AA had fewer recurrences (4.35% vs 22.0% W, p 0.06). Of the total 220 operated patients, 88% lived in Georgia and 59% in Metropolitan Atlanta. In the latter group, W represented 75% of ACM and 62% of CD patients; AA 16% ACM and 28% CD; Hispanics (H) 0% ACM and 6.5% CD; Asian 8.2% ACM and 3% CD. Census racial distribution during study period was 58-67% W, 33-34% AA, 7-10% H, and 3-5% Asians. Conclusions To our knowledge, this is the first report of race-specific patient characteristics in CD and ACM. Proportion of AA and H with ACM operated at our tertiary referral center was lower than expected, while such disparity was not seen in CD. In addition AA with ACM exhibited different clinical presentations and milder biochemical activity. Notably, the long-term outcomes of patients with ACM and CD treated at our center were similar in AA and W. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

MON-436 Clinical Phenotypes of GNAS Gene Mutations in Acromegalic Patients

Introduction Acromegaly is mostly caused by growth hormone (GH) hypersecretion. Guanine nucleotide-binding protein, α stimulating (GNAS) gene have been reported to be associated with GH secreting pituitary adenoma. Approximately 40% of patients with acromegaly have GNAS mutation. In this study, we investigated the prevalence of GNAS mutation in Korean acromegalic patients and assessed whether mutation status correlated with the biochemical or clinical characteristics. Method We studied acromegalic patients who underwent surgery between from July 2005 to January 2007 in Severance Hospital. Tumor genomic DNA was extracted using QIAamp DNA FFPE Tissue Kit from paraffin blocks of surgically resected tissue. GNAS gene analysis was performed with amplications of regions containing hotspot 2 sites of activating somatic mutations in codons 201 and 227. We evaluated the age, gender, GH, IGF-1 levels and immunohistochemical staining results of tumor. Biochemical remission of acromegaly was defined as a normal serum IGF-1 level or nadir GH after oral glucose tolerance test (OGTT) was less than 1ng/ml. Biochemical characteristics had been followed up at least 10 years. Result We analyzed 126 patients. GNAS mutations were present in 75 of the 126 acromegalic pateints (59.5%). Among the GNAS mutant patient, 61 subjects (81%) had mutation in codon 201. Patients with and without GNAS mutations were similar in age distribution and Hardy classification. The mutation negative group was 76.5% female and the mutation positive group was 48.0% female (p=0.006). GNAS mutant group had higher prevalence of overall GH expression in immunohistochemical staining (98.7% vs. 92.2%, p = 0.015). GNAS mutant patients are associated with higher IGF-1 level preoperatively (791.3 vs. 697.0ng/ml, p=0.045). Immediate postoperative basal GH (0.9 vs. 1.0ng/ml, p = 0.191) and nadir GH (0.3 vs. 0.6ng/ml, p=0.012) in OGTT was lower in GNAS mutant patients. Surgical remission rates were significantly higher in GNAS mutant patients, evaluated both at immediately and at 6 months after operation (70.7% vs. 54.9%, p=0.011; 85.3% vs. 82.4%, p=0.007, respectively). Conclusion In conclusion, GNAS mutation was more frequently found in Korean acromegalic patients. GNAS mutation positive tumors tended to have higher preoperative IGF-1 level, surgical remission rate and lower immediate postoperative nadir GH on OGTT. Identifying the GNAS mutation would be helpful in predicting patient’s clinical features and prognosis.