Active Acromegaly Research Articles

Influence of disease activity and gonadal status on bone mineral density and turnover in acromegaly.

The purpose of this study was to evaluate the impact of disease activity and gonadal status on bone mineral density (BMD) and turnover markers (BTMs) in individuals with acromegaly. Subjects underwent laboratory tests for PTH, 25-hydroxyvitamin D, calcium, phosphorus, osteocalcin (OC) and C-telopeptide (CTX-1) and bone densitometry at the lumbar spine (LS), femoral neck (FN) and total hip (TH). Sixty participants (48.6 ± 11.0years; 66,7% female) were included in this cross-sectional study. Phosphorus, OC, CTX-1, and LS BMD were greater in the active disease group than in the controlled/cured disease group (P = 0.025, P < 0.001, P = 0.007, and P = 0.016, respectively). When analyzing gonadal status, phosphorus, OC and CTX-1 were greater in the hypogonadal group than in the eugonadal group (P = 0.017, P = 0.015, and P = 0.033, respectively). Patients with hypogonadism had a higher prevalence of reduced bone mass compared to eugonadal patients (44 vs. 17%, P = 0.023). This study revealed increased levels of phosphorus and BTMs in patients with active acromegaly. In this group, the greater LS BMD values are likely due to the anabolic effects of GH and IGF-1 and/or to the influence of LS arthropathy. Moreover, hypogonadism negatively impacts bone metabolism in acromegaly, leading to elevated BTMs and a higher prevalence of reduced bone mass in individuals affected by both conditions.

Approach to the patient with controlled acromegaly and acromegalic arthropathy: clinical diagnosis and management.

Following the description of an illustrative case of a 70-year-old female patient with longstanding active acromegaly and invalidating, progressive joint complaints, current insights regarding diagnosis, treatment, and long-term management of acromegalic arthropathy are summarized. Since clinical trials on this topic are lacking, the reported recommendations are based on extensive clinical and research experience with this clinical entity, and on established diagnostics and interventions in patients with other rheumatic diseases. The cornerstones of the management of acromegalic arthropathy remains normalization of growth hormone and insulin growth factor-1 levels. However, patients with severe or progressive acromegalic arthropathy require a multidisciplinary approach to determine adequate diagnostics and treatment options. Because of the high prevalence and invalidating character of acromegalic arthropathy, developing evidence-based effective prevention and treatment strategies, preferably by international collaboration within rare disease networks, e.g., Endo-ERN, is a clear unmet need.

9191 Real-world Biochemical And Symptoms Outcomes With Oral Octreotide: Management Of Acromegaly (MACRO) Registry Experience

Abstract Disclosure: K.C. Yuen: Consulting Fee; Self; Novo Nordisk, Neurocrine, Crinetics, Recordati, Ascendis, Chiesi. Grant Recipient; Self; Ascendis, Corcept Therapeutics, Chiesi, Sparrow. Speaker; Self; Recordati, Novo Nordisk. W. Huang: Advisory Board Member; Self; Chiesi, Novo Nordisk, Neurocrine, Crinetics, Recordati. Speaker; Self; Chiesi, Recordati. M. Fleseriu: Consulting Fee; Self; Camurus, Crinetics, Recordati. Grant Recipient; Self; Crinetics (via institution). E.B. Geer: Advisory Board Member; Self; Chiesi, Crinetics. Consulting Fee; Self; Crinetics. T. Araki: Advisory Board Member; Self; Chiesi. A. Labadzhyan: None. P.U. Freda: None. A.G. Ioachimescu: Consulting Fee; Self; Crinetics, Camurus, Xeris. E.A. Christofides: Advisory Board Member; Self; Chiesi. Speaker; Self; Chiesi. J. Sisco: Advisory Board Member; Self; Novo Nordisk. Speaker; Self; Pfizer, Inc.. N.R. Biermasz: None. J.A. Crompton: Employee; Self; Chiesi. M.E. Molitch: Consulting Fee; Self; Chiesi, Takeda, Sention, Jansen Pharmaceuticals. Background: MACRO is a non-interventional, prospective, disease-based cohort registry that collects data on patients with active acromegaly. We report data of real-world experience with oral octreotide capsules (OOC) using paired data from acromegaly patients and their physicians. Methods: Patients (pts) and physicians completed questionnaires at enrollment and every 3 mos (up to 3 yrs) on demographic, disease activity, treatment information, ratings of symptom and biochemical control (“well”, “partially”, “not”, “unsure”), and patient-reported outcomes. Descriptive statistics were analyzed. Results: Out of 230 pts, 32 (14%) received OOC at baseline [30 monotherapy; 1 combination w/pegvisomant (PEG), 1 w/cabergoline (CBG)] and 26 (11%) initiated post-baseline [20 monotherapy; 6 combination (3 w/CBG; 1 w/PEG; 1 w/PEG&amp;CBG; 1 w/bromocriptine)]. Reasons for initiating OOC included patient preference (13, 50%) and lack of symptom control (10, 38%) or biochemical control (7, 27%). Starting dose was unknown, 40, 60, or 80mg/day in 1 (4%), 20 (77%), 2 (8%), and 3 (12%) of newly-initiated pts. Mean (±SD) time on OOC was 19.7±18.1 mos with 42 (72%) receiving for ≥ 6 mos. Last recorded daily dose (n, %) for pts remaining on OOC monotherapy (n=31) was 20 (1, 3%), 40 (16, 52%), 60 (5, 16%), and 80mg (9, 29%). In pts with available IGF-I levels at last follow-up, 81% (39/48) overall and 100% (33/33) on monotherapy were ≤ 1x ULN (mean ± SD = 0.8 ± 0.4 for overall group). Among all pts, 19 (33%) discontinued OOC [5 (9%), 3 (5%), and 9 (16%) for lack of biochemical control, symptom control or adverse events, respectively]. Median (range) time on OOC prior to discontinuation was 5 (2-72) mos. In monotherapy pts discontinued solely for lack of biochemical and/or symptom control, 3/4 (75%) were receiving &amp;lt; 80mg/day. Of 39 pts remaining on OOC-based therapy (31 monotherapy, 8 in combination), 34 (87%) were biochemically well-controlled at last follow-up and 24/34 (71%) were also symptomatically well-controlled per patient report. In the 16 pts initiated on OOC post-baseline and remaining on therapy (8 monotherapy; 8 in combination), 12 (75%) were biochemically well-controlled. Patient-reported symptom control was maintained or improved in newly-initiated pts in 11/16 (69%). Last patient reported symptom control in newly-initiated OOC pts (n, %) was well (8, 50%), partially (4, 25%), not controlled (1, 6%) or unsure/not reported (3, 19%). Conclusions: Most patients were on OOC as monotherapy at 40mg/day and maintained or achieved biochemical control. Discontinuation reasons were consistent with clinical trial experience. In over half of patients discontinuing OOC due to inadequate biochemical or symptom control, dose titration up to 80mg/day was not implemented. Approximately half of patients receiving OOC reported well-controlled symptoms. Presentation: 6/2/2024

Efficacy and safety of pasireotide treatment in acromegaly: A systematic review and single arm meta-analysis.

Acromegaly is a rare chronic endocrine disorder associated with significant comorbidities. Many patients fail to achieve biochemical control with current medical therapies, including surgery and first-generation somatostatin ligands (fg-SRLs). We aimed to perform a systematic review and single-arm meta-analysis to evaluate the efficacy of the multi-receptor somatostatin ligand pasireotidein patients with active or uncontrolled acromegaly. We systematically searched PubMed, Embase, and Cochrane databases for studies that assessed the efficacy of pasireotide in patients withacromegaly and reported the outcomes of (1)biochemical control and its composite indicators; (2)normalized IGF-1 level and (3)low GH level.For the statistical analysis, we used R software. We included nine studies with a total of 590 patients: four clinical trials and five observational cohorts. 82.2% of the overall population consisted of inadequately controlled acromegaly patients. After a follow-up of 12months, the pooled biochemical control rate was 26.50% (95% CI 14.87-42.66). The prevalence of normalized IGF-1 and low GH levels was 36.27% (95% CI 29.15-43.39) and 34.76% (95% CI 24.58-44.95), respectively. Additionally, biochemical response rates were sustained throughout the extension phase of these studies. In a pooled analysis including four studies with extension phase results, the prevalence of biochemical control rate was 29.03% (95% CI 11.49-46.58) with 76 events out of 281 patients. The most commonly reported adverse events were gastrointestinal disturbances in 31.26% (95% CI 7.44-72.01) and hyperglycemia in 29.55% (95% CI 21.80-37.29) of patients. The incidence of new-onset diabetes mellitus significantly increased after pasireotide treatment, with a rate of 23.36% (95% CI 19.58-27.13). Pasireotide demonstrates biochemical control in patients with active or uncontrolled acromegaly. Although a high rate of hyperglycemic adverse events and diabetes mellitus related to the treatment were observed, most of them were manageable.

Body Composition, Sarcopenia, and Serum Myokines in Acromegaly: A Narrative Review.

Patients with active acromegaly have a higher percentage of lean body mass, a lower percentage of fat body mass, and an increase in their extracellular water compartment compared to healthy individuals. However, muscle function appears to be compromised in patients with acromegaly, with some experiencing worsened physical performance and sarcopenia. Myokine alterations, insulin resistance, dysregulation of protein metabolism, muscle oxidative stress, neuromuscular junction impairment, and increased ectopic intramuscular fat deposits may play roles in muscle dysfunction in patients with acromegaly.

The Role of the GH Receptor Polymorphisms as a Prognostic Factor of Vertebral Fractures in Acromegalic Patients Resistant to First-generation SSAs and Treated with Pegvisomant or Pasireotide LAR.

Acromegaly is associated with skeletal fragility and increased prevalence of vertebral fractures (VF). Two isoforms of GH receptor (GHR) have been described, which differ in the presence or absence of a transcript of exon 3 of the GHR gene. Both isoforms produce a functional receptor, but the exon 3-deleted isoforms (d3-GHR) have greater sensitivity to endogenous and recombinant GH than the full-length isoform (fl-GHR). We conducted a longitudinal, retrospective, observational, single-center study to investigate the role of GHR polymorphism as a prognostic factor of incidental VF (I-VF) in firstgeneration somatostatin analogs (fg-SSAs)-resistant acromegalic patients and treated with Pegvisomant or Pasireotide LAR. Seventy-two patients with active acromegaly were included: 28 patients carried the d3-GHR isoform, and 44 patients carried the fl-GHR isoform. Forty-six patients were treated with Pegvisomant in combination with fg-SSAs, and 26 were treated with Pasireotide LAR. At the last follow-up, 58 patients achieved biochemical control of acromegaly. Eighteen patients carried prevalent VF (P-VFs), while 14 patients experienced the occurrence of I-VFs. From the group treated with Pegvisomant in combination with fg-SSAs, 32 patients carried the fl-GHR isoform, and 14 carried the d3-GHR isoform. From the group treated with Pasireotide LAR, 12 patients had the fl-GHR isoform, and 14 patients carried the d3-GHR isoform. I-VF occurred more frequently in patients with the fl-GHR isoform compared to d3-GHR (p =0.04); otherwise, I-VF occurred more frequently in patients with the d3-GHR isoform than fl-GHR (p =0.01). The GHR polymorphisms could improve the therapeutic approach in acromegaly, tailored to the individual patient, in the context of personalized medicine.

Long-term Pegvisomant Therapy of Acromegaly: Effects on Bone Density, Turnover and Microstructure Using HRpQCT.

Fracture rate is increased in patients with active acromegaly and those in remission. Abnormalities of bone microstructure are present in patients with active disease and persist despite biochemical control after surgery. Effects of treatment with the GH receptor antagonist pegvisomant on bone microstructure were unknown. We studied 25 patients with acromegaly (15 men, 10 women). In 20, we evaluated areal bone mineral density (BMD) by dual-energy X-ray absorptiometry and bone turnover markers (BTMs) longitudinally, before and during pegvisomant treatment. After long-term pegvisomant in 17, we cross-sectionally assessed volumetric BMD, microarchitecture, stiffness, and failure load of the distal radius and tibia using high-resolution peripheral quantitative computed tomography (HRpQCT) and compared these results to those of healthy controls and 2 comparison groups of nonpegvisomant-treated acromegaly patients, remission, and active disease, matched for other therapies and characteristics. In the longitudinal study, areal BMD improved at the lumbar spine but decreased at the hip in men after a median ∼7 years of pegvisomant. In the cross-sectional study, patients on a median ∼9 years of pegvisomant had significantly larger bones, lower trabecular and cortical volumetric density, and disrupted trabecular microarchitecture compared to healthy controls. Microstructure was similar in the pegvisomant and acromegaly comparison groups. BTMs were lowered, then stable over time. In this, the first study to examine bone microstructure in pegvisomant-treated acromegaly, we found deficits in volumetric BMD and microarchitecture of the peripheral skeleton. BTM levels remained stable with long-term therapy. Deficits in bone quality identified by HRpQCT may play a role in the pathogenesis of fragility in treated acromegaly.

Recurrence in acromegaly: two tertiary centers experience and review of the literature

BackgroundRecurrence of acromegaly after successful surgery is a rare event, but no clear data are reported in the literature about its recurrence rates. This study aimed to evaluate the recurrence rate in a series of acromegalic patients treated by transsphenoidal surgery (TSS) with a long follow-up.MethodsWe retrospectively analyzed data from 283 acromegalic patients who underwent TSS at two pituitary units in Milan (Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and IRCCS Humanitas Research Hospital). The diagnosis and recurrence of acromegaly were defined by both elevated IGF-1 levels and a lack of GH suppression based on appropriate criteria for the assay used at the time of diagnosis.ResultsAfter surgery, 143 patients (50%) were defined as not cured, 132 (47%) as cured and 8 (3%) as partially cured because of normalization of only one parameter, either IGF1 or GH. In the cured group, at the last follow-up (median time 86.8 months after surgery), only 1 patient (0.7%) showed full recurrence (IGF-1 + 5.61 SDS, GH nadir 1.27 µg/l), while 4 patients (3%) showed only increased IGF1. In the partially cured group at the last follow-up, 2/8 (25%) patients showed active acromegaly (IGF-1 SDS + 2.75 and + 3.62; GH nadir 0.6 and 0.5 µg/l, respectively).ConclusionsIn the literature, recurrence rates range widely, from 0 to 18%. In our series, recurrence occurred in 3.7% of patients, and in fewer than 1%, recurrence occurred with elevation of both IGF-1 and the GH nadir. More frequently (25%), recurrence came in the form of incomplete normalization of either IGF-1 or GH after surgery.

Glucose intolerance in acromegaly is driven by low insulin secretion; results from an intravenous glucose tolerance test.

Insulin sensitivity (Si) and its role in glucose intolerance of acromegaly has been extensively evaluated. However, data on insulin secretion is limited. We aimed to assess stimulated insulin secretion using an intravenous glucose tolerance test (IVGTT) in active acromegaly. We performed an IVGTT in 25 patients with active acromegaly (13 normal glucose tolerance [NGT], 6 impaired glucose tolerance [IGT] and 6 diabetes mellitus [DM]) and 23 controls (8 lean NGT, 8 obese NGT and 7 obese IGT). Serum glucose and insulin were measured at 20 time points along the test to calculate Si and acute insulin response (AIRg). Medical treatment for acromegaly or diabetes was not allowed. In acromegaly, patients with NGT had significantly (p for trend < 0.001) higher AIRg (3383 ± 1082 pmol*min/L) than IGT (1215 ± 1069) and DM (506 ± 600). AIRg was higher in NGT (4764 ± 1180 pmol*min/L) and IGT (3183 ± 3261) controls with obesity than NGT (p = 0.01) or IGT (p = 0.17) acromegaly. Si was not significantly lower in IGT (0.68 [0.37, 0.88] 106*L/pmol*min) and DM (0.60 [0.42, 0.84]) than in NGT (0.81 [0.58, 1.55]) patients with acromegaly. NGT (0.33 [0.30, 0.47] 106*L/pmol*min) and IGT (0.37 [0.21, 0.66]) controls with obesity had lower Si than NGT (p = 0.001) and IGT (p = 0.43) acromegaly. We demonstrated that low insulin secretion is the main driver behind glucose intolerance in acromegaly. Compared to NGT and IGT controls with obesity, patients with NGT or IGT acromegaly had higher Si. Together, these findings suggest that impaired insulin secretion might be a specific mechanism for glucose intolerance in acromegaly.

Efficacy of pasireotide LAR for acromegaly: a prolonged real-world monocentric study.

Acromegaly is caused by excessive growth hormone (GH) and insulin-like growth factor 1 (IGF1). Medical therapy plays a role as a treatment option for persistent disease after non-curative surgery or as a first-line therapy when surgery is not feasible. Pasireotide-LAR (Pas-LAR) is recommended for patients with acromegaly as second-line treatment. To evaluate the patients characteristics predictive of an adequate response to Pas-LAR and the long-term efficacy and safety of the Pas-LAR treatment. Data from 19 patients with active acromegaly, who were and resistant or intolerant to first-line medical therapy and were switched to pas-LAR have been retrospectively collected. We compared the baseline clinical and biochemical characteristics of patients who were found to respond to Pas-LAR therapy (responders, n=14) with those of patients who did not respond (non-responders, n=5). We then evaluated the Pas-LAR efficacy and safety during long-term follow-up in responders. IGF1 normalization occurred in 71.4% of responders after one injection. IGF1 levels, [median(interquartile range) of the upper limit of the normal range (ULN) fold increase] were higher in non-responders compared to responders within the initial month of therapy [1.40(1.30-2.34) vs 0.70(0.55-1.25), respectively, p=0.009] and after three [1.77(1.74-2.29) vs 0.94(0.82-1.13), respectively, p=0.029] and six months [1.68(1.33-1.72) vs 1.00(0.65 -1.28), respectively, p=0.002]. Out of 6 patients with symptomatic headache (all in responder group), 5 and 1 reported the resolution and improvement of headache, respectively, already after the first injection. Median HbA1c levels tended to increase from baseline to 6 months both in responder (36 mMol/Mol to 42 mMol/Mol) and non-responder patients (45 mMol/Mol to 48 mMol/Mol). During long term follow up, in the responder group 2 new patients developed diabetes. Tumor shrinkage was observed in 6 out of 7 evaluated responders, with no cases of size increase during the long-term follow-up. Pas-LAR is effective and safe and the early identification of responders is possible just after the first administration.

Serum Phosphorus and Calcium as Biomarkers of Disease Status in Acromegaly.

Acromegaly is a chronic disease caused by the hypersecretion of growth hormone (GH), leading to changes in the growth of visceral tissues and glucose impairment. Serum biomarkers that correlate with disease status are still unclear. This study aims to assess the potential of phosphorus and calcium as biomarkers in the clinical evaluation of patients with acromegaly and clarify their relationship with SAGIT and other common biomarkers. We retrospectively analyzed data from 306 medical records of patients with acromegaly hospitalized between 2015 and 2020. Factors such as patient biometrics, duration of disease, SAGIT score, tumor size, GH, insulin-like growth factor 1 (IGF-1), calcium, phosphorus, parathormone, and vitamin D were analyzed concerning current disease status (naïve, non-remission, remission). The results showed that serum phosphorus significantly correlated with IGF-1 and SAGIT scores for patients with active acromegaly. Specifically, the best predictor for the remission of acromegaly was a phosphorus level < 3.98 mg/dL and serum calcium levels < 9.88 mg/dL. Based on logistic regression, the higher the serum phosphorus level, the lower the odds of achieving remission (an increase in one unit leads to a decrease in the chance of about 80%). In conclusion, phosphorus and calcium can be effective biochemical markers for predicting disease status in acromegaly.

THU059 Increased Intracellular And Extracellular Myocardial Masses On Cardiac Magnetic Resonance Imaging In Patents With Acromegaly

Abstract Disclosure: P. Wolf: None. K. Bouazizi: None. N. Kachenoura: None. C. Piedvache: None. A. Gallo: None. S. Salenave: None. L. Maione: None. J. Young: None. M. Prigent: None. A. Lecoq: None. E. Kuhn: None. H. Agostini: None. S. Trabado: None. A. Redheuil: None. P. Chanson: Research Investigator; Self; Pfizer. P. Kamenicky: None. Background: Acromegaly is associated with an increased left ventricular mass, as reported in echo-based and more recently in few cardiac MRI studies. One possible explanation of this increased ventricular mass could be water retention and consequently edema of the ventricular wall. Methods: In this prospective, cross-sectional study 26 patients with active acromegaly and 31 control subjects of comparable age and sex were investigated by cardiac MRI. Patients were explored before and after GH/IGF-I lowering treatment. Cardiac morphology, function and myocardial tissue characteristics were assessed. T2 times were used as a reflect of intramyocardial water content. Results: Ventricular mass (58.08 (54.71; 68.6) vs 46.02 (41.27; 49.82) g/m2; p&amp;lt;0.001) and volume (97.25 (88; 101.21) vs 81.64 (78.08; 96.23) mL/m2; p= 0.0069) were higher in patients compared to controls, without affecting cardiac function. T2 times were not increased in active acromegaly. Both, intracellular (87.9 (71.2; 103.6) vs 67.2 (51.6; 76.9) g/m2; p&amp;lt;0.001) and extracellular (31.9 (26.1; 36.6) vs 21.8 (19.2;24.7) g/m2; p&amp;lt;0.001) myocardial mass were higher in patients compared to controls. GH, but not IGF-I strongly correlated with myocardial mass (r=0.756; p&amp;lt;0.001). In multiple regression analysis, in addition to male sex and HDL cholesterol, the presence of acromegaly was an independent predictor of total myocardial mass and extracellular mass, whereas systolic arterial blood pressure predicted intracellular mass. GH/IGF-I lowering treatment reduced intracellular mass and ventricular volume, without affecting other myocardial tissue characteristics. Discussion: Acromegaly results in a disease specific form of myocardial hypertrophy, characterized by an increase in intra- and extracellular mass, which is reversed after GH/IGF-I lowering treatment. This increase in ventricular mass is thus different to previous observations in essential hypertension. No differences in T2 times suggest against myocardial water retention in active acromegaly as explication of increased extracellular mass. Presentation: Thursday, June 15, 2023

SAT622 Matched Physician- And Patient-reported Responses Of Acromegaly Symptom Control: Comparisons From The Macro Registry

Abstract Disclosure: E.B. Geer: Consulting Fee; Self; Amryt. Research Investigator; Self; Ionis, Amryt. W. Huang: Consulting Fee; Self; Amryt. Speaker; Self; Amryt. M.B. Gordon: Consulting Fee; Self; Recordati, Novo Nordisk. Research Investigator; Self; Amryt, Crinetics, Recordati, Novo Nordisk. K.C. Yuen: Consulting Fee; Self; Novo Nordisk, Ipsen, Amryt, Crinetics, Recordati, Xeris. Speaker; Self; Recordati. S.E. Lubitz: None. R. Salvatori: Consulting Fee; Self; Novo Nordisk, Camurus, Recordati, Ipsen. M. Fleseriu: Consulting Fee; Self; Amryt, Camurus, Debiopharm, Ipsen, Recordati, Pfizer, Inc. Research Investigator; Self; Amryt, Crinetics, Ionis. A.G. Ioachimescu: Consulting Fee; Self; Amryt, Recordati, Camurus. E.A. Christofides: Advisory Board Member; Self; Amryt. Speaker; Self; Amryt. J. Sisco: None. S.D. Mathias: Employee; Self; Health Outcomes Solutions. Other; Self; Amryt. J.A. Crompton: Employee; Self; Amryt. M.E. Molitch: Consulting Fee; Self; Amryt, Takeda, Sention, Janssen Research &amp; Development Company. BACKGROUND: The Management of Acromegaly (MACRO) registry is a prospective, observational cohort study of patients with active acromegaly on medical therapy or eligible for medical therapy that includes paired data from patients and their physicians allowing for comparison of symptom-related data. METHODS: Patients and physicians completed questionnaires at enrollment and then every 3 months for up to 3 years. Information collected included demographic, disease activity, and treatment information, including ratings of symptom and biochemical control, and patient-reported outcomes (PROs) (AcroQOL, Acro-TSQ, and WPAI). Descriptive, concordance and correlation statistics were calculated. RESULTS: Data from 199 patients were available (54% female; mean age = 52; mean time since diagnosis = 10 years). IGF-I data was available in 191/199 (96%) patients of which 147/191 (77%) patients were biochemically controlled (defined as a baseline IGF-I level ≤ 1x ULN). Symptoms in biochemically controlled patients at enrollment were as follows: joint pain (54%), fatigue (52%), memory problems (42%), sleep apnea (39%), swelling (31%), headaches (25%), sweating (22%), and visual changes (20%). In the biochemically controlled group, 107/147 (73%) patients and 106/147 (72%) physicians reported symptoms as well-controlled. Conversely, concordance within individual patients between their physician’s and their own rating of symptom control was low (kappa = 0.272; p&amp;lt;0.001). Memory problems, fatigue, and joint pain were the most frequent symptoms reported at baseline by biochemically controlled patients that were not reported by their matched physician (33, 25 and 18% of patients, respectively). In the 45 biochemically controlled patients that rated any of their symptoms as severe, physicians who also reported the symptom provided the same rating of severity in only 5 (11%) cases. In the remaining cases rated as severe by patients, 26 (58%) and 14 (31%) were rated by their physician as mild or moderate. Well-controlled symptoms as reported by patients were associated with significantly higher (better) AcroQOL scores across all scales and 5 of the 6 Acro-TSQ domains (p &amp;lt; 0.001 except injection site interference) and less impairment on 3 of 4 WPAI scales (p &amp;lt; 0.001 except absenteeism). CONCLUSIONS: Symptoms persist in acromegaly patients despite achieving biochemical control. Adequate symptom control and physician-patient agreement on the extent of symptom control continues to be underrecognized and constitutes an unmet need in acromegaly patients despite its association with better patient-reported outcomes. Presentation: Saturday, June 17, 2023

THU068 Evaluation Of Nonalcoholic Fatty Liver Disease, Liver Fibrosis And Serum Angiopoietin-like Protein Levels In Patients With Acromegaly

Abstract Disclosure: I. Eroglu: None. B. Gonul Iremli: None. I. Idilman: None. D. Yuce: None. I. Lay: None. D. Akata: None. T. Erbas: None. Background: Due to their impaired glucose and lipid metabolism, acromegaly patients are potentially at risk for NAFLD. However, limited data exist about acromegaly and NAFLD relation. In this study (cross-sectional, case-controlled), we evaluated the risk of NAFLD and hepatic fibrosis in acromegalic patients and its association with noninvasive hepatosteatosis scores (NS) and angiopoietin-like protein-8 (ANGPTL-8) level for the first time in the literature. Methods: Thirty-two (15F/17M - median age=50.15 yrs) acromegalic patients (n=15 active acromegaly - AA and n=17 controlled acromegaly - CA) compared to 19 healthy controls (C) in terms of liver fat ratio (LFR), liver stiffness measurement (LSM), and ANGPTL-8 levels. Subjects had MRI-PDFF to determine LFR and MR elastography to quantify LSM. NAFLD was confirmed in those with LFR of ≥5%, and increased LSM in those with LSM of ≥2.5 kPa. VAI (visceral adipocity index), FLI (fatty liver index), HSI (hepatic steatosis index), and TyG (Triglyceride-glucose index) were calculated as NS. Results: Age, gender and BMI were similiar across groups. The GH and IGF-1 levels in AA group was greater than in CA, and C (p&amp;lt; 0.001). The CA had greater frequency of NAFLD than AA (p&amp;lt;0.001). Increased LSM was detected in three (21.4%) of AA, four (23.5%) of CA, and two (10.5%) of C.The median LFR was 1.75% in the AA group, 6.5% in the CA group, and 3.5% in the control group. LFR was lower in the AA group than in the CA (p=0.026). According to MRI-PDFF results, none of the patients in the AA group were diagnosed with NAFLD, while 58.8% (n=10) in the CA group and 26.3% (n=5) in the control group were diagnosed with NAFLD. The prevalence of NAFLD was found to be higher in the CA group than in the AA group (p&amp;lt;0.001). In acromegaly patients, LFR was positively correlated with TyG (r=0.675, p&amp;lt;0.001), VAI (r=0.508, p=0.004), and FLI (r=0.482, p=0.006). However, no correlation was seen between LFR and traditional risk factors for NAFLD (including BMI, waist circumference, Hba1c, HOMA-IR, and CRP) in acromegalics.ANGPTL-8 was lower in CA group (0.61 ng/mL) than in AA group (0.89 ng/mL) (p=0.006). When all acromegaly patients were evaluated independently, those with NAFLD had lower ANGPTL-8 levels than those without NAFLD (p=0.036). Conclusion: In conclusion, high GH levels seem to be protective against fatty liver in patients with active acromegaly, even if the metabolic profileis impaired. There was no relation observed between LFR and conventional risk factors in acromegaly patients. The strongest connection was found between LFR and TyG index among the noninvasive hepatosteatosis scores. ANGPTL-8 levels were lower in acromegaly patients with NAFLD, suggesting that high levels represent a reaction to insulin resistance rather than a cause of NAFLD. Treatment planning at a level that does not cause GH deficiency while maintaining disease control may be helpful to prevent NAFLD in acromegaly. Presentation: Thursday, June 15, 2023

THU056 Reference Interval For Serum Soluble Alpha Klotho, A Sensitive Biomarker Of Growth Hormone (GH) Excess

Abstract Disclosure: J.R. Schweizer: None. K. Schilbach: None. M. Haenelt: None. A.P. Gagliardo: None. A. Peters: None. B. Thorand: None. S. Störmann: None. J. Schopohl: None. M. Bidlingmaier: None. Background: We recently have shown that serum concentrations of soluble alpha klotho (sαKL) are high in active acromegaly and decrease with disease control. This indicates it could be an interesting biomarker for growth hormone (GH)-related diseases. However, robust data on the reference interval of sαKL in healthy subjects are lacking. Furthermore, limited information is available about the potential impact of biological variables on sαKL in healthy subjects. Methods: SαKL was measured by ELISA (IBL, Hamburg, Germany) in healthy subjects (A, n = 890, ∼120 subjects/decade, 51% females, 20-89 years). Reference intervals were calculated by median (interquartile (IQR)) for each decade and 2.5-97.5% percentile for all healthy subjects. We also investigated the impact of biological variables (age, BMI, sex and use of estrogens). In addition, we analyzed samples from patients with non-functioning pituitary adenoma (NFPA) (B, n = 18, 50% females, 24-87 years) or prolactinoma (C, n = 66, 60% females, age 17-82 years). Results: In healthy subjects the median (IQR)) for the total group of IGF-I (μg/L), IGFBP 3 (μg/L) and sαKL (pg/mL) were 114.6 (88.4-152.7), 3869 (3318-4390) and 672 (543-846), respectively. The 2.5-97.5% percentiles for sαKL measured in the healthy subjects are 152-1303 pg/mL. SαKL in males was slightly lower than in females (651 (537-815) vs. 687 (546-881), p = 0.01). As expected, IGF-I and IGFBP 3 significantly differed between age decades, while sαKL mainly differed between individuals &amp;lt; 40 as compared to &amp;gt; 70 years (p &amp;lt; 0.05 for all comparisons). SαKL correlated to IGF-I (rs = 0.31, p &amp;lt; 0.0001), but not to IGFBP 3 (p = 0.56). SαKL exhibited a weak negative correlation to creatinine (rs = -0.12, p = 0.002), age and BMI (rs = -0.30 and rs = -0.13, respectively, p &amp;lt;0.0001 for both). These correlations were remarkably weaker than those observed for IGF-I to age and BMI (rs = -0.59 and rs = -0.24, respectively, p &amp;lt;0.0001 for both). Use of estrogen slightly reduced sαKL. SαKL was higher in prolactinoma (902 (754-1228) as compared to healthy subjects (673 (543-846), A vs. C, p &amp;lt; 0.0001), but not different between healthy subjects and NFPA (p &amp;gt; 0.05). Conclusion: Our study provides robust reference intervals for sαKL from a large sample of Caucasian subjects. They are similar to those previously reported from a smaller pilot study in an Asian population, indicating that ethnicity might have a minor impact. Notably, biological variables such as age, sex and BMI have less impact on sαKL than on IGF-I and IGFBP 3. Oral estrogens seem to slightly reduce sαKL, perhaps through induction of hepatic GH-resistance as described for IGF-I. In contrast, prolactin seems to somewhat increase sαKL concentrations within the reference intervals. This could be due to the somatotropic activity of prolactin. The availability of reference intervals might facilitate the use of sαKL as a biomarker in GH-related diseases. Presentation: Thursday, June 15, 2023

THU050 The Role Of The GH Receptor Polymorphism As Prognostic Factor Of Vertebral Fractures In Acromegaly Patients Resistant To First Generation SSAs And Treated With GH Receptor Antagonist Or Second Generation Somatostatin Ligand

Abstract Disclosure: F. Costanza: None. S. Chiloiro: None. A. Giampietro: None. P. Mattogno: None. A. Infante: None. F. Angelini: None. L. Lauretti: None. A. Olivi: None. A. Pontecorvi: None. F. Doglietto: None. L. De Marinis: None. A. Bianchi: None. Acromegaly is associated with skeletal fragility and an increased prevalence of vertebral fractures (VF). In recent years several authors have tried to investigate the markers that can predict the risk of bone fragility in this endocrine disorder. Two different isoforms of the GH receptor (GHR) have been described so far, which differ in the presence or absence of a transcript of exon 3 of the GHR gene. Both isoforms produce a functional receptor, but the exon 3-deleted isoforms (d3-GHR) have greater sensitivity to endogenous and recombinant GH than the full-length isoform (fl-GHR). We conducted a longitudinal, retrospective, observational, single-center study of first-generation SSA-resistant acromegaly patients, with the aim of investigating the role of GHR polymorphism as a prognostic factor of incidental VF (I-VF) in first-generation SSA-resistant acromegalic patients and treated with GH receptor antagonist (Pegvisomant) or second-generation somatostatin ligand (Pasireotide Lar).72 patients with acromegaly were included. 28 patients carried d3-GHR isoform (38.9%) and 44 patients carried fl-GHR isoform (61.1%). At baseline, all patients were affected by active acromegaly; 46 patients were treated with Pegvisomant in combination with first generation SSA and 26 were treated with Pasireotide Lar. 18 patients (25%) carried P-VFs. At last follow-up, 58 patients achieved biochemical control of acromegaly (80.6%). 14 patients experienced the occurrence of I-VFs. From the group treated with Pegvisomant in combination with first generation SSA, 32 patients carried fl-GHR polymorphism and 14 carried d3-GHR polymorphism. At baseline, 10 patients (21.7%) were I-VF carriers. At follow-up, 8 patients developed P-VF (17.4%). I-VF occurred more frequently in patients carrying fl-GHR isoform compared to d3-GHR (p=0.04). From the group treated with Pasireotide Lar, 12 patients carried fl-GHR isoform and 14 patients carried d3-GHR isoform. At baseline, 8 patients (30.8%) were I-VF carriers. At follow-up, 6 patients developed P-VF (23.1%). I-VF occurred more frequently in patients carrying d3-GHR isoform than fl-GHR (p=0.01) and in patients with P-VF as compared to patients without P-VF (p=0.05).In conclusion, the GH receptor polymorphism could assume greater relevance as a prognostic factor of VF in acromegaly patients. In the future, the knowledge of the GHR polymorphism may improve the therapeutic approach of acromegaly patients, tailored to the individual patient, in the context of personalized medicine. Presentation: Thursday, June 15, 2023

THU028 Novel Approach To Management Of Acromegaly With De Novo Oral Octreotide Or Combination Therapy With Cabergoline: A Case Series

Abstract Disclosure: A. Halstrom: None. G.A. Dobri: None. Acromegaly is a rare disorder characterized by tumoral hypersecretion of growth hormone (GH) leading to overproduction of insulin-like growth factor 1 (IGF-1). Patients present with physical changes, and systemic complications. Treatment involves surgery and medical therapy with the goal of normalizing IGF-1. First line medical therapy consists of first-generation injectable somatostatin receptor ligands (SRL) (octreotide LAR, lanreotide autogel). Dopamine agonists (cabergoline) can be used in patients with mild IGF-1 elevation. If IGF-1 levels do not normalize, pasireotide or pegvisomant can be tried. Until recently, SRLs were administered only as a deep tissue injection. Patients have reported injection site reactions, frustration, and breakthrough acromegaly symptoms between doses. Two trials were conducted which showed that oral octreotide is an effective alternative for patients after achieving biochemical control with the injectable formulation. Two cases are presented below in which patients with acromegaly were treated with de novo oral octreotide either or as combination therapy with cabergoline, after a significant time lapse since injection SRL. Our first case is a 24 year old female with a 19mm mammosomatotroph adenoma, resected 8 years prior, with questionable remnant on postoperative MRI and biochemically active acromegaly. She was started on octreotide LAR 20mg which was titrated up to 30mg. However, she had not achieved biochemical control, with lowest IGF-1 543ng/mL (83-456ng/mL), Z-score 2.4, and GH 5.8ng/mL (&amp;lt;= 7.1ng/mL). She wanted a break from medical therapy and discontinued octreotide LAR. She was later started on pegvisomant 15mg but stopped after 10 days due to an allergic reaction and was switched to cabergoline. Cabergoline was up titrated to 3.5mg weekly, still without biochemical control, IGF-1 417ng/mL (103-326ng/mL), Z-score 2.5, GH 7.69ng/mL (0.05-8ng/mL), at which time oral octreotide 20mg twice daily was started and cabergoline decreased to 2.5mg weekly. Oral octreotide was increased to 60mg daily and IGF-1 levels normalized to 294ng/mL (83-456ng/mL), Z-score 1. The second case is a 70 year old female with type 2 diabetes, arthritis, left ventricular hypertrophy, obstructive sleep apnea and colon polyps found to have a 10mm pituitary adenoma with IGF-1 481ng/mL (32-238ng/mL), Z-score 3.1, GH 1.28ng/mL (0.05-8ng/mL). She declined surgical resection and opted for medical management. Oral octreotide 20mg twice daily was started and further increased to 60mg daily IGF-1 went as low as 327ng/mL (28-231ng/mL), Z-score 2.5 and GH 0.4ng/mL (0.05-8ng/mL). The dose was increased to 80 mg daily are lab results are pending. These are the first two published cases describing a novel approach to treating acromegaly in which patients were found to have a biochemical response to de novo oral octreotide either alone or combined with cabergoline. Presentation: Thursday, June 15, 2023

THU065 Evaluation Of Sarcopenia And Bone Health In Patients With Acromegaly

Abstract Disclosure: I. Eroglu: None. B. Gonul İremli: None. A. Erkoc: None. I. Idilman: None. D. Yuce: None. E. C. Kutukcu: None. D. Akata: None. T. Erbas: None. Background: Although many complications related to high GH exposure develop in patients with acromegaly, musculoskeletal complications are among the most important complications that reduce the quality of life of patients. However, the effects of acromegaly on muscle and bone have not been adequately researched and are still not entirely understood. We aimed to investigate muscle and bone quality in acromegalic patients in this cross-sectional, case-controlled study. Methods: The study consisted of thirty-two (15F/17M) acromegalic patients (n=15 active acromegaly - AA and n=17 controlled acromegaly - CA) and 19 healthy controls (C). Dual energy X-ray absorptiometry (DXA) was used to determine body composition, appendicular skeletal muscle mass (ASM), relative skeletal muscle index (RSMI), and bone mineral density (BMD). The handgrip strength (HGS) and quadriceps muscle strength were measured by hand dynamometer. Magnetic resonans imaging at the L3 level was used to measure total abdominal muscle area (TAMA, cm2) and vertebral fat ratio (VFR). HGS adjusted by ASM (HGS/ASM) was used to define skeletal muscle quality (SMQ). SMQ was regarded “normal” when the HGS/ASM ratio was &amp;gt;1.53, and “weak” when the ratio was ≤1.36 in males and ≤1.35 in women. The SMQ of those with HGS/ASM levels between these ranges was considered “low”. Results: Age, gender, and BMI were similar between groups. The GH and IGF-1 levels in AA was greater than in CA, and C (p&amp;lt;0.001 for all). While lean tissue was higher in AA than CA and C (p=0.038 and p=0.041, resp.), body fat ratio was lower in AA than CA and C (p=0.04 and p=0.042 resp.). ASM, RSMI, TAMA, HGS and quadriceps strength were similar between groups. Median (IQR) HGS/ASM were 1.67 (1.15-1.9) in AA, 1.57 (1.36-1.79) in CA and 1.77 (1.67-1.93) in C. This difference was found to be significant between CA and C (p=0.008). According to skelatal muscle quality, 94.7% of the individuals in the C group were of normal SMQ, while this rate was 60% in the AA and 52.9% in CA. The ratio of those with low/weak SMQ was higher in the AA and CA compared to C (p=0.012 and p=0.013, resp.). Total and vertebra BMD were similar across groups. Pelvic BMD in CA was lower than C (p=0.02). VFR was higher in CA (56.5%) than in AA (43.75%) and C (42.6%) (p=0.04 and p=0.001 resp.). Conclusion: We showed for the first time that patients with acromegaly had lower muscle quality and pelvic BMD, while patients with controlled acromegaly had higher vertebral fat ratio. Even though lean tissue increased in AA patients, regional muscle distributions (ASM and TAMA) were shown to be similar. The increased muscle mass in acromegaly patients is not expressed as muscular strength, and muscle quality is low in these patients. The high vertebral fat ratio seen in patients with CA may be a result of ectopic adiposity with disease control, as well as the reason for the increased frequency of vertebral fractures seen in patients with acromegaly. Presentation: Thursday, June 15, 2023

The Relationship between the Burden of Acromegaly, Associated Comorbidities, Complications and Disease Status.

Uncontrolled acromegaly causes increased morbidity and mortality. The analysis of acromegaly comorbidities and complications is important when establishing a standard of care for the entire population of acromegaly patients. The aim of this study was to determine the frequency of comorbidities and complications of acromegaly and their dependence on the activity of the disease. A retrospective analysis of medical records from 124 patients with acromegaly was carried out, including 39 who were cured, 73 treated with somatostatin analogs and 12 newly diagnosed patients. The incidence of comorbidities and complications was very high, and those most frequently observed were arterial hypertension, multinodular goiter, lipid disorders, hypopituitarism and degenerative changes. At least one complication of acromegaly was observed in 92% of patients undergoing successful neurosurgery and in all pharmacologically treated patients. By contrast, two or more complications were observed in 77% of cured patients and in pharmacologically controlled and uncontrolled patients, 82% and 91%, respectively. Conclusions: Acromegaly is associated with a high prevalence of complications. Active acromegaly is associated with a higher incidence of complications than in treated groups. Untreated patients have more complications than treated patients. Successfully cured patients have significantly fewer complications than pharmacologically controlled patients and patients with active acromegaly.

Predictors of long-term remission in acromegaly – an updated review

Abstract Acromegaly is a rare chronic disorder due to growth hormone (GH) - secreting pituitary tumor. The first-line treatment of acromegaly is a transsphenoidal adenomectomy. Surgical remission rates range from 30-50% for macroadenomas to 70-90% for microadenomas. Thus in patients with active acromegaly after surgery, medical treatment is recommended. Treatment outcome on medical therapy differs a lot depending on medications. The aim of this paper is to summerize the current knowledge of factors predicting acromegaly remission after surgery and biochemical control on medical treatment. Factors affecting treatment outcome, not related to the patient and the tumor, are neurosurgeon’s experience and visualisation tools used during surgery. Younger patients, as well as women tend to achieve acromegaly remission after surgery less often. Patients with lower GH and insulin-like growth factor-1 (IGF-1) concentrations at diagnosis, in oral glucose tolerance test (OGTT) and postoperatively have a greater chance of surgical remission. However, some publications do not confirm that. Patients presenting with larger and more invasive tumors achieve surgical remisson less often. Hypointensive tumors on T2-weighted magnetic resonance imaging (MRI) scans are associated with better response to first-generation somatostatin receptor ligands (SRLs) and to pasireotide. Pathologic factors increasing the chance of acromegaly remission are densely granulated tumors, lower Ki-67 index, high expression of somatostatin receptors (SSTRs) and high expression of E-cadherin. A thorough analysis of the abovementioned factors predicting the treatment outcome in acromegaly may be helpful for selecting the best treatment option for each patient.