Acromegaly Research Articles

Double pituitary neuroendocrine tumors in a patient with normal growth hormone level acromegaly: A case report and review of the literature

Background: Acromegaly is a rare disease caused by growth hormone (GH) hypersecretion caused by a pituitary neuroendocrine tumor (PitNET). However, some acromegaly patients show normal GH levels, and they can be a pitfall in clinical diagnosis. Moreover, rarely, synchronous true double or multiple PitNETs are encountered. Moreover, these PitNETs increase the risk of a left lesion during surgical exploration. Case Description: The patient, who was a 73-year-old female, was referred to our hospital with a chief complaint of headache. Assessment of basal anterior pituitary function revealed a slightly high level of insulin-like growth factor-1 (IGF-1) (standard deviation, 2.4), and her physical findings exhibited mild acromegalic features. The endocrine evaluation confirmed acromegaly and magnetic resonance imaging (MRI) showed a macro PitNET with suprasellar extension. Endoscopic endonasal surgery (EES) was performed to remove the macro PitNET. Although postoperative MRI showed complete removal of the macro PitNET, endocrinological testing indicated no improvement in GH or IGF-1 excess. Pathological examination of the surgical specimen revealed a gonadotropic PitNET. Therefore, we repeated the MRI scan and found a micro PitNET in the thin left normal pituitary gland. A second EES was successfully performed to remove the micro PitNET completely, and both endocrinological and pathological examinations confirmed that the disease was cured. Conclusion: Diagnosing acromegaly with low GH levels requires close monitoring. Double PitNETs are relatively rare and can cause incomplete remission of functional PitNETs.

Diabetes mellitus in acromegaly: prevalence, pathophysiological particulars and treatment strategies

The prevalence of diabetes mellitus in acromegaly is significantly higher than that in the general population. Carbohydrate metabolism abnormalities often precede other phenotypic manifestations of acromegaly. The review presents data on the prevalence of carbohydrate metabolism disorders in acromegaly and describes their pathophysiological characteristics and approaches to treatment.
 Growth hormone (GH) excess is recognized as a key factor of glucose homeostasis abnormalities due to decreased insulin sensitivity (resulting from active lipolysis) and direct stimulation of insulin secretion. Insulin-like growth factor 1 (IGF1) improves insulin sensitivity; however, the GH diabetogenic effects prevail over the insulin-sensitizing impact of IGF1. Surgical and radiation treatment for somatotropinoma may indirectly improve carbohydrate metabolism, because they decrease the GH levels. Treatment with first generation somatostatin analogues can both improve glycemic control due to decreased GH levels and worsen it due to deterioration of postprandial insulin release, especially in patients with already manifest carbohydrate metabolism disorders. The GH receptor antagonist pegvisomant blocks the effects of excess GH on the target tissues without suppressing insulin secretion, which results in better glucose control; treatment with this agent can be preferred in patients with acromegaly and diabetes mellitus. Management of carbohydrate metabolism disorders in acromegaly is done in accordance with general treatment principles for type 2 diabetes mellitus.

The clinical presentation of PIT1 positive pituitary neuroendocrine tumor immunonegative for growth hormone, prolactin, and thyroid stimulating hormone with analysis of clinical and immunostaining dissociation

BackgroundPIT1 is a pituitary transcription factor that is associated with either growth hormone (GH), prolactin (PRL), or thyroid-stimulating hormone (TSH) production. However, PIT1-positive pituitary neuroendocrine tumors (PitNETs) are occasionally immunonegative for GH, PRL, and TSH. This paper describes the clinical presentation of PIT1 positive however immunonegative PitNETs. MethodsWe conducted a retrospective analysis, identifying 228 PIT1-positive PitNET patients between 2017 and 2022. Out of these, ten (4%) tested negative for GH, PRL, and TSH. Functioning PitNETs were defined as those causing hormonal excess symptoms or hormonal overproduction. ResultsAs for 10 patients immunonegative for all three hormones however PIT1-positive, the mean ( ± standard deviation) age was 46 ± 13 years with 70% women. Six patients exhibited signs of excess GH or PRL, and three had visual problems. Additionally, one patient had secondary hypothyroidism and adrenal insufficiency resulting from the mass effect. All tumors were macroadenoma, with a median volume of 2.1 cm3 (range, 0.8–17.5 cm3). Gross total resection was attained in six patients by trans-sphenoidal surgery. Postoperatively, eight patients experienced clinical improvement: three in vision, two in amenorrhea, two in headache, and one in acromegaly symptoms. Biochemical improvement was observed in six patients, with all experiencing remission in hormonal excess and one showing improvement in secondary hypothyroidism. Stereotactic radiosurgery was performed in three patients. ConclusionsPatients with functioning PitNETs may exhibit PIT1 staining without GH, PRL, or TSH staining. Hormonally active tumors exist in this patient population; therefore, close endocrine follow-up is necessary despite the lack of staining for GH, PRL, and TSH.

Impact of Variation between Assays and Reference Intervals in the Diagnosis of Endocrine Disorders.

Method-related variations in the measurement of hormones and the reference intervals used in the clinical laboratory can have a significant, but often under-appreciated, impact on the diagnosis and management of endocrine disorders. This variation in laboratory practice has the potential to lead to an errant approach to patient care and thus could cause harm. It may also be the source of confusion or result in excessive or inadequate investigation. It is important that laboratory professionals and clinicians know about these impacts, their sources, and how to detect and mitigate them when they do arise. In this review article, we describe the historical and scientific context from which inconsistency in the clinical laboratory arises. Examples from the published literature of the impact of the method, reference interval, and clinical decision threshold-related discordances on the assessment and monitoring of various endocrine disorders are discussed to illustrate the sources, causes, and effects of this variability. Its potential impact on the evaluation of growth hormone deficiency and excess, thyroid and parathyroid disorders, hyperandrogenism, hypogonadism, glucocorticoid excess and deficiency, and diabetes mellitus is elaborated. Strategies for assessment and mitigation of the discordance are discussed. The clinical laboratory has a responsibility to recognise and address these issues, and although a lot has been accomplished in this area already, there remains more to be done.

Growth hormone excess in children with pituitary adenomas associated with endocrine syndromes

Growth hormone excess in children with pituitary adenomas associated with endocrine syndromes

The role of hormonal status, morphological subtypes and proliferative marker Ki-67 labeling index on long-term outcomes in patients with acromegaly: a single tertiary center’s experience

Aims: Acromegaly is a rare disorder resulting from benign growth hormone secreting pituitary adenomas. Many factors affect long-term outcomes in acromegaly. In this study we aimed to investigate effects of hormonal status, morphological subtypes, immunohistochemical expression of pituitary hormones and Ki-67 labeling index on long-term outcomes in patients with acromegaly.
 Methods:. We collected the medical and pathological records of sixty-four patients who underwent surgery for growth hormone (GH) secreting somatotroph tumors between 2005-2017.
 Results: The remission rate after surgery was 48% (31/64) in all patients (33% for macroadenomas, 94% for microadenomas; p

Сytotoxic T lymphocyte-associated protein 4 (CTLA4) is overexpressed in a subset of prolactin- and growth hormone-secreting pituitary adenomas.

Cytotoxic T lymphocyte-associated protein 4 (CTLA4), a negative regulator typically expressed on the surface of T lymphocytes, is targeted by immunotherapy in patients with an ever-expanding spectrum of cancers. Characterizing the expression of CTLA4 in the pituitary gland could provide additional rationale for using immune checkpoint inhibitors in pituitary adenoma patients who do not respond to conventional treatments. We assessed the expression of CTLA4 mRNA and protein in a panel of 157 human pituitary glands, 45 collected at autopsy and 112 at surgery. These specimens included 50 normal glands and 107 adenomas: 41 nonsecreting, 25 PRL-, 24 ACTH-, 11 GH-, 2 TSH-, 1 FSH-secreting, and 3 atypical. Specimens were stained for CTLA4 and adenohypophyseal hormones using RNAscope in situ hybridization, immunohistochemistry, and RNAscope Multiplex Fluorescent Assay. CTLA4 mRNA was detectable in most normal pituitary glands (48 of 50, 96%) but varied in expression, with a histological score (H-score) ranging from 0.6 to 20. The variation did not depend upon the patient's gender and age and was not significantly affected by the archival storage time. CTLA4 expression was higher (P = 0.022) in pituitary adenomas than normal glands, with the greatest levels seen in PRL- and GH-secreting adenomas (P = 0.009 and 0.023 versus normal, respectively). Eight of 25 (32%) prolactinomas and 3 of 11 (27%) GH-adenomas had an H-score greater than 20, while no differences were seen for the other types. These novel data highlight the expression of an immune checkpoint such as CTLA4 on pituitary endocrine cells, a finding that could be exploited for therapeutical applications.

Clinical characteristics and therapeutic outcomes of acromegalic patients with giant growth hormone-secreting pituitary adenomas: a single-center study of 67 cases.

Acromegalic patients with giant growth hormone-secreting pituitary adenomas (GHPAs) (≥ 40mm) are relatively rare, and their clinical characteristics and treatment outcome data are limited. This study aims to analyze the clinical practice experience of giant GHPAs. Sixty-seven acromegalic patients with giant GHPAs and 67 patients with macro GHPAs (10-39mm), matched for age and gender from the same hospital during the same period, were retrospectively recruited. The clinical characteristics, treatment, and outcomes were analyzed. Enlargement of the extremities and facial features were the most common symptoms in most patients (92.5%). Compared with the macroadenoma group, more frequent visual impairment (86.6% vs. 25.4%, P < 0.001) and gonadal axis dysfunction (49.3% vs. 34.3%, P = 0.008), higher preoperative fasting GH, nadir GH after OGTT and IGF-1 levels, and a higher proportion of extrasellar tumor invasion were seen in the giant adenoma group. As the adenoma size increases, the total resection rate decreases, and postoperative complications and multimodal treatment strategies increase significantly. Fasting and nadir GH levels remained higher at 1week postoperatively, and there were more surgical complications and cases of anterior hypopituitarism in the giant group. After a median follow-up of 36months, 12 patients (36.4%) in the giant GHPA group and 17 (36.2%) in the macro GHPA group achieved biochemical remission. Other factors such as age of onset, age of diagnosis, delayed diagnosis time, metabolic complications, p53 positive rate, and Ki-67 index showed no significant difference between the two groups. With aggressive multimodal therapy, the biochemical remission rate of acromegalic patients with giant GHPAs is comparable to that of patients with macro adenoma. However, postoperative complications and hypopituitarism need to be closely monitored.

Development and characterisation of a novel inhibitory anti-GH monoclonal antibody.

Excess growth hormone (GH) has been implicated in multiple cancer types and there is increasing interest in the development of therapeutic inhibitors targeting GH-GH receptor (GHR) signalling. Here we describe a panel of anti-GH monoclonal antibodies (mAbs) generated using a hybridoma approach and identify two novel inhibitory mAbs (1-8-2 and 1-46-3) that neutralised GH signalling. mAbs 1-8-2 and 1-46-3 exhibited strong inhibitory activity against GH-dependent cell growth in a Ba/F3-GHR cell viability assay, with EC50 values of 1.00 ± 0.27 and 0.5 ± 0.1 µg/mL, respectively. Cross-reactivity with the human placental hormones, placental lactogen (PL) and placental GH, was observed by ELISA, but neither antibody cross-reacted with mouse GH or human prolactin (PRL). mAb 1-8-2 had a binding affinity for GH of KD 0.62 ± 0.5 nM, while mAb 1-46-3 had a KD of 2.68 ± 0.53 nM, as determined by bio-layer interferometry. mAb 1-46-3 inhibited GH-dependent signal transduction in T-47D and LNCaP cancer cell lines and reduced GH-dependent cell growth and migration in the breast cancer cell line T-47D. mAb 1-46-3 inhibited T-47D cell viability more effectively than the GHR antagonist B2036. In conclusion, we describe two novel inhibitory anti-GH mAbs and provide in vitro evidence supporting development of these entities as anti-cancer therapeutics.

Salivary microbiome profiles for different clinical phenotypes of pituitary adenomas by single-molecular long-read sequencing.

Pituitary adenomas (PAs) are common benign brain tumors. Although associations between the gastrointestinal microbiome and PA have been reported previously, studies on the distributions of salivary microbial species in PA patients and among their different clinical phenotypes are currently lacking. In this study, saliva samples from 42 patients and 20 healthy individuals were selected for third-generation sequencing. The PA group included four clinical phenotypes: adrenocorticotropic hormone-secreting PA (n = 6), growth hormone-secreting PA (n = 9), prolactin-secreting PA (n = 18), and nonfunctioning PA (n = 9). All samples were sequenced, and the data were clustered and de-chimerized to obtain information regarding the abundance of operational taxonomic units. We found that the species distributions in the saliva of PA patients were more abundant than those of healthy individuals. A total of 82 genera were identified across all samples, of which 14 and 17 genera were more abundant in the saliva samples of patients with PA and healthy individuals, respectively. In the phenotypic functional prediction, the phenotypes of anaerobic and Gram-positive organisms were more commonly seen in patients with PA than in healthy individuals. The bioinformatics prediction indicated that multiple metabolic pathways were involved in the pathogenesis of PA. In conclusion, this study highlighted the associations of salivary microbiome profiles with PA, which may improve the existing understanding of the pathogenesis of PA and provide diagnostic and therapeutic targets for PA.IMPORTANCEThe gut and salivary microbiomes have been widely reported to be significantly associated with a number of neurological disorders. The stability of the microbiome in the oral cavity makes it a potentially ideal sample that can be conveniently obtained for the investigation of microbiome-based pathogenesis in diseases. In the present study, we used a single-molecule long-read sequencing technique to study the distribution of the salivary microbiota in patients with pituitary adenoma (PA) and healthy individuals, as well as among four clinical phenotypes of PA. We found that the diversity of salivary microbes was more abundant in PA patients than in healthy individuals. We also observed some unique genera in different PA phenotypes. The bioinformatics-based functional predictions identified potential links between microbes and different clinical phenotypes of PA. This study improves the existing understanding of the pathogenesis of PA and may provide diagnostic and therapeutic targets for PA.

Hipofizės adenoma: literatūros apžvalga ir sąsajos su TAS2R16 (rs978739, rs1357949) geno polimorfizmais

The pituitary gland is the primary regulatory gland in the endocrine system transmitting signals from the hypothalamus to target organs through hormone release. Through the release of hormones, the pituitary gland regulates vital physiological functions: growth, reproduction, metabolism, and the stress response. Disorders in the pituitary gland can cause damage, such as pituitary adenomas (PA). PA is the most common benign tumor arising from epithelial cells of the anterior pituitary gland. PA is one of the most common tumors of the central nervous system. PA is differentiated by hormone secretion into non-secretory (non- functional) and secretory (functionally active). Excess hormones secreted by PA can cause clinical syndromes, such as hyperprolactinemia (caused by excessive secretion of prolactin), acromegaly (due to excess growth hormone), and Cushing’s syndrome (due to excessive production of the adrenocorticotropic hormone ACTH)). Studies show that the prevalence of adenomas in the population is approximately 80/100,000. The occurrence of PA is influenced not only by somatic or germ cell defects but also by environmental factors. The exact cause of PA is still unclear, but it is known that a small part (~5%) of PA due to hereditary syndromes is caused by gene changes. Considering the influence of environmental factors and genetic alterations that affect the occurrence of PA, new genetic markers can be searched to detect this disease. One of the risk factors contributing to the development of PA and its aggressiveness is alcohol consumption. Excessive alcohol consumption affects not only the development of PA but also the manifestation of other cancers. A recent study has investigated the association of TAS2R16 gene single nucleotide polymorphisms (SNPs) with colon cancer, as SNPs in this gene have been found to increase alcohol dependence. Based on the association of TAS2R16 SNPs with cancer, we decided to investigate the association of TAS2R16 gene (rs978739, rs1357949) polymorphisms with PA.

THU061 Treatment Patterns In Acromegaly: Analysis Of Real-World US Insurance Claims From The MarketScan® Database

Abstract Disclosure: M. Fleseriu: Advisory Board Member; Self; Amryt, Ipsen, Recordati Rare Diseases, Pfizer, Inc. Grant Recipient; Self; Amryt, Crinetics, Ionis Pharmaceuticals Inc. A.L. Barkan: None. T.C. Brue: Advisory Board Member; Self; Advanz Pharma, Debio Pharm, Recordati Rare Diseases. Consulting Fee; Self; Ipsen, Recordati Rare Diseases, Novartis Pharmaceuticals, Pfizer, Inc. Grant Recipient; Self; Pfizer, Inc. Other; Self; Ipsen, Recordati Rare Diseases, Novartis Pharmaceuticals, Pfizer, Inc. E. Duquesne: Employee; Self; Ipsen. A. Houchard: Employee; Self; Ipsen. Stock Owner; Self; Ipsen. M. del Pilar Schneider: Employee; Self; Ipsen. A. Ribeiro-Oliveira Jr.: Employee; Self; Ipsen. Stock Owner; Self; Ipsen. S. Melmed: Advisory Board Member; Self; Ionis Pharmaceuticals Inc., Ipsen, Novo Nordisk, Recordati Rare Diseases. Grant Recipient; Self; Pfizer, Inc. Background: Medical treatment for acromegaly (characterized by excess growth hormone [GH] production) includes somatostatin receptor ligands (SRLs), dopamine agonists (DAs), and GH receptor antagonists (GHRAs). However, there are few real-world treatment evaluations in the US. We present treatment patterns for patients receiving medications for acromegaly (1/1/2010-7/31/2022). Methods: De-identified data were extracted from MarketScan®, a US health insurance claims database. Eligible patients: those receiving monotherapy or combination therapy (≥2 treatments overlapping for &amp;gt;3 months [m]) for ≥90 days without treatment gaps; ≥2 claims associated with acromegaly; data ≥3 m before and ≥6 m after diagnosis/first treatment claim (earlier date); and ≥18 years (y) old at diagnosis. Outcomes were: demographic characteristics; treatment frequency by line of treatment (LOT) and changes between LOTs (Sankey plot); treatment persistence for first LOT (LOT 1) monotherapies (Kaplan-Meier estimator); and treatment up-/downtitration (≥30% dose change, evaluated for octreotide long-acting release [OCT] and lanreotide depot [LAN]). Biochemical control values were unavailable in the database. Results: Of 882 patients, 50.1% were female; mean age at diagnosis was 48.6 y (standard deviation 13.6 y). In the cohort, 59.4% had exactly 1 LOT, 23.1% had exactly 2 LOTs, and 17.5% had exactly 3 LOTs. The most common LOT 1 medication class was first-generation SRLs: OCT (27.7%) and LAN (21.1%). Other LOT 1 classes were Das (cabergoline; 34.5%) and GHRAs (pegvisomant; 10.5%). Only 7 patients received second-generation SRL pasireotide and no patients received oral octreotide in LOT 1. Most patients initiated treatment with monotherapies (94.6%). In monotherapy LOT 1, GHRAs had the longest median persistence (pegvisomant; 24.8 m; 95% confidence interval [CI]: 16.59-32.49 m; n=93), followed by OCT and LAN (20.0 m; 95% CI: 16.98-23.87 m; n=430). Das had the shortest persistence (cabergoline; 14.4 m; 95% CI: 12.23-16.82 m; n=304). Among patients receiving OCT or LAN, 67.6% had ≥1 dose increase and 45.0% had ≥1 dose reduction. Conclusions: Despite guidelines recommending DA monotherapy for few select patients with acromegaly,1 our real-world analysis found that approximately one-third of patients initiated treatment with this class with the shortest treatment persistence. OCT and LAN monotherapies were also commonly used as LOT 1 and had longer persistence. GHRAs, the class with the longest persistence, were not common monotherapy in LOT 1, possibly because they do not target pituitary adenomas directly. Interestingly, only 5% of patients initiated treatment with combination therapies. Recommendations for individualized therapy2 should consider medication persistence and real-world treatment patterns. 1Giustina et al. Rev Endocr Metab Disord. 2020 2Fleseriu et al. Lancet Diabetes Endocrinol. 2022 Presentation: Thursday, June 15, 2023

THU483 Role Of Excess GH On Breast Cancer Aggressiveness And Metastasis In Acromegaly

Abstract Disclosure: J. Oh: None. C. Kang: None. E. Wang: None. S. Lee: None. J. Nam: None. C. Ku: None. E. Lee: None. Introduction Acromegaly is a rare disease characterized by chronic growth hormone (GH) and insulin-like growth factor-1 hypersecretion. In previous studies, it is known that the incidence of breast cancer increases in patients with acromegaly. For breast cancers, autocrine GH and GHR are expressed in primary lesion, which is significantly increased in metastatic one. To date, however, the precise mechanism of endocrine GH in breast cancer metastasis has not been defined. This study aimed to investigate the role of endocrine excess GH facilitating breast cancer metastasis in acromegaly mice model. Method We used Aiplox/lox (Con) and rGHp-Cretg/+; Aiplox/lox mice (Acro), which was previously established to model the phenotype of human acromegaly. To generate orthotopic xenograft model, we used C57BL/6 female mouse derived breast cancer cell line Py230 cells. Py230 cells were injected into mammary gland and tumor volumes were measured every 2 days. Tumor growth and metastasis were confirmed by bioluminescent in vivo imaging system (IVIS). Also, we investigated the effects of GH on triple negative breast cancer cell lines, which have the higher expression of GHR. To define GH induced pathway, we performed RT2 array. Cell proliferation was investigated with MTT assay and cell migration was investigated with wound healing assay and transwell invasion assay. Results In mouse orthotopic xenograft studies, tumor volumes of Acro mice were higher than that of Con mice (increase of 310%, 846.04±290.7 vs. 205.97±33.7 mm3, p=0.001). The tumor volume and serum GH level showed positive correlation (R2= 0.4739, p=0.027). After 14 weeks, the Acro mice showed significantly increased bioluminescence activity in the lung (increase of 1023%, 494666.7±104668.2 vs. 44037.7±6641.9 AU, p=0.0127). When GHR antagonist was treated, tumor growth and lung metastasis were decreased. We excised primary tumor and lung metastatic foci and performed RT2 array. We found Tcf-20 gene, which is upregulated in both primary tumor and lung metastatic burden (increase of 216%, p=0.0153). We confirmed GH induced Tcf-20 gene induction (increase of 57% (p=0.043), 41% (p=0.05), 67% (p=0.0021) in Hs578T, Py230 (p=0.05), and Hcc1806 cells each). We knocked down Ghr or Tcf-20 genes and observed decrease of invasion and migration compared to GH treated siCON HCC1806 (decrease of 64.5% in siGHR, decrease of 83.3% in siTCF-20, compared to siCON cells, p=0.000819977) and Py230 cells (decrease of 47.3% in siGHR transfected, decrese of 49.3% in siTCF-20 transfected, compared to siCON cells, p=0.0012). Conclusion Excess GH in acromegaly possess a strong potential to promotes tumor development and metastasis. We identified a molecular mechanism by which GH-induced TCF-20 promote tumor aggression and metastasis. These findings can aid in the development of improved strategies for managing cancer in acromegalic patients. Presentation: Thursday, June 15, 2023

OR0304 Novel Dual Antagonists Of The Growth Hormone Receptor And The Prolactin Receptor

Abstract Disclosure: R. Basu: None. J.J. Kopchick: None. An excess of the human growth hormone (hGH) is associated with multiple pathophysiology including acromegaly, diabetes, cancer, renal dysfunction and age-associated cognitive impairment. On the other hand, a congenital lack of GH action in humans and mice render a protective effect from the above co-morbidities. Consequently, there exists significant pharmaceutical interest in developing antagonists of GH action - rendered via binding and activating the GHR, as well as the prolactin receptor (PRLR), which is particularly relevant for PRLR-rich cancers of the breast and prostate. Our laboratory has pioneered the discovery of the first and only FDA approved GHR antagonist - Somavert (pegvisomant for injection, Pfizer Inc., USA) - currently prescribed for the treatment of acromegaly. Here we present two new and unique designs of antagonists which block the complete spectrum of GH action at both GHR and PRLR binding. The first GHR antagonist design is a full-length G120K-hGH peptide at the core, incorporating targeted cysteine (single or double) substitutions at carefully selected solvent-accessible residues distal to the binding sites. To these substituted cysteines, maleimide activated discrete PEGs (MAL-dPEG; neutral or anionic, branched, different sizes) were specifically conjugated to build a library of multiple putative GHR antagonists. Binding studies and biochemical activities reveal multiple promising GHRA candidates with high binding affinities to both GHR and PRLR, while the biological assays show robust inhibition of GH driven intracellular signaling and oncogenic processes in cultured human cancer cell lines. Intraperitoneal administration of a selected candidate (compound-G) in mice significantly reduced serum IGF1 and IGFBP3 as well, confirming in vivo efficacy. The second candidate antagonist termed ‘S1H’ is a 16-amino-acid peptide designed as a direct sequence mimetic of a unique fragment of the site-1 binding helix of the hGH molecule. To this end we have characterized S1H with mass spectrometry, circular dichroism spectropolarimetry, and in vitro biological assays using human cell lines expressing GHR. S1H inhibited GH as well as PRL induced STAT5 phosphorylation in a dose-dependent manner in multiple cell lines. Moreover, using alanine scanning mutagenesis studies, we identified a strong correlation between the helical propensity and biological activity of S1H - allowing extensive structure activity relationship studies. Thus, we present two distinct designs, preparation and characterization of dual antagonists of the GH action at the level of GHR and PRLR, with prospective applications in pathologies associated with a GH excess and also as valuable compounds to study the nature of human GH-GHR interactions. We currently continue to develop both compounds for pre-clinical validations. Presentation: Thursday, June 15, 2023

FRI356 SIADH In Acromegaly And Cerebrovascular Accident

Abstract Disclosure: S. Siddiqui: None. I.A. Guatemala Funes: None. G. Simranpreet: None. T. Zahedi: None. F. Zhang: None. Introduction: Acromegaly is characterized by excess growth hormone secretion with distinctive features of acral overgrowth, soft tissue swelling, arthralgia, jaw prognostication, hyperglycemia, hyperhidrosis, and frontal bone bossing. Hypotonic hyponatremia may occur in patients with syndrome of inappropriate antidiuretic hormone secretion (SIADH), hypothyroidism, hypocortisolism, polydipsia, medications, heart failure, liver disease, or renal dysfunction. We reported a rare case of a patient with acromegaly treated with octreotide (somatostatin analogue) who was admitted for cerebrovascular accident and developed hyponatremia due to SIADH. Case Report: Patient is an 81 year old female with typical clinical features of acromegaly who presented with expressive aphasia and left sided facial droop. MRI and CT head revealed a 26 x 14 x 29 mm densely calcified/ossified extra-axial mass in the posterior fossa, displacing the brainstem and small vessel ischemia. Patient was treated with monthly intramuscular injection of octreotide for more than 20 years before she was switched to oral octreotide formula two weeks ago. Patient had nausea, vomiting, and altered mental status. Labs showed hyponatremia with serum Na 118 mmol/L, low serum osmolality 247 mOsm/kg, high urine osmolality 437 mOsm/kg, and urine Na 104 mmol/L. Serum Na further dropped to 115 mmol/L after IV normal saline which may be related to the desalination phenomenon of SIADH. Tolvaptan and hypertonic saline were initiated followed by treatment with salt tablets and furosemide. After several days, her serum Na level slowly trending up back to normal 135 mmol/L and patient recovered with no focal neurological deficits. Discussion: Treatment for acromegaly involves multiple approaches, such as somatostatin receptor ligands, GH antagonism, surgery, radiotherapy, and dopamine receptor agonists. Life-treating endocrine disorder may result from pituitary infarction or hemorrhage in patient with acromegaly. Although gastrointestinal sodium loss may precipitate hyponatremia in our patient, her elevated urine sodium and urine osmolality were consistent with SIADH. Clinicians should be cautious of the sudden onset of hyponatremia due to SIADH in acromegaly patients and prompt treatment is warranted. Presentation: Friday, June 16, 2023

FRI023 Increased Fibrosis In White Adipose Tissue Of Male And Female bGH Transgenic Mice Appears Independent Of TGF-β Action

Abstract Disclosure: G. Lach: None. S. Bell: None. J.A. Young: None. E.O. List: None. R. Basu: None. D. Geitgey: None. K.Y. Lee: None. D. Swegan: None. L.J. Caggiano: None. S. Okada: None. J.J. Kopchick: None. D.E. Berryman: None. Fibrosis is a pathological state caused by excess deposition of extracellular matrix proteins, which can disrupt tissue structure and function. Previous work has shown that male bovine growth hormone (bGH) transgenic mice have high levels of circulating growth hormone (GH) and insulin-like growth factor 1 (IGF-1), marked decrease in lifespan, and increased fibrosis in several tissues including white adipose tissue (WAT), which is more pronounced in the subcutaneous (Sc) depot. The current study expanded on these findings, evaluating: 1) WAT fibrosis in female bGH mice, 2) levels of circulating factors implicated in fibrosis, and 3) the role of TGF-β, a central mediator of fibrogenesis, in the development of bGH WAT fibrosis. Our findings confirmed that female bGH mice exhibit increased WAT fibrosis, most prominent in the Sc depot, like male bGH mice, but also significantly increased in the perigonadal depot, unlike male bGH mice. bGH mice of both sexes have elevated circulating levels of several markers of collagen turnover (plasma P1NP, P3NP and ICTP) and FGF21 relative to controls but no genotype-dependent alteration in fibroblast activation protein (FAP). TGF-β and TGF-β signaling in serum or WAT was either unchanged or reduced in male and female bGH mice at both young and mature ages. The treatment of bGH mice with a TGF-β antagonist, pirfenidone, did not attenuate bGH WAT fibrosis. Contrary to the effects of the chronic exposure to excess GH, acute GH treatments in vivo or in vitro did elicit a modest increase in TGF-β signaling. Finally, single nucleus RNA sequencing confirmed no perturbation in TGF-β or its receptor gene expression in any WAT cell population within subcutaneous bGH WAT; however, a striking increase in B lymphocyte infiltration in Sc bGH WAT was observed. Overall, these data suggest that bGH WAT fibrosis is independent of the action of TGF-β and reveals an intriguing shift in immune cells, particularly B cells, in bGH WAT that should be further explored considering the increasing importance of B cell-mediated WAT fibrosis and aging. Acknowledgements:This work was sponsored, in part, by ASPIRE grant funding from Pfizer. This work was also supported by the State of Ohio’s Eminent Scholar Program to J. J. K. that includes a gift from Milton and Lawrence Goll and by the startup funds from the Heritage College of Osteopathic Medicine at Ohio University, Athens, OH. Presentation: Friday, June 16, 2023

Lesion Expansion in Gnathic Fibrous Dysplasia: Natural History, Indicators of Progression, and Response to Bisphosphonates.

Fibrous dysplasia (FD) is characterized by expansile fibro-osseous lesions that may occur in association with endocrinopathies as part of McCune-Albright syndrome (MAS). Craniofacial FD is a significant source of morbidity and most commonly involves the gnathic bones. There is a critical need to understand the natural history and risk factors for gnathic FD progression to develop preventative trials and identify candidates for intervention. The purpose of this study was to characterize gnathic FD lesion expansion and to identify risk factors associated with lesion growth. Patients with gnathic FD and serial CT imaging were evaluated. Volumetric analyses of CT scans were performed using MIM Encore software. Generalized mixed model analysis was used to account for intra-subject correlation, with FD lesion volume as the dependent variable. In addition to age, effects of MAS-associated endocrinopathies, sex, disease severity, and bisphosphonate treatment were evaluated. A total of 104 total lesions in 52 patients were characterized longitudinally. Median age at initial scan was 8.8 years (range 3.4-18.8), and median age at final scan was 16.8 years (range 6.9-33.4 years). The median number of scans per subject was 4 (range 2-14). FD lesion volume increased with age (2.50 cm3 /yr, 95% confidence interval [CI] 1.95-3.04, p < 0.001). However, lesion expansion rate decreased over time (-0.05 cm3 /yr, 95% CI -0.07 to 0.04, p < 0.001). Mandibular lesions tended to expand at a greater rate than maxillary lesions (p < 0.001). Growth hormone excess was associated with accelerated expansion rate (p = 0.002). Other MAS-associated endocrinopathies, pubertal status, sex, weight, lesion density, disease severity, and bisphosphonate treatment were not associated with lesion volume or expansion. Gnathic FD lesion expansion is most rapid in younger children and declines as patients approach adulthood. The availability of quantitative natural history data will guide clinicians in identifying patients who are candidates for medical and surgical interventions and clinical trials for preventative therapies. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.

Somatostatin receptor expression and clinical outcome of multilineage pituitary tumours expressing PIT1 and SF1.

The application of transcription factor immunohistochemistry to pituitary neuroendocrine tumour (PitNET) assessment has allowed identification of tumours that do not conform to a single lineage. Multilineage pituitary transcription factor 1 (PIT1) and steroidogenic factor 1 (SF1) PitNETs are a rare and relatively newly described tumour subtype. These tumours express both transcription factors and may also express combinations of hormones corresponding to both lineages. Histological and clinical characteristics can vary, and overall clinical behaviour and prognosis is not known. We describe the clinical outcomes and somatostatin receptor status (SSTR) of a series of nine cases identified from our cohort of pituitary tumours at Westmead Hospital. Eight PitNETs (88.9%) expressed growth hormone and caused acromegaly at presentation. Of the seven macrotumours that caused acromegaly, one had cavernous sinus invasion. The Ki-67 labeling index score ranged from 0.6% to 3.6%. About 88% of tumours that secreted excess growth hormone exhibited strong immunostaining for SSTR 2 and all tumours displayed weak immunoreactivity for SSTR5. In 62.5% of patients with acromegaly, cure was achieved after surgical resection. Somatostatin receptor ligands resulted in clinical remission in cases where medical treatment was initiated. There was no new tumour recurrence or regrowth over an overall mean follow-up period of 62.5 months.

Uric acid levels correlate with disease activity in growth hormone-secreting pituitary adenoma patients.

Few studies reported the effects of growth hormone-secreting pituitary adenoma (GHPA) on uric acid (UA) metabolism and the relationship between growth hormone (GH)/insulin-like growth factor-1 (IGF-1) levels and UA are controversial. This study aimed to evaluate the relationship between IGF-1 and UA in patients with GHPA and to further clarify whether UA levels are associated with GHPA disease activity by follow-up. A longitudinal study of 424 GHPA patients presenting to Beijing Tiantan Hospital, Capital Medical University between January 2015 and January 2023 was conducted. Spearman's correlation tests were performed to examine the relationship between IGF-1 and UA at baseline. Univariate and multivariate linear regression analysis was conducted to investigate the independent association between UA and IGF-1. Changes in postoperative IGF-1 and UA levels were followed prospectively, and the differences in UA levels between the biochemical remission and nonremission groups were compared. At baseline, male patients, the lower the age, the higher the IGF-1 and body mass index (BMI), and the higher the UA levels. IGF-1 was significantly associated with UA after controlling for sex, age, and BMI (r = 0.122, P = 0.012). In adjusted multiple linear regression analysis, IGF-1 was independently associated with UA, and UA levels increased significantly with increasing IGF-1. During postoperative follow-up, UA decreased gradually as IGF-1 levels decreased. At 12 months postoperatively, UA levels were significantly lower in the biochemical remission group than in the nonremission group (P = 0.038). In patients with GHPA, UA levels are associated with disease activity. Changes in UA levels should be taken into account in the comprehensive treatment of GHPA, patients presenting with HUA should be given lifestyle guidance and appropriate urate-lowering treatment according to their condition to better improve their prognosis.

Impact of growth hormone on physical performance

Growth hormone (GH) is an anabolic hormone produced by the pituitary gland. The action of growth hormone is not only to promote growth in children, but it has a significant effect on metabolism and body composition also in adults. Growth hormone deficiency (GHD) leads to physical impairment (worsen muscle strength, aerobic and anaerobic capacity) and altered body composition - with increased fat and reduced lean body mass, particularly reduced skeletal muscle mass. On the other hand, GH excess in patients with acromegaly impairs physical function, especially aerobic capacity and muscle strength irrespective of GH-dependent muscle hypertrophy. There is unclear data about GH impact on physical performance among healthy populations. Some studies showed improvement in anaerobic capacity during recombinant human GH (rh-GH) administration, others showed no significant difference. Muscle strength did not improve after rh-GH administration among healthy adults. However, recombinant GH is abused by professional and recreational athletes to improve their physical performance.