Acromegaly Research Articles

Co-expression of multiple transcription factors is associated with clinical features and endocrine prognosis in growth hormone-secreting pituitary adenomas.

The types of growth hormone-secreting pituitary adenomas are diverse, we have found that there are significant differences in clinical features and prognosis between PIT-1 single-cell spectrum growth hormone adenomas and growth hormone phenotypic polyhormonal adenomas. This study examined a cohort of 193 patients with growth hormone-secreting pituitary adenoma (GHPA), stratifying them into two groups: PIT-1 single transcription factor positive growth hormone adenoma (STF-GHPA) and Multiple transcription factor-positive growth hormone-secreting adenomas (MTF-GHPA). The objective was to compare these two groups' clinical characteristics. Within the MTF-GHPA group, we further subtyped them based on transcription factors to evaluate potential variations in clinical manifestations. Logistic regression analyses were employed to develop a risk factor model for investigating factors influencing hormone remission. There were no statistically significant differences in terms of age, gender, serum GH, and IGF-1 levels between patients diagnosed with MTF-GHPA and STF-GHPA. However, patients with MTF-GHPA exhibited a higher proportion of hypopituitarism compared to those with STF-GHPA. Furthermore, MTF-GHPA were characterized by smaller tumor size and less invasiveness, as indicated by lower Knosp classes. However, patients with MTF-GHPA have a lower rate of hormonal remission (30.8%) and more postoperative complications (31.0%), which means that STF-GHPA (hormonal remission:71.6%; postoperative complications:13.4%) has a better endocrine outcome than MTF-GHPA patients. Between the PIT-1 + SF-1+ and PIT-1 + TPIT+ subtypes within MTF-GHPA, significant differences were also observed in tumor size, endocrine outcomes, and postoperative complications. Risk factors influencing hormonal remission for GHPA included preoperative GH level, primary/recurrent, extent of resection, and transcription factor expression. Co-expression of multiple transcription factors is an important factor associated with clinical behavior and endocrine outcomes in patients with GHPA.

Octreotide subcutaneous depot for acromegaly: A randomized, double-blind, placebo-controlled phase 3 trial, ACROINNOVA 1.

Acromegaly, characterized by excessive growth hormone (GH) and insulin-like growth factor-1 (IGF-1), impacts quality of life (QoL) and mortality. Standard of care (SoC; octreotide long-acting repeatable or lanreotide autogel) treatment typically requires healthcare provider administration. CAM2029, a novel subcutaneous octreotide depot with increased bioavailability using FluidCrystal technology, enables self-administration and room-temperature storage. Assess superiority of CAM2029 versus placebo for biochemical control in patients with controlled acromegaly. 24-week, multinational, randomized, double-blind, phase 3 trial (NCT04076462). 45 sites; ten countries. 72 patients on SoC with biochemical control at screening (IGF-1 ≤upper limit of normal [ULN]; mean GH <2.5 μg/L). Patients were randomized 2:1 to once-monthly CAM2029 (n=48) or placebo (n=24). Primary endpoint was proportion of patients with IGF-1 ≤ULN (Week 22/24 mean), with dose-reduced patients classified as non-responders; first key secondary endpoint was the same, including dose-reduced responders. Second key secondary endpoint was proportion of patients with IGF-1 ≤ULN (Week 22/24) and mean GH <2.5 μg/L (Week 24). At Week 22/24 (intention-to-treat analysis), CAM2029-treated patients demonstrated superior response rates versus placebo for IGF-1 (72.2% versus 37.5%; risk difference: 34.6, 95% confidence interval: 11.3, 57.9; p=0.0018), and combined IGF-1/GH (70.0% versus 37.5%; p=0.0035). CAM2029-treated patients had well-controlled symptoms, improved QoL and treatment satisfaction versus placebo and baseline. CAM2029 was well tolerated; safety was consistent with SoC. CAM2029 provides a convenient and effective treatment option for acromegaly, with superior biochemical control versus placebo. Symptom control, QoL and satisfaction were improved from baseline SoC.

12571 Ultrasonography Is A Potential Cost-effective Tool To Evaluate Muscle Impairment In Patients With Controlled Cushing’S Disease And Acromegaly

Abstract Disclosure: L. Martel-Duguech: None. H. Bascuñana: None. S. Webb: None. E. Valassi: None. Myopathy is a frequent feature in patients with Cushing’s syndrome (CS) and in patients with acromegaly (ACRO) long-term after biochemical control is achieved. Although ultrasonography (US) is an easy and cost-effective tool to evaluate muscle impairment in the clinical setting, its usefulness in patients with “controlled” ACRO end CS patients has not been established The aim of our study was to evaluate muscle structure using US and assess the correlation between US parameters, muscle function and quality of life (QoL). We included 36 female patients with CS [mean (±SD) age, 50±12 years; mean (±SD) BMI, 26.7±3.8] and 36 age- and BMI-matched healthy women. Mean (±SD) duration of remission was 132±87 months. We also included 36 patients with ACRO [20 females and 16 males, mean (±SD) age, 53±9 years, BMI 27±4 Kg/m2 and duration of control 92±58 months], and 36 age, gender and BMI-matched controls. We obtained transverse ultrasound images of the rectus femoris and assessed muscle intensity at both the midpoint (QmitR) and the distal third (QtercR), between the anterior inferior iliac spine and the proximal end of the patella. We scored muscle intensity using the Heckmatt’s rating scale and classified our findings as follows: 1-normal, 2-mildy increased muscle echoes with normal bone reflection, 3-moderately increased muscle echoes with reduced bone, 4-severely increased muscle echoes with absent bone reflection. We found that mean US intensity score was increased in patients with CS (QmitR p&amp;lt;0.001) and in patients with ACRO (QmitR p&amp;lt;0.05; QtercR p&amp;lt;0.001) vs. the controls, suggesting more impaired muscle architecture in the former, likely due to fibrosis/fatty infiltration. We also measured muscle function using the following tests: gait speed velocity (GS), timed up and go (TUG) and 30-second chair stand. QoL was assessed using both generic (SF-36) and disease-specific (CushingQoL and AcroQoL) questionnaires. US parameters, QoL and muscle function were correlated; in CS patients, higher QtercR was associated with slower GS (r=-0.421, p=0.041) and lower scores in social dimensions on CushingQoL ( friends/family , r=-0.510, p=0.013; and work/study, r=-0.523, p=0.010) . In ACRO patients, higher QmedR was associated with slower GS (r=-0.382, p=0.031) and decreased TUG (r=-0.497, p=0.004) and 30-second chair stand (r=-0.444, p=0.011) in all patients. Higher QmedR was also associated with lower score in physical function (ρ=-0.734, p=0.024), vitality (ρ=-0.728, p=0.026), and AcroQoL total score (ρ=-0.725, p=0.027), in male patients only. Conclusion: muscle US architectural parameters are impaired in “controlled” CS and ACRO patients, and are correlated with muscle function and QoL in both groups of patients. US may be a useful technique to identify, in a clinical setting, those CS and ACRO patients showing residual myopathy. This work was supported by PI17/00749 and PI21/01223 and FEDER funds Presentation: 6/3/2024

8068 Beneficial Effects of a Personalized Exercise Program for Patients with Cushing's Disease and Acromegaly After Biochemical Control

Abstract Disclosure: E. Valassi: None. L. Martel-Duguech: None. H. Bascuñana: None. V. Priego-Corredor: None. J. Viñals-Ribé: None. O. González-Viñuela: None. T. Caparrós-Pons: None. S.M. Webb: None. Background: Patients with Cushing’s disease (CD) in remission and controlled acromegaly (ACRO) present with residual metabolic derangements, muscle dysfunction, and poor quality of life (QoL). Although exercise is known to exert positive effects on psychophysical health in several conditions, evidence demonstrating its potential benefits in pituitary diseases is scanty. Main hypothesis: A personalized program of combined (aerobic and resistance training) exercise lasting 12 weeks improves cardiometabolic parameters, body composition, physical performance and QoL in patients with CD in remission and controlled ACRO. Methodology: Ten female patients with CD in remission [mean (±SD) age, 59±4 years, mean (±SD) BMI, 35±2 Kg/m2, median (IQR) duration of remission, 5(4) years] and 10 male patients with controlled ACRO [mean (±SD) age, 53±9 years, mean (±SD) BMI, 27±4 Kg/m2, median (IQR) duration of control, 6(3) years] underwent a 12-week, structured, personalized program of combined aerobic and resistance exercise, under the supervision of professional trainers. We evaluated the following parameters at baseline and within 72 hours after the completion of the exercise program: blood pressure (BP), BMI, waist and neck circumferences; physical performance (gait speed, hand grip strength, 30-Second Chair Stand; Timed “Up and Go”); lumbar and femoral bone mineral density (BMD) and body composition, using dual x-ray absorptiometry (DXA); muscle thickness (cm) at the middle and distal third of rectus femoris (RF) and vastus intermedius (VI) on both sides, using muscle ultrasound scans in the transverse plane (Philips Affiniti 70; The Netherlands); quality of life (QoL), using the questionnaires CushingQoL in CD patients and AcroQoL in ACRO patients. Major results: After completion of the exercise program, CD patients had lower diastolic BP and waist circumference as compared with baseline (p&amp;lt;0.05). Physical performance globally improved (p&amp;lt;0.01 for all function tests). Femoral BMD was higher, percentage of lean mass increased while trunk fat decreased (p&amp;lt;0.01). RF and VI muscle thickness was greater at both the middle and distal third on the right side (p&amp;lt;0.01), and at the distal third on the left as compared with baseline (p&amp;lt;0.05). ACRO patients had a lower systolic BP as compared with baseline. Gait speed and hand grip strength increased while performance on the 30-Second Chair Stand improved (p&amp;lt;0.05). Muscle thickness at the middle third of the right RF was greater as compared with baseline (p&amp;lt;0.05). QoL was unchanged in both CS and ACRO patients at the end of the program. Conclusions: A customized exercise program promotes beneficial cardiometabolic and muscle changes in patients with CD and ACRO and, therefore, should be offered in a specialized pituitary clinic, within an integrated multidisciplinary team approach. Study financed by ISCIII research project number FIS PI21/01223 Presentation: 6/1/2024

7248 Spliceosome component TCERG1 regulates the aggressiveness of somatotroph adenoma

Abstract Disclosure: K. Kim: None. The role of the spliceosome in the development of pituitary tumors is not well understood, despite preliminary studies indicating abnormal expression of oncogenic splicing variants in these neuroendocrine tumors. We aimed to identify differentially expressed spliceosome components in growth hormone (GH)-secreting pituitary tumors and investigate their roles in pathogenesis.We performed transcriptome analysis of 20 somatotroph adenomas and 6 normal pituitary tissues to select dysregulated spliceosome components. Clinical characteristics were analyzed based on gene expression in 64 patients with acromegaly. GH secreting pituitary adenomas were confirmed by 75 g oral glucose tolerance and immunohistochemical staining. Proliferation, invasion, and hormonal activity of GH secreting pituitary adenoma cells were investigated after modulating gene expression.TCERG1 expression was significantly higher in somatotroph adenomas than in normal cells (log2 fold change 0.59, adjusted P=0.0002*). Genotype-phenotype analysis revealed that patients with higher TCERG1 expression had lower surgical remission rates than those with lower expression (63.64% vs. 95.45%, P=0.009*). TCERG1 expression was significantly higher in groups with cavernous sinus (CS) invasion or Ki67 index over 1.5 (2.06 vs. 1.65, P=0.011*; 2.02 vs. 1.66, P=0.043*). TCERG1 overexpression led to a 16.91% increase in proliferation after 72 h (P&amp;lt;0.001*) and a 249.47% increase in invasion after 48 h in GH3 cells (P=0.026*). Conversely, TCERG1 silencing significantly decreased cell proliferation (10.15% at 72 h, P&amp;lt;0.001*) and invasion (96.87% at 48 h, P=0.029*). Vimentin was increased, but E-cadherin was decreased in both TCERG1 overexpressed GH3 cells and somatotroph adenomas. And TCERG1 silence reversed the expression of the genes (CDH2, SNAI1, ZEB2, and VIM) in GH3 cells. Additionally, GH secretion increased when TCERG1 was overexpressed in GH3 cells. Spliceosome machinery provide novel insights into the pathogenesis of GH-secreting pituitary tumor and highlight the potential role of TCERG1 as a therapeutic target. Presentation: 6/2/2024

6509 IGF-1 receptor and insulin receptor in LepRb neurons coordinates body growth, reproduction, and metabolism

Abstract Disclosure: M. Wang: None. J.W. Hill: None. Growth and reproduction are tightly linked. Growth hormone (GH) deficiency results in a profound suppression of postnatal growth accompanied by severely delayed puberty and reproductive senescence, while GH excess is correlated with the reverse. The specific mechanism underlying this delay is undefined. Although leptin receptor (LepRb)-expressing neurons are known to link body growth and reproduction, the role of insulin-like growth factor 1 receptor (IGF1R) signaling in LepRb neuron function is unknown. Previous studies have shown that IGF-1 and insulin can bind to each other’s receptor, permitting IGF-1 signaling in the absence of IGF1R. Therefore, we created mice lacking IGF1R exclusively in LepRb neurons (IGF1RLepRb mice) and mice simultaneously lacking IGF1R and IR in LepRb neurons (IGF1R/IRLepRb mice) to test if IGF1R and insulin receptor (IR) cooperatively regulate metabolic and reproductive functions. IGF1RLepRb and IGF1R/IRLepRb mice displayed delayed onset of puberty and impaired fertility in both sexes, which suggested that both IGF1R and IR in LepRb neurons are required for normal reproduction. Additionally, we found transient growth retardation in IGF1RLepRb and IGF1R/IRLepRb mice. Loss of IGF1R in LepRb neurons led to lower serum IGF-1 and GH levels in male mice and impaired trabecular and cortical bone development in mice of both sexes. Only transient and mild changes were noticed in the body weight. However, we found IGF1R and IR in LepRb neurons jointly regulate body mass composition, energy homeostasis and glucose homeostasis, as shown by elevated fat mass composition, low energy expenditure and low physical activity in IGF1R/IRLepRb mice. Taken together, these studies identify the unique and cooperative role of LepRb IGF1R and IRs in the regulation of body growth, reproduction, and metabolism. Presentation: 6/3/2024

6469 Supplement Misadventures: A Case Of Acute Heart Failure, Cardiogenic Shock, And Hormonal Dysregulation Secondary To Surreptitious Use Of Multiple Hormonal Supplements

Abstract Disclosure: K.N. Grennan: None. S. Thota-Kammili: None. A.L. McKenna: None. C.G. Coyle: None. S.L. Samson: None. Introduction: Supplement misuse in the bodybuilding community is prevalent. With the availability of internet ordering and purchasing, patients have access to hormonal supplements without prescription or regulation. Here we present the case of a patient on self-administered hormonal supplements who presented in acute heart failure leading to cardiogenic shock in the setting of concurrent thyroid, adrenal, and gonadal axis dysfunction. Case Description: A 28-year-old male with no significant medical history was transferred to our hospital after presenting to an outside emergency room with dyspnea, cough, nausea, and a subjective fever. He developed acute hypoxic respiratory failure requiring intubation. Echocardiogram performed showed an ejection fraction (EF) of 10%. He was started on two vasopressors and methylprednisolone 1 g daily for two days, due to concern for myocarditis versus giant cell arteritis. Hormonal work-up showed TSH 0.02 mIU/L (normal range 0.3-4.2), free T4 0.4 ng/dL (0.9-1.7), total T3 48 ng/dL (80-200), FSH &amp;lt;0.3 IU/L (1.2-15.8), LH &amp;lt;0.2 IU/L (1.3-9.6), ACTH &amp;lt;5.0 pg/mL (7.2-63), cortisol 1.7 mcg/dL (2.5-12), estradiol 171 pg/mL (8.0-35), total testosterone 1730 ng/dL (240-950), and prolactin 47 ng/mL (4.0-15.2). He received 10 mg dexamethasone at the outside facility. A medication bag found by his family included online purchases of non-prescribed testosterone cypionate and enanthate, liothyronine, anastrozole, and clomiphene. None were medical grade. He was also taking the anabolic steroid clenbuterol for 3 days prior. Echocardiogram on day 3 of admission showed an improved EF of 36%. Cardiac magnetic resonance imaging (MRI) showed a papillary fibroelastoma and myocarditis. Patient was weaned off vasopressors and the ventilator. He was discharged on levothyroxine 50 mcg daily and hydrocortisone 10 mg twice daily for outpatient reassessment. Transesophageal echocardiogram confirmed diagnosis of papillary fibroelastoma. One month Endocrinology clinic follow-up showed no evidence of posterior pituitary, thyroid, or adrenal axis dysfunction or growth hormone excess, but he continued to have gonadal axis suppression with elevated prolactin and estradiol, the latter thought to be secondary to conversion from testosterone. Pituitary MRI showed no micro or macroadenoma. His EF recovered to 50%. He is pending surgical removal of the aortic valve fibroelastoma. Discussion: With hormonal supplements easily accessible online, it is important for physicians to counsel patients about the dangers of misuse. This case highlights a previously healthy 28-year-old man who presented in critical condition with cardiogenic shock and hypothalamic-pituitary axis dysfunction from supplements he purchased online. There should be targeted educational interventions regarding the harm of supplements aimed at the bodybuilding community to prevent similar cases. Presentation: 6/2/2024

8479 A Challenging Case of Hypercortisolism in an Adult Patient With McCune Albright Syndrome

Abstract Disclosure: P. Kesavan Chary: None. S. Jasim: None. Background: McCune Albright Syndrome (MAS) is a rare genetic disorder that occurs due to a spontaneous post-zygotic missense mutation in the GNAS gene resulting in activating gain of function mutations in G-proteins. MAS classically presents as a triad of café-au-lait skin pigmentation, fibrous dysplasia of bone, and precocious puberty. However, continuous autonomous stimulation of endocrine glands can also result in various other endocrinopathies. We present a rare case of hypercortisolism due to bilateral multinodular adrenal hyperplasia (BMAH) in an adult patient with MAS. Case Report: A 38 year old female had MAS, clinically manifested by precocious puberty, renal phosphate wasting with rickets and osteomalacia, fibrous dysplasia of bone with history of multiple fractures, growth hormone excess, and multinodular thyroid status-post total thyroidectomy. A surveillance CT abdomen showed bilateral (right 3.8 x 1.3 cm and left 1.0 x 0.9 cm) adrenal adenomas with low intrinsic attenuation and washout. On diagnosis, the patient had an AM cortisol of 32.5 ug/dL (6.2-19.4 ug/dL) after a low-dose dexamethasone suppression test (DST), and an AM cortisol of 27.3 ug/dL after a high-dose DST. Late night salivary cortisol was 0.518 ug/dL (&amp;lt;0.010-0.090 ug/dL), 24-hour urine cortisol was 78 ug/24hrs (6-42 ug/24hrs), and ACTH was &amp;lt;1.5 pg/mL (7.2-63.3 pg/mL). The patient was initially asymptomatic and monitored for a few months, but subsequently developed easy bruising, recurrent skin infections, and irritability. The patient declined surgical intervention and was initiated on Osilodrostat. Shortly after medication initiation, she was hospitalized for perforated diverticulitis, hypokalemia, and hypomagnesemia. During hospitalization, AM Cortisol was 49 mcg/dL (4.8-19.5 mcg/dL) and 24-hour urine cortisol was 1023 mcg/24hrs (normal range 3.5-45 mcg/24hrs; the patient’s level prior to admission was 170-190 mcg/24hrs). Osilodrostat was held and the patient was initiated on Etomidate infusion. Once plasma cortisol levels normalized, she resumed Osilodrostat prior to discharge. The patient subsequently tried multiple medical therapy options before undergoing a bilateral adrenalectomy as a definitive treatment choice. Conclusion: The gain of function mutations in MAS result in autonomous endocrine gland function that can manifest clinically as various endocrinopathies. While the most common endocrinopathies in MAS are precocious puberty, hyperthyroidism, and pituitary dysfunction, active surveillance is critical to monitor for less common presentations such as hypercortisolism. This is the first report of adrenal Cushing’s in an adult patient with MAS. Presentation: 6/3/2024

7373 CAM2029, Octreotide Subcutaneous Depot, Provides Sustained Biochemical Control of Acromegaly: Interim Results From a Phase 3 Study (ACROINNOVA 2)

Abstract Disclosure: D. Ferone: Consulting Fee; Self; Camurus AB, Recordati, Novartis-AAA, Ipsen. Grant Recipient; Self; Camurus AB, Recordati, Novartis-AAA, Ipsen. Research Investigator; Self; Camurus AB. J. Silverstein: Consulting Fee; Self; Xeris Pharmaceuticals. Research Investigator; Self; Camurus AB. P. Freda: Research Investigator; Self; Camurus AB. L. Katznelson: Advisory Board Member; Self; Camurus AB, Recordati. F. Gatto: Advisory Board Member; Self; Camurus AB. Research Investigator; Self; Camurus AB. P. Kadioglu: None. P. Maffei: Research Investigator; Self; Camurus AB. J. Seufert: Research Investigator; Self; Camurus AB. J.L. Spencer-Segal: Advisory Board Member; Self; Camurus AB. Research Investigator; Self; Camurus AB. E. Isaeva: None. A. Dreval: None. M. Harrie: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A. Svedberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A.M. Pedroncelli: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. F. Tiberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. Background: Acromegaly is characterized by excess growth hormone (GH) and insulin-like growth factor 1 (IGF-1) production. A key treatment goal is long-term biochemical control to minimize adverse effects of prolonged excess GH. CAM2029 is a novel, subcutaneous, octreotide depot, designed for convenient monthly self-administration using a pre-filled injection/pen. In a 24-week Phase 3 trial (ACROINNOVA 1, NCT04076462), CAM2029 achieved superior IGF-1 control vs placebo (IGF-1 ≤ upper limit of normal [ULN]: 72.2 vs 37.5%; P=0.0018) in acromegaly patients previously controlled with standard-of-care (SoC; octreotide long-acting repeatable/lanreotide Autogel). On trial completion, patients could roll over to a Phase 3, 52-week, open-label, long-term safety trial (ACROINNOVA 2, NCT04125836). Here, we report data from an interim analysis of roll-over patients in ACROINNOVA 2. Methods: Roll-over patients received monthly CAM2029 20 mg for 28 weeks in ACROINNOVA 2. Primary endpoint: occurrence of adverse events (AEs). Key secondary endpoints: proportion of patients with available assessments who had (i) IGF-1 ≤1x ULN (mean of weeks 50/52 measurements) and (ii) both IGF-1 ≤1x ULN (weeks 50/52 mean) and mean GH &amp;lt;2.5 µg/L (week 52). Data are reported according to prior treatment in ACROINNOVA 1. Safety data from the whole trial period are reported. Results: Fifty-four of the 64 patients completing ACROINNOVA 1 (prior CAM2029 n=36; prior placebo n=18) entered ACROINNOVA 2. At data cut-off (May 23, 2023) 28 and 15 patients in the prior CAM2029 and prior placebo groups, respectively, had completed treatment week 52; 7 and 3 were ongoing; 1 and 0 had discontinued. The medication was well tolerated with a safety profile comparable to SoC treatment; no new safety signals were observed. One treatment-related serious AE (cholelithiasis, moderate severity, resolved) occurred in the prior placebo group. Injection site treatment-emergent AEs (Grade ≤2) occurred in 50% of patients in the prior CAM2029 (18/36) and prior placebo (9/18) groups. Of evaluable patients in the prior CAM2029 and prior placebo groups, 89.3% (25/28) and 100% (15/15) had IGF ≤1x ULN at weeks 50/52; 88.5% (23/26) and 100% (14/14) had both IGF ≤1x ULN (week 50/52) and GH &amp;lt;2.5 µg/L (week 52). Mean IGF-1 levels remained &amp;lt;ULN throughout the 52-week study period for the prior CAM2029 group; in the prior placebo group, mean IGF-1 increased above 1x ULN during placebo treatment, returning to &amp;lt;ULN after switching to CAM2029 for 28 weeks. All patients previously treated with placebo regained IGF-I control upon switching to CAM2029. Conclusions: The safety profile of CAM2029 was consistent with SoC, with no new or unexpected safety signals during extended treatment. CAM2029 provided persistent control of IGF-1 and GH during 52 weeks of treatment. All patients in the prior placebo group regained biochemical control of acromegaly after switching to CAM2029. Presentation: 6/1/2024

12525 Feline Hypersomatotropism In The USA And Canada: Demographics Of 4620 Cats With Presumed Acromegaly

Abstract Disclosure: R.J. Egbert: None. R.C. Fowkes: None. S.J. Niessen: None. B.K. Petroff: None. Spontaneous models of endocrinopathies are powerful tools to understand disease etiology. Endocrine diseases in companion animals are particularly useful to study, as they share their environment with humans and typically present with clinical disease that phenocopies human symptoms. One such disease in domestic cats, hypersomatotropism (HST, feline acromegaly), is a disorder of excessive growth hormone and increased IGF-1 (Insulin like Growth Factor 1), usually caused by hyperplasia or neuroendocrine tumors of the pars distalis of the pituitary gland. This retrospective study used serum IGF-1 results to investigate population characteristics for domestic cats with HST in the United States and Canada. Laboratory records from 1Jan06 to 31Dec22 were reviewed and animals with a circulating IGF-1 hormone concentration of 190 nmol/L (1,450 ng/mL) or greater were presumed to have acromegaly. This review identified 4,620 such cats with a mean age (n=4,351) of 11.2 years (median: 11.2, range: .5-20.3yr) and mean weight (n=2,086) of 6.03 Kg (median: 5.91, range: 2.27-15.0 Kg). Males outnumbered females in the database, which included 3,048 males and 1,181 females. Domestic Short/Medium/Longhair cats were the most prevalent breed (n=3,563; 77%), followed by Maine Coon cats (n=120; 2.6%) and Siamese cats (n=111, 2.4%). Just under half of the animals (n=2,037, 44%) had a history of diabetes mellitus on the submission form. Most submissions were from the US (n=4,347, 94%) with the most hypersomatotropic cats from California (n=841, 18.2%), New York (n=604, 13.1%), Massachusetts (n=402, 8.7%), Colorado (225, 4.9%), and Texas (200, 4.3%). The mean serum IGF-1 concentration of these animals was 358 nmol/mL (median: 345, range 190-761 nmol/mL). For comparison, an age and sex matched control group of 95 animals with residual samples previously submitted for unrelated testing was selected. The mean IGF-1 concentration for the control group was 97 nmol/mL (median: 85, range 0-311 nmol/mL). In summary, HST is diagnosed most frequently in older male cats in urbanized North America, and potentially displays some breed disposition, suggesting both a genetic and environmental component to the disease etiology. Presentation: 6/2/2024

Spliceosome component TCERG1 regulates the aggressiveness of somatotroph adenoma.

We aimed to identify differentially expressed spliceosome components in growth hormone (GH)-secreting pituitary tumors and investigate their roles in pathogenesis. We performed transcriptome analysis of 20 somatotroph adenomas and 6 normal pituitary tissues to select dysregulated spliceosome components. Clinical characteristics were analyzed based on gene expression in 64 patients with acromegaly. Proliferation, invasion, and hormonal activity of GH secreting pituitary adenoma cells were investigated. TCERG1 expression was significantly higher in somatotroph adenomas than in normal pituitaries (log2 fold change 0.59, adjusted P = 0.0002*). Genotype-phenotype analysis revealed that patients with higher TCERG1 expression had lower surgical remission rates than those with lower expression (63.64% vs. 95.45%, P = 0.009*). TCERG1 expression was significantly higher in groups with cavernous sinus (CS) invasion or Ki67 index over 3 (all P>0.05*). TCERG1 overexpression led to a 29.60% increase in proliferation (P<0.001*) and a 249.47% increase in invasion after 48h in GH3 cells (P = 0.026*). Conversely, TCERG1 silencing significantly decreased cell proliferation (25.76% at 72h, P<0.001*) and invasion (96.87% at 48h, P = 0.029*). E-cadherin was decreased, but vimentin was increased in both TCERG1 overexpressed GH3 cells and somatotroph adenomas. And TCERG1 silence reversed the expression of the genes (CDH2, SNAI1, ZEB2, and VIM) in GH3 cells. Spliceosome machinery provide novel insights into the pathogenesis of GH-secreting pituitary tumor and highlight the potential role of TCERG1 as a biomarker for tumor aggressiveness.

Distinct clinical characteristics and prognosis of pediatric-onset growth hormone-secreting pituitary adenoma (GHPA) patients compared to adult-onset patients.

To explore the clinical characteristics, treatment, and prognosis of growth hormone-secreting pituitary adenoma (GHPA) patients with pediatric-onset, so as to facilitate clinical management. A retrospective cohort study was carried out between 102 pediatric-onset GHPA patients admitted to our hospital from January 2013 to June 2022 and 204 adult-onset GHPA patients who were randomly matched. GHPA with pediatric-onset was predominantly male, associated with higher proportion of genetic syndromes, longer course, and delayed diagnosis. Clinical symptoms of visual field defects and menstrual abnormality were more common. The pediatric-onset group exhibited higher growth hormone (GH) nadir during oral glucose tolerance test (OGTT), higher rates of hyperprolactinemia, larger maximum diameter of adenoma, and higher rates of optic chiasm compression, suprasellar invasion, and pituitary apoplexy. Hypertension, diabetes, and obstructive sleep apnea-hypopnea syndrome (OSAHS) were more common in the adult-onset group. Echocardiography results were similar between the two groups. The pediatric-onset group owned significantly higher treatment scores and proportions of multimodal therapy modality, more surgical complications, and a higher proportion of ki67 ≥ 3%. There was no significant difference in the final cure rate, but male patients with adult-onset had a worse prognosis. The recurrence rate was also similar between two groups. Hypopituitarism was more prevalent in the pediatric-onset group, while the adult-onset group had a higher incidence of other tumors. Pediatric-onset GHPA patients exhibit distinct clinical characteristics compared to adult-onset patients. Multimodal therapy modalities could help to achieve a cure rate comparable to that of adult-onset patients.

Establishment of IGF-1 and IGFBP-3 continuous reference percentiles from data of healthy children using three kinds of immunoassay systems

Background and aimsAppropriate continuous reference intervals (RIs) for serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) are important for diagnosing growth hormone deficiency or excess. Material and methodsWe retrospectively reviewed serum IGF-1 and IGFBP-3 levels in Korean children aged 0–17 years who were diagnosed as healthy during a short stature workup in the outpatient clinics of three hospitals. IGF-1 and IGFBP-3 levels were measured using various immunoassays, including Liaison XL for IGF-1, an immunoradiometric assay (IRMA) for IGFBP-3 (n = 5522), and Immulite 2000 (n = 3036) and cobas e801 (n = 314). We established RIs from the 2.5th to 97.5th percentile RI curves using the lambda–mu–sigma (LMS) method for each sex group. ResultsPediatric serum continuous IGF-1 and IGFBP-3 reference percentiles by LMS method were found to be immunoassay method-dependent, but aligned relatively well with the manufacturers’ RIs. IGFBP-3 levels displayed notable discrepancies among the different immunoassay methods. ConclusionAge- and sex-specific pediatric LMS based continuous reference intervals are method dependent and they should be calculated for dynamic parameters that show variations throughout childhood.

Every Third Male Patient with Acromegaly Recovers from Hypogonadism after Neurosurgical Treatment.

Background: Acromegaly is a rare endocrine condition caused by excessive growth hormone (GH) production. Hypogonadotropic hypogonadism (HH) affects 30%-50% of acromegaly patients. Objectives: This study examined the frequency of HH in men with acromegaly and the effects of neurosurgical treatment during the follow-up period. Materials and Methods: A retrospective analysis of medical records from January 2015 to December 2022 was conducted. Data included clinical history, laboratory results, and pituitary MRI findings. Statistical analysis was performed using Statistica 13.3. Results: Patients were divided into two groups: a cross-sectional sample (preoperative n = 62; postoperative n = 60) and a longitudinal sample (n = 53). In the longitudinal sample, preoperative HH was diagnosed in 41 males (77.36%). Post-surgery, HH prevalence decreased to 58.49% (n = 31), with a significant increase in postoperative testosterone levels (9.1 vs. 12.1 nmol/L; p < 0.001), particularly in patients with preoperative HH (7.2 vs. 10.2 nmol/L; p < 0.001). Among 41 patients with HH, 12 (29.27%) showed recovery. Testosterone levels were lower in patients with macroadenomas (7.2 nmol/L vs. 11.05 nmol/L; p < 0.001). Patients with HH had higher baseline levels of GH and insulin-like growth factor 1 (IGF-1) (GH: 3.37 ng/mL; IGF-1: 551 ng/mL vs. GH: 1.36 ng/mL; IGF-1: 355 ng/mL). Luteinizing hormone (LH) levels above 3.3 mIU/mL and follicle-stimulating hormone (FSH) levels above 4.4 mIU/mL predicted hypogonadism remission (Area under the curve (AUC): 0.838 and 0.792, respectively). Conclusions: Younger patients with macroadenoma and hyperprolactinemia are more likely to have preoperative hypogonadism. Neurosurgical treatment can normalize LH, FSH, and total testosterone in approximately 30% of these patients.

The Use of Kidney Biomarkers, Nephrin and KIM-1, for the Detection of Early Glomerular and Tubular Damage in Patients with Acromegaly: A Case-Control Pilot Study.

Acromegaly is a rare disorder caused by excessive growth hormone (GH) secreted from a pituitary tumor. High levels of GH and insulin growth factor-1 can lead to renal hypertrophy, as well as to diabetes mellitus and hypertension, which negatively impact kidney function. It is believed that high GH may also be involved in the onset of diabetic nephropathy, the main cause of end-stage kidney disease in developed countries. This case-control study was conducted on 23 acromegalic patients and on a control group represented by 21 healthy subjects. The following parameters were determined for all the subjects: serum creatinine, serum urea, estimated glomerular filtration rate (eGFR), urinary albumin/creatinine ratio (UACR), nephrin and kidney injury molecule 1 (KIM-1). Patients with acromegaly showed higher levels of UACR and lower levels of eGFR as compared to healthy subjects. No significant correlations were found between clinical or biochemical parameters associated with acromegaly and nephrin or KIM-1. There was no glomerular or proximal tubular damage at the time of the study, as proven by the normal levels of the biomarkers nephrin and KIM-1. Studies including more patients with uncontrolled disease are needed to clarify the utility of nephrin and KIM-1 for the detection of early kidney involvement in acromegalic patients.

Impact of growth hormone-secreting pituitary adenoma on limbic system and its correlation with cognitive impairment

PurposeTo assess the quantitative gray matter volume of the limbic system in growth hormone-secreting pituitary adenoma (GHPAs) patients and its correlation to cognitive function. Method91 right-handed patients with pituitary adenomas were retrospectively included from the First Affiliated Hospital of Sun Yat-sen University −48 with GHPAs and 43 with non-functioning pituitary adenomas (NFPAs). Participants underwent serum hormone assessment, regular sellar MRI scanning with T1WI-MPRAGE. Cognitive function was gauged using MoCA and MMSE. Brain region auto-segmentation and gray matter volume calculation were conducted on the Brainsite platform. ResultsCompared to NFPAs patients, GHPAs patients had higher gray matter volume (758,285 vs 674,610 mm³, p < 0.001). No significant volumetric differences in both sides of limbic system gray matter while there were evident differences in the relative volumes of limbic system gray matter between groups. GHPAs patients scored lower on MOCA (24.0 (2.18) vs 25.1 (2.28), p < 0.031), with no difference in MMSE. We observed a significant correlation between the relative limbic volume and MOCA scales, while no evident correlation was found between relative limbic volume and serum hormone or tumor aggressiveness. Univariate and multivariate Logistic regression showed that hippocampus and limbic cortex (parahippocampal gyrus and internal olfactory area) of advantageous hemisphere correlated significantly with occurrence of mild cognitive impairment with the C-statistic reaching 0.90. ConclusionPatients with GHPAs show a relative decrease in limbic gray matter volume, especially in the hippocampus and limbic cortex of the dominant hemisphere, which is associated with mild cognitive impairment.

Clinical characteristics and management of gonadotropin-independent precocious puberty in McCune–Albright syndrome in children – A case series from a tertiary care center, Sri Lanka

McCune–Albright syndrome (MAS) is characterized by the triad of monostotic/polyostotic fibrous dysplasia (FD), café-au-lait spots, and precocious puberty. Gonadotropin-independent precocious puberty (GIPP) is frequently the presenting feature among many hyperfunctioning endocrinopathies seen in MAS. We report the clinical profile and management of four cases of MAS who were being followed up in a children’s hospital in Sri Lanka. Patient 1 presented with GIPP along with growth hormone excess at the age of 7 years and was started on spironolactone. Patient 2 presented at the age of 4 years but developed GIPP after 2 years and was started on letrozole. Patient 3 initially presented with thyrotoxicosis and hypophosphatemic rickets at 2 years of age and, after 9 months, developed GIPP and a unilateral ovarian cyst and was started on letrozole. Patient 4 presented at the age of 3 years with GIPP with a unilateral ovarian cyst, and letrozole was started. MAS is a clinically heterogeneous entity with various clinical manifestations, with GIPP being one of the most common presentations. Management options are varied with aromatase inhibitors showing promising results. However, long-term studies are needed to comment on the final heights of children with MAS with GIPP.

Serum phosphate levels at diagnosis predict long-term risk for hypopituitarism in patients with acromegaly.

Excess growth hormone (GH) secretion in acromegaly has a major impact on mineral balance and serum phosphate levels. However, the clinical utilization of serum phosphate levels as a marker for long-term disease outcomes in acromegaly has not been evaluated. This is a retrospective study of patients with acromegaly who were followed in a tertiary center. Data were retrieved on patient characteristics, endocrine and biochemical evaluation, and tumor parameters. Comparisons were performed by measuring baseline phosphate levels and conductingcorrelation analysis and multivariable logistic regression. Sixty-one patients were followed for 4.5years (range 1-21). Patients with hyperphosphatemia (> 4.5mg/dl) at baseline had larger adenomas (15.0mm [8.0, 47.0] vs. 10.0mm [3.0, 24.0], p = 0.001), a rate chance of invasive adenoma (16 [80.0%] vs. 14 [46.7%], p = 0.02), and lower serum cortisol levels (226.0nmol/l [27.6, 516.0] vs. 294.0nmol/l [32.0, 610.0], p = 0.02). Baseline serum phosphate levels positively correlated with IGF-1 levels (r = 0.43, p = 0.003) and negatively correlated with morning plasma cortisol levels (r = -0.46, p = 0.002). Regarding long-term impact, baseline phosphate levels correlated with the number of pituitary axes involved 6months after diagnosis (r-0.34, p = 0.01). In multivariable analysis, baseline plasma phosphate levels were independently associated with risk for disease progression/recurrence (odds ratio [OR] 9.66, 95% confidence interval [CI] 1.5, 105.9, p = 0.03) and for invasive adenoma (OR 6.21, 95% CI 1.6, 28.7, p = 0.01). Elevated pretreatment serum phosphate levels are associated with a greater risk of disease persistence and recurrence and with altered pituitary function in patients with acromegaly.

Excess endocrine growth hormone in acromegaly promotes the aggressiveness and metastasis of triple-negative breast cancer

Pituitary adenoma-induced excess endocrine growth hormone (GH) secretion can lead to breast cancer development and metastasis. Herein, we used an acromegaly mouse model to investigate the role of excess endocrine GH on triple-negative breast cancer (TNBC) growth and metastasis. Additionally, we aimed to elucidate the molecular mechanism of transcription factor 20 (TCF20)/nuclear factor erythroid 2-related factor 2 (NRF2) signaling-mediated aggressiveness and metastasis of TNBC. Excess endocrine GH induced TCF20 activates the transcription of NRF2 and NRF2-target genes to facilitate TNBC metastasis. Inhibition of GH receptor (GHR) and TCF20 activity using the GHR antagonist or small-interfering RNA-induced gene knockdown resulted in reduced tumor volume and metastasis, suggesting that excess endocrine GH stimulates TCF20/NRF2 pathways in TNBC and promotes metastasis to the lung. GHR inhibitors present an effective therapeutic strategy to prevent TNBC cell growth and metastasis. Our findings revealed functional and mechanistic roles of the GH-TCF20-NRF2 signaling axis in TBNC progression.

Growth hormone-receptor disruption in mice reduces osteoarthritis and chondrocyte hypertrophy

Excessive growth hormone (GH) has been shown to promote joint degeneration in both preclinical and clinical studies. Little is known about the effect of disrupted GH or GH receptor (GHR) on joint health. The goal of this study is to investigate joint pathology in mice with either germline (GHR-/-) or adult inducible (iGHR-/-) GHR deficiency. Knee joints from male and female GHR-/- and WT mice at 24 months of age were processed for histological analysis. Also, knee joints from male and female iGHR-/- and WT mice at 22 months of age were scanned by micro-CT (μCT) for subchondral bone changes and characterized via histology for cartilage degeneration. Joint sections were also stained for the chondrocyte hypertrophy marker, COLX, and the cartilage degeneration marker, ADAMTS-5, using immunohistochemistry. Compared to WT mice, GHR-/- mice had remarkably smooth articular joint surfaces and an even distribution of proteoglycan with no signs of degeneration. Quantitatively, GHR-/- mice had lower OARSI and Mankin scores compared to WT controls. By contrast, iGHR-/- mice were only moderately protected from developing aging-associated OA. iGHR-/- mice had a significantly lower Mankin score compared to WT. However, Mankin scores were not significantly different between iGHR-/- and WT when males and females were analyzed separately. OARSI scores did not differ significantly between WT and iGHR-/- in either individual or combined sex analyses. Both GHR-/- and iGHR-/- mice had fewer COLX+ hypertrophic chondrocytes compared to WT, while no significant difference was observed in ADAMTS-5 staining. Compared to WT, a significantly lower trabecular thickness in the subchondral bone was observed in the iGHR-/- male mice but not in the female mice. However, there were no significant differences between WT and iGHR-/- mice in the bone volume to total tissue volume (BV/TV), bone mineral density (BMD), and trabecular number in either sex. This study identified that both germline and adult-induced GHR deficiency protected mice from developing aging-associated OA with more effective protection in GHR-/- mice.