Acromegaly Research Articles (Page 1)

Acromegaly is a rare disease caused by the elevated and autonomous secretion of growth hormone (GH) from a pituitary somatotroph tumor or neuroendocrine tumors, and the subsequent hypersecretion of insulin-like growth factor I (IGF-I) in peripheral tissues.Excess GH and IGF-I cause several chronic and systemic complications that impact mortality, morbidity, and quality of life in patients with acromegaly. Excess GH and IGF-I play a crucial role in bone remodeling by increasing osteoclastogenesis and impairing osteoblastogenesis. Several studies have demonstrated an increased prevalence and incidence of fragility vertebral fractures (VFs) in patients with acromegaly. Long-term exposure to high levels of GH and IGF-I is recognized as a risk factor for fragility fractures in patients with acromegaly. Recent studies have shown that first- and second-generation somatostatin receptor ligands (SRLs) can reduce the incidence of vertebral fractures (i-VFs). However, a direct effect of these molecules on bone metabolism has not yet been reported.Aims: This review summarizes the results of studies investigating the frequency of i-VFs according to different GH/IGF-I-lowering drugs and the potential effects of these treatments on bone metabolism, as well as preclinical data on potential molecular pathways that interact between GH/IGF-I-lowering drugs and bone metabolism.

Acromegaly is a rare disorder caused by a growth hormone-secreting pituitary adenoma. Clinical trial evidence for its management is limited. This study compared medical treatments for acromegaly through a network meta-analysis, assessing biochemical and radiological responses. A systematic review and network meta-analysis were conducted following the preferred reporting items for systematic reviews and network meta-analyses guidelines and Cochrane Handbook recommendations (PROSPERO registration: CRD42023364373). PubMed, Scopus and Web of Science were searched up to June 2024. Included studies were randomized controlled trials and non-randomized studies evaluating the efficacy or safety of acromegaly treatments. Primary outcomes were the percentage of adjusted insulin-like growth factor 1 (IGF-1) normalization and tumor shrinkage. Twenty-seven studies, involving 4131 patients and 11 treatments were included. Pegvisomant was the best treatment for IGF-1 normalization, followed by pasireotide LAR. Both outperformed first-generation somatostatin analogs (SRLs) combined with dopamine agonists (OR 1.83; 95% CIs 1.37-2.46 and OR 1.46; 95% CIs 1.02-2.08, respectively; I2=41%). Octreotide LAR was superior to oral octreotide capsules (OR 5.41; 95% CIs 1.89-15.52). For tumor shrinkage, pasireotide LAR was more effective than SRLs (n=1059; OR 11.47; 95% CIs 1.5-87.64; I2=0%). Methodological heterogeneity may have affected comparability. Our findings suggest pasireotide LAR and pegvisomant as the most effective treatments for IGF-1 normalization. Pasireotide LAR was the best treatment for tumor shrinkage, though the evidence base was limited, requiring cautious interpretation. Their potential role as first-line options after surgery requires further research. Clinical decisions should consider cost, safety and patient-specific parameters to optimize outcomes.

Disclosure: D.H. Tran: None. J.D. Carmichael: None. T.E. Angell: None.Background: Acromegaly is a rare condition typically caused by excess growth hormone (GH) secreted from a pituitary adenoma. In addition to the canonical signs and symptoms, chronic exposure to elevated GH and insulin-like growth factor-1 (IGF-1) may result in less well-recognized manifestations, including thyroid goiter and nodules. Here, we present a case of thyroid cancer associated with persistent elevated IGF-1 levels and acromegaly. Clinical Case: A 40-year-old female was referred to endocrinology clinic for a progressively enlarging thyroid over several years, now with choking sensation, difficulties breathing, and vocal changes. She had no prior head or neck radiation exposure. Her medical history included diabetes mellitus, hypertension, hyperlipidemia, obstructive sleep apnea, and a remote history of acromegaly for which she underwent transphenoidal pituitary adenoma resection. Upon further questioning, her symptoms additionally included dull, diffuse, and episodic headaches, swelling of her face, enlarging fingers, and skin tags. She denied mouth crowding or dental issues, or symptoms suggestive of other pituitary hormone deficiency. Physical exam was notable for palpable thyroid enlargement without lymphadenopathy, and coarse facial features, widely spaced teeth, spade-like fingers, and skin tags. Thyroid ultrasound showed multiple TIRADS 4 nodules, up to 55mm in size. Fine-needle aspiration biopsy (FNA) of one nodule in each lobe showed benign cytology. Because of compressive symptoms, total thyroidectomy was performed and histopathology revealed multifocal follicular thyroid carcinoma (FTC), greatest tumor size of 35mm, focal vascular invasion and no extrathyroidal extension, T2NXMX. Results also showed elevated IGF-1 of 475 ng/mL (52-328 ng/mL), Z-score 2.9 without other pituitary hormone abnormalities noted. A brain MRI demonstrated a well-circumscribed sellar mass, 25 x 24 x 27 mm with mass effect on the optic chiasm. The patient underwent resection for persistent acromegaly secondary to residual pituitary tumor. Conclusion: Acromegaly may be associated with thyroid goiter and tumorigenesis putatively due to the effects of IGF-1 on increased cell proliferation and differentiation. Screening patients with acromegaly for thyroid cancer is controversial, but this case highlights the need for increased attention to thyroid cancer risk for patients with acromegaly.Presentation: Monday, July 14, 2025

Disclosure: K. Kurylo: Marea Therapeutics, Inc. W. Huynh: Marea Therapeutics, Inc. P.R. Bouchard: Marea Therapeutics, Inc. M.N. Milton: Marea Therapeutics, Inc. P.F. Moesta: Marea Therapeutics, Inc. L.E. Dichtel: Marea Therapeutics, Inc., Recordati, Lumos Pharma, Perspectum, Novo Nordisk, Third Rock Ventures, Merida Biosciences, Flare Therapeutics. J. Gromada: Marea Therapeutics, Inc. V. Ramanan: Marea Therapeutics, Inc. M.P. Joing: Marea Therapeutics, Inc. B.B. Cummings: Marea Therapeutics, Inc. E.J. Weiss: Marea Therapeutics, Inc..Acromegaly is a rare disease characterized by excessive growth hormone (GH) production from a benign anterior pituitary adenoma. Elevated GH levels lead to increased production of IGF-1 from the liver, and acromegaly is linked to increased morbidity and mortality. GH receptor antagonists (GHRA) are an attractive therapeutic option, as they directly block GH action, lower IGF-1, and improve insulin sensitivity. However, the only currently available GHRA, pegvisomant, requires daily administration, resulting in low patient compliance and reduced real-world efficacy. Here, we report the development and characterization of MAR002, a novel half-life extended GHRA monoclonal antibody with the potential to enhance ease of use, improve efficacy, and elevate the quality of life for patients with acromegaly. In vitro, MAR002 had a significantly stronger binding affinity to GHR and resulted in more potent dose-dependent inhibition of GH-induced GHR signaling (IC50: 1 nM) vs. pegvisomant (IC50: 122nM). The greater potency of MAR002 was maintained when GH was pre-bound to GHR. MAR002 maintained stable GHR signaling suppression with supraphysiological GH levels (≥90% suppression), whereas such levels of GH outcompeted pegvisomant (no suppression). Epitope mapping revealed that unlike pegvisomant, MAR002 does not bind known GH binding sites on GHR, and additional binding assays confirmed MAR002 and GH can bind simultaneously to GHR. Together, these data demonstrate that MAR002 binds allosterically to inhibit GHR signaling; a novel GH-binding independent mechanism distinct from pegvisomant, which is an orthosteric inhibitor known to occupy the same binding site as GH. In cynomolgus monkeys, administration of equimolar doses of MAR002 and pegvisomant was well tolerated and demonstrated similar peak IGF-1 suppression (80% reduction, n=3 per group). MAR002 demonstrated a more favorable PK/PD profile, as it was detected in serum concentrations that resulted in ≥50% IGF-1 suppression for 36 days vs.15 days for pegvisomant. Of note, half-life extending mutations in monoclonal antibodies are reported to be up to 3x more durable in humans than in monkeys. This, in addition to the more favorable serum residence time of MAR002 predicts a substantially longer duration of IGF-1 lowering in humans compared to pegvisomant. In summary, we developed and characterized a novel half-life extended, allosteric, inhibitory GHR antibody with a mechanism distinct from pegvisomant. Stronger inhibitory activity of MAR002 against GHR in vitro, combined with a superior PK/PD profile in cynomolgus monkeys, should provide a prolonged therapeutic effect in patients, requiring less-frequent dosing vs. pegvisomant (e.g. potentially biweekly, monthly, or less frequent). This work enables continued MAR002 development to assess its safety, efficacy, and potential to improve the care for patients with acromegaly.Presentation: Sunday, July 13, 2025

Disclosure: B. Zaidan: None. S. Khalid: None. M. Pennant: None.Introduction: Acromegaly, a rare endocrine disorder caused by excess growth hormone (GH), is typically due to a pituitary adenoma. It is associated with metabolic, cardiovascular, and neurological complications, including a 20-50% prevalence of type 2 diabetes mellitus (T2DM) (1,2). Pituitary apoplexy, occurring in 2-12% of adenoma cases, results from hemorrhage or infarction and can sometimes normalize hormone secretion (3). This case report details a 64-year-old woman with uncontrolled T2DM and acromegaly who experienced significant diabetes improvement following pituitary apoplexy. Case Presentation: A 64-year-old female with a past medical history of uncontrolled type 2 diabetes mellitus (T2DM) presented to the emergency room with new-onset headache, nausea, vomiting and MRI of the brain revealed a 3.4 cm seller/suprasellar mass exerting mass effect on the optic chiasm consistent with pituitary macroadenoma. She recalled experiencing increasing show and ring size. Hormonal work up at the time revealed IGF-1 elevated at 557 ng/mL (normal range: 41 - 279 ng/mL), ACTH 8 pg/mL (range 6-60 pg/mL), Free T4 1.2 ng/dL (0.8-1.8) and cortisol level of 11.8 mcg/dL. A week later she was noted to have diplopia and marked right abduction deficit indicative of CN VI palsy. MRI at the time revealed increase size of the mass with cavernous sinus invasion, mass effect of optic chiasm and new internal foci of T1 hyper-intensity suspicious for apoplexy. Repeat IGF-1 level at that time was normal at 182 ng/mL (normal range: 41 - 279 ng/mL) along with low FT4 of 0.7 ng/dL and cortisol of 4.3 μg/dL. She eventually underwent transsphenoidal resection of the tumor. Histopathological examination confirmed a neuroendocrine tumor secreting IGF-1 characterized as a densely granulated somatotroph tumor. She had poorly controlled diabetes pre-operatively with HbA1c of 11.8% that improved to 9% after apoplexy and post operatively her A1c normalized to 5.3% and she was taken off all diabetes medications. Conclusion: Diabetes in patients with acromegaly is associated with increased overall and cardiovascular mortality and morbidity (2,4). This case underscores the critical role of recognizing underlying conditions, such as acromegaly, that contribute to resistant type 2 diabetes mellitus (T2DM). The excess growth hormone played a key role in the patient's uncontrolled T2DM, as evidenced by a significant reduction in HbA1c and blood glucose levels following her presentation with apoplexy. Timely diagnosis and appropriate surgical intervention can lead to substantial metabolic improvement and even resolution of diabetes. However, the potential for postoperative complications, such as diabetes insipidus, highlights the necessity of vigilant monitoring and comprehensive management to optimize patient outcomes.Presentation: Monday, July 14, 2025

Disclosure: M.C. Duarte: None. R. Mattos: None. T.R. Costa: None. I.S. Freitas: None. J.B. Drummond: None. B.S. Soares: None.Introduction: Marfan Syndrome (MFS) is an autosomal hereditary disorder with skeletal, ocular, and cardiovascular manifestations, while acromegaly results from excess growth hormone (GH), leading to skin thickening, extremity enlargement, and macroglossia. Both conditions are individually described, but their coexistence is rare. This case presents a unique instance of both MFS and acromegaly in one patient.Case: A 56-year-old male with classic features of MFS, including joint laxity, pectus carinatum, arm span-to-height ratio of 1.06, and positive thumb and wrist signs, also had significant cardiovascular involvement, having undergone aortic valve replacement and aneurysmectomy of the descending aorta. Despite a negative family history, his clinical features met MFS diagnostic criteria. Ten years after diagnosis, he noticed progressive changes in his hands, feet, and facial features, including a prominent nose, lips, and jaw.He sought endocrinological evaluation, and during the physical examination, signs of joint swelling and severe heart failure symptoms, including dyspnea, bilateral leg edema, and a grade V systolic murmur, were noted.Laboratory tests showed elevated IGF-1 (346 ng/mL) and GH (11 ng/mL) levels after an oral glucose tolerance test. MRI revealed a macroadenoma (1.2x0.8x0.8 cm). Due to his decompensated heart condition, surgery was postponed, and he began monthly lanreotide injections (120 mg), which reduced IGF-1 to 256 ng/mL and improved symptoms of aortic insufficiency and heart failure. One year later, cabergoline (1.5 mg/week) was added, and MRI showed tumor shrinkage (1.0x0.8x0.7 cm), though IGF-1 remained elevated at 296 ng/mL. After stabilizing his cardiac condition, the patient underwent transsphenoidal surgery. One month post-surgery, IGF-1 levels normalized, and he reported relief from swelling and pain.Whole exome sequencing (NGS) revealed no pathogenic variants linked to MFS, Multiple Endocrine Neoplasia type 1 and/or Isolated Familial Acromegaly. However, several potential pathogenic variants were identified in heterozygous form across six genes: WDR87 (p.Arg131Ter), POLR3A (c.1909+22G>A), CTNS (48 kb deletion), DUOX (p.Ser205Ter), FLG (p.Arg501Ter), and HFE (p.Cys282Tyr), though their clinical relevance is uncertain.Discussion:. In patients with Marfan-like phenotypes, fewer than 10% show pathogenic variants in the FBN1 gene, possibly due to complex genetic alterations. The identification of potential pathogenic variants in multiple genes highlights the complexity of genetic contributions to the patient’s condition, warranting further investigation. The coexistence of MFS and acromegaly in a single patient raises significant considerations about the diagnostic process, treatment strategies, and genetic evaluation for complex diseases.Presentation: Monday, July 14, 2025

Disclosure: L. Lee: None. R.C. Rajasoorya: None.Background: Acromegaly is characterized by excessive growth hormone (GH) secretion leading to insidious somatic changes. These manifestations may overlap with gender-related traits or effects of hormone therapy, potentially contributing to delayed diagnosis in transgender individuals.Clinical Case: A 51-year-old Chinese transgender woman presented with progressive coarsening of facial features, voice deepening, and enlargement of the hands over several years. She attributed these changes to the discontinuation of feminizing hormone therapy a decade earlier. Historical photographs taken eight years prior corroborated the gradual progression. On further history, she had headaches, bilateral carpal tunnel syndrome with thenar wasting, recent-onset hypertension, and a history of rectal carcinoma resection. Given the constellation of features, acromegaly was suspected. Investigations showed elevated basal GH (12.9 mU/L) with a paradoxical rise to 36.2 mU/L after a 75 g oral glucose load. IGF-1 was markedly elevated at 888.9 µg/L (NR 114-492). Other pituitary hormones were normal. Magnetic resonance imaging (MRI) identified a pituitary macroadenoma measuring 1.4 × 0.7 × 0.8 cm. She underwent successful transsphenoidal surgery, achieving biochemical remission with normalization of GH and IGF-1 levels. Postoperatively, she developed arginine vasopressin (AVP) deficiency requiring long-term desmopressin therapy. She expressed satisfaction with the reversal of acromegalic features and restoration of a more feminised appearance. Conclusion: To our knowledge, this is the first reported case of acromegaly in a male-to-female transgender individual. A prior case described a female-to-male transgender patient whose features of acromegaly were initially misattributed to gender-affirming hormonal therapy1. This case underscores the importance of maintaining a broad differential diagnosis when evaluating new somatic changes in transgender individuals. The overlap between acromegalic features and gender-related traits can obscure the clinical picture, leading to delayed diagnosis. Clinicians should remain vigilant for alternative endocrine pathologies in transgender patients to ensure timely and appropriate management.

Disclosure: B. Bashir: None. F. Benencia: None. S. Duran Ortiz: None. F. Brown: None. E.O. List: None. J.J. Kopchick: None. D.E. Berryman: None.Aging is an inevitable pathophysiological process that leads to progressive immune dysfunction known as immunosenescence. With the increasing size of the aging population, understanding immunosenescence is crucial, as it contributes to increased vulnerability to metabolic, infectious, and autoimmune conditions with age. Interestingly, growth hormone (GH) action has been shown to correlate with aging, e.g., excess GH shortens lifespan in bovine GH transgenic (bGH) mice, while no GH action due to disruption of the GH receptor gene (GHR-/- mice) results in the longest-lived laboratory mouse on record. Because GH receptors are highly expressed in immune cells (particularly B cells, macrophages, and T cells) and undergo age-related changes that impact immune function, we hypothesize that excess GH action positively correlates with immune aging and immunosenescence. This study aimed to characterize differences in B cell populations within lymphoid organs of young (3 months) and aged (12-13 months of age) bGH mice compared to wild-type controls. Single-cell suspensions were prepared from harvested spleens and bone marrow, followed by B cell staining with fluorophore-conjugated monoclonal antibodies and analysis by multicolor flow cytometry. bGH mice showed a significantly larger spleen as compared to age-matched WT controls for both ages and sexes, even when normalized to body weight. No significant differences in B cell populations were observed in the young cohort. However, aged bGH mice showed a decrease in anti-inflammatory follicular (FO) B cells and an increase in pro-inflammatory aging-associated B cells (ABCs) in both spleen and bone marrow compared to age-matched WT controls. In conclusion, bGH mice showed shifts in the lymphocyte population that are characteristic of premature aging, suggesting that excess GH action accelerates immunosenescence. These findings suggest the potential therapeutic use of the drug that decreases GH action, such as the GH antagonist, Pegvisomant (FDA-approved drug to treat acromegaly), to mitigate immune aging and improve various aspects of healthspan. Acknowledgments: This work is supported in part by the NIH grant AG059779, and the State of Ohio’s Eminent Scholar Program includes a gift from Milton and Lawrence GollPresentation: Sunday, July 13, 2025

Disclosure: A. Rothstein Costris: None. S. Athimulam: None. S.W. Lahiri: None. A. Yaseen: None.Background: Acromegaly is a disease due to chronic growth hormone (GH) excess and pathological increase of insulin growth factor (IGF) - 1 levels. This rare endocrine disorder is associated with increased risk of cardiometabolic disease and cardiovascular events. There is limited literature in gender-specific differences in prevalence and outcomes of cardiometabolic disease in patients with acromegaly. Objective: To determine the gender differences in cardiometabolic disease and outcomes in patients with acromegaly. Design: Retrospective cross-sectional study of patients diagnosed with acromegaly over a 28-year period (Jan 1996 - Dec 2024). Setting: Academic primary and tertiary care setting. Main outcomes measured: Prevalence of cardiometabolic disease (hypertension, impaired glycemic control - type 2 diabetes mellitus and prediabetes, hyperlipidemia, obstructive sleep apnea) and cardiovascular events requiring procedural intervention (angioplasty) in patients with acromegaly. Results: In this retrospective study of consecutive 111 acromegaly patients [(59 women (53%) with a median age of 45 years at diagnosis, 85 white (77%), 16 black (14%) and 10 other races (9%)] were included. There was no significant difference in age, body mass index (BMI), tumor size, pre-operative Insulin Growth Factor (IGF) - 1 level and follow up period between men and women with acromegaly. Hypertension [(n=54,49%) men (n=31) vs women (n=23), p=0.03] is the most prevalent cardiometabolic risk factor with a significant gender difference in mean systolic BP (men (116 mmHg) vs women (110mmHg), p = 0.02). There were no significant gender differences in the prevalence of obstructive sleep apnea (n=48, 43%) hyperlipidemia (n=42, 38%), and impaired glycemic control (n=40, 36%). 8 male patients (7%) had cardiovascular events requiring angioplasty. In men, multivariate analysis (age at diagnosis, gender, pre-op IGF-1 levels, BMI at diagnosis, tumor size, systolic BP at diagnosis, presence of cavernous sinus invasion and need for post-op adjuvant treatment) identified elevated systolic BP > 130mmHg (p=0.03) and presence of cavernous since invasion (p=0.01) as predictors for increased risk of cardiovascular events requiring intervention. Conclusion: Hypertension is the most common cardiometabolic disease in patients with acromegaly, with significantly higher prevalence and systolic BP in men. Male acromegalic patients with higher systolic BP and aggressive disease (cavernous sinus invasion) at presentation are at increased risk of cardiovascular events requiring intervention.Presentation: Saturday, July 12, 2025

Disclosure: F.P. Salvador-Badilles: None. M.B. Cating-Cabral: None. B.I. Cabral: None.Acromegaly is a condition caused by overproduction of growth hormone (GH). Characteristics include facial changes, acral enlargement, and metabolic dysfunction. This manifests gradually with ∼10 years of unrecognized clinical activity. Diagnosis can be difficult when the typical features are altered when acromegaly goes undiagnosed and the patient resorts to cosmetic surgery to correct these changes. This case presents the difficulty in diagnosing a GH secreting pituitary adenoma in the setting of multiple facial reconstructive surgeries. We report a 54-year-old female, hypertensive, who initially consulted for work up of hypercalcemia and recurrent nephrolithiasis. She was diagnosed with primary hyperparathyroidism due to a parathyroid adenoma with a concomitant multinodular goiter, then underwent subtotal thyroidectomy and parathyroidectomy. Histopathology confirmed findings of parathyroid adenoma, and incidentally, papillary microcarcinoma. Post surgery, calcium levels normalized. On follow-up after a year, she reported galactorrhea. Further review of past medical history and comprehensive review of systems revealed that for many years, she had been noticing that rings no longer fit, increased shoe size, and diagnosis of bilateral carpal tunnel syndrome. Additionally, she reported that she started to undergo multiple facial reconstructive surgeries, including 2 blepharoplasties and 3 rhinoplasties because of changes in her appearance. Despite these procedures, her nose continued to increase in size which prompted further work up. Prolactin was 82.69 ng/mL, IGF-1 was 854 ng/mL and GH was 9.97 ng/mL and remained elevated with documented hyperglycemia with oral glucose load. Cranial MRI showed a 1.7 x 1.0 x 1.0 cm mass extending to the right cavernous sinus, encasing the right internal carotid artery, and sphenoid sinus. A transsphenoidal excision of the pituitary tumor was done and histopathology showed a pituitary adenoma. Immunohistochemistry was positive for GH and prolactin. Her facial features were observed to have softened following the surgery. 6 months post excision, IGF-1 decreased to 419 ng/mL, GH decreased to 1.23 ng/mL , and prolactin decreased to 21.3 ng/mL. 4 years later, GH was 1.57 ng/mL, prolactin was 36.47 ng/mL, and repeat cranial MRI showed no tumor recurrence. The case depicts the challenge in diagnosing GH secreting pituitary adenoma in a patient with a history of multiple facial surgeries which masked the typical features of acromegaly. This emphasizes the importance of thorough clinical evaluation, complete history, and comprehensive review of systems in identifying subtle manifestations of this disorder. Immediate diagnosis and management are crucial to prevent long term effects associated with growth hormone excess.Presentation: Monday, July 14, 2025

Disclosure: H. Hagog Natour: None. S. Koeneman: None. R. Zheng: None. N. Hanna: None. H. Lavu: None. C. Yeo: None. A. Nevler: None. W. Bowne: None.Background: Acromegaly is caused by excessive growth hormone secretion leading to increased levels of insulin-like growth factor-1 (IGF-1), which has been linked to higher cancer risk. However, the exact cancer prevalence in acromegaly patients compared to the general population is not well established. This study aims to investigate the cancer prevalence in patients with acromegaly as compared to patients without acromegaly. Methods: In this retrospective cohort analysis, we employed a multi-national, multi-institutional research network platform (TriNetX). Acromegaly patients were identified and matched 10:1 to controls without acromegaly based on sex and birth year, resulting in a cohort of 10,207 acromegaly patients and 102,070 matched controls. Demographic data cancer prevalence was recorded for this cohort, and logistic regression modeling controlling the effects of demographic and health covariates was employed to assess effect of being a case vs. a control on cancer prevalence. Results: A total of 10,207 acromegaly patients were identified (4,811 male patients and 5,396 female patients with a M/F ratio of 0.89 and the mean age at acromegaly onset was 43.18 years).Acromegaly patients had a significantly higher prevalence of cancer, including leukemia/lymphoma (OR 3.32, 95% CI 2.35-4.69, ovarian cancer (OR 1.89, 95% CI 1.30-2.76), breast cancer (OR 1.78, 95% CI 1.54-2.06), lung cancer (OR 1.85, 95% CI 1.51-2.27), prostate cancer (OR 1.49, 95% CI 1.25-1.77). Acromegaly patients experienced statistically significantly earlier diagnoses for ovarian cancer (7.3 years earlier, 95% CI: -13.9 - -0.6), lung cancer (3.4 years earlier, 95% CI: -6.0 – -0.9) and prostate cancer (1.78 years earlier, 95% CI -3.55 - -0.002). Conclusion: Acromegaly remains under-recognized as a significant risk factor for cancer. In this large, multi-institutional analysis, we demonstrate a compelling association between acromegaly and a markedly elevated risk of leukemia/lymphoma, as well as breast, ovarian, lung and prostate cancers. These alarming findings emphasize the critical need for proactive, targeted cancer screening in acromegaly patients to mitigate the heightened risk and improve early detection outcomes. Keywords: GH: growth hormone, IGF-I: insulin-like growth factor IGF-IPresentation: Monday, July 14, 2025

Abstract Disclosure: Y. Tsujimoto: None. A. Ishida: None. H. Shichi: None. N. Yamamoto: None. Y. Motomura: None. Y. Oi-Yo: None. Y. Sasaki: None. M. Suzuki: None. S. Urai: None. H. Bando: None. M. Yamamoto: None. M. Takahashi: None. G. Iguchi: None. N. Inoshita: None. S. Yamada: None. W. Ogawa: None. H. Fukuoka: None. Background: Several predictive markers for drug selection in acromegaly (Acro) are known, most based on hormonal suppression effects. Acro is characterized by excessive growth hormone secretion and clinical tumor effects due to the high prevalence of macroadenomas, making it essential to predict drug responsiveness for tumor shrinkage. In oncology, patient-derived 3D tumor culture systems have proven to be reliable tools for evaluating drug responses, bridging the gap between in vitro experiments and clinical studies. This study aimed to develop a similar model for Acro to assess drug responsiveness and evaluate its potential for predicting treatment outcomes. Methods: Tumor specimens from 27 Acro patients (median age: 46 [range: 36-56] years; female/male ratio: 13/14) were collected postoperatively and processed into 3D cell culture, as previously described (Tsujimoto Y, et al. J Endocr Soc. 2021; bvab055.). The culture cells were treated with therapeutic agents—octreotide (Oct) 10 nM, cabergoline (Cab) 10 nM, pasireotide (Pas) 10 nM, or vehicle—under standardized conditions. The drug response was defined as a statistically significant reduction in cell viability compared to vehicle-treated controls, as measured by the RealTime-Glo™ MT Cell Viability Assay, which provided real-time feedback on the drugs' cytotoxic effects. Fisher's exact tests and Mann-Whitney U test evaluated associations between responsiveness and clinical or histological factors. Results: Among the 27 cases, 9 (33%) responded to Oct, with an association observed in tumors with T2WI hypointensity on MRI (p = 0.04). The responsiveness to Cab was observed in 9 cases (33%), with an association in patients who responded to the bromocriptine test (p = 0.04). Pas exhibited the highest response rate (11 cases, 40%), which was associated with sparsely granulated tumors (p = 0.04).Discussion:The use of a 3D tumor culture system derived from Acro patients provided insights into drug-specific responsiveness, aligning with previously identified predictive factors for Oct, Cab, and Pas. However, it is important to note that most previously reported predictive factors focus primarily on biochemical remission. The assay's ability to measure real-time cell viability represents a significant advancement in evaluating treatment efficacy, particularly for tumor shrinkage, which has historically been challenging to predict. Integrating this approach into clinical practice, particularly for postoperative residual cases, could enable personalized medicine by refining drug selection based on tumor characteristics. Further validation in larger cohorts and prospective clinical trials is warranted to establish its broader applicability and cost-effectiveness. Presentation: Saturday, July 12, 2025

Abstract Background and Aims Chronic kidney disease (CKD) is characterized by low levels of the anti-aging protein α-Klotho. Growth hormone (GH) is thought to stimulate calcitriol production and the phosphaturic and vascular actions of FGF23 by upregulation of FGF23/Klotho axis. This is based on the observation that short-term GH treatment and endogenous GH excess enhances serum sKlotho concentrations in health subjects, patients with CKD stage 3 and acromegalic patients. The current study investigated the effects of long-term GH treatment on FGF23/Klotho axis in pediatric patients with CKD. Method We performed a case-cohort study within the Cardiovascular Comorbidity in Children with chronic kidney disease (4C) study including 101 children with CKD stages 3-5 treated with and without GH treatment. Patients were assessed for somatomedin insulin-like growth factor 1 (IGF1) and mineral bone metabolism parameters including intact parathormone (iPTH,) 1,25(OH)2D3, serum sKlotho, and intact fibroblast growth factor 23 (iFGF23) at two time points 12 months apart (E1 and E2). Age and sex adjusted z scores were calculated for height, IGF1, sKlotho and iFGF23. Results Mean age of the study population was 12.1 ± 2.8 years, and median duration of GH treatment in the GH group amounted to 21.5 months (IQR, 7.0–56.7 months). At the time of first observation (E1), GH-treated and untreated patients did not significantly differ with respect to anthropometric parameters, median eGFR, BP values, hemoglobin, serum phosphate, iPTH, 1,25(OH)2D3, and lipids values. IGF1 z-scores were significantly higher in the GH group compared to controls (P < 0.001). sKlotho z-scores were also significantly higher in GH treated patients (P < 0.001), while iFGF23 z-scores did not differ between groups. The median change in eGFR during the observation period did not differ between the groups (GH group: −1.08 ml/min/1.73 m2 (IQR, −4.5 to 0.69); controls: −2.26 ml/min/1.73 m2 (IQR, −5.09 to −0.09), P = 0.5). During the observation period, serum IGF1 levels and height z-score significantly increased in GH treated patients, but not in controls. sKlotho z-score, iFGF23 z-score, and 1,25(OH)2D3 concentrations did not significantly change within patient groups, while iPTH levels increased in controls only (P = 0.006). sKlotho z-score at the final observation (E2) was positively associated with eGFR (R2 = 0.051, P < 0.05), IGF1 z-score (R2 = 0.153 P < 0.001), 1,25(OH)2D3 (R2 = 0.038, P = 0.05) levels, and negatively associated with iFGF23 z-score (R2 = 0.093, P = 0.002), and total cholesterol levels (R2 = 0.058, P < 0.05). The slope of the regression line between sKlotho and eGFR at E2 was significant only in controls (β = 1.035, 95%CI 1.01–1.06, P = 0.005, for interaction between control group and final eGFR) (Fig. 1). In GEE multivariable model, sKlotho z-sores during the observation period were significantly associated with GH treatment, IGF1 z-score, iFGF23 z-score, and total cholesterol levels, while iFGF23 z-scores were associated with eGFR, male sex, calcium and sKlotho z-score. Conclusion In this case-cohort study, children with CKD stages 3-5 on long-term GH treatment showed improved levels of sKlotho compared to controls and the difference remained significant during the observation period. GH treatment may attenuate the adverse effect of decreasing eGFR on renal α-Klotho synthesis and thus, sKlotho levels, likely mediated by IGF1, and independently of FGF23.

The effect of treatment with somatostatin analogs in children with neurofibromatosis type 1 and growth hormone excess.

Acne, a chronic inflammatory disease, is influenced by insulin-like growth factor 1 (IGF-1). Acromegaly, characterized by excessive growth hormone (GH) and IGF-1, is associated with a higher prevalence of acne, though the underlying mechanisms remain unclear. This study aims to explore the underlying mechanisms why patients with acromegaly are more susceptible to acne, especially refractory acne. An acromegaly rat model was established via biweekly long-acting recombinant human GH (rhGH) injections for eight weeks. Serum levels of GH, IGF-1, and glucose were measured, and skin pathology was examined. Immunohistochemistry, transcriptomics, and proteomics were performed to explore molecular pathways, with RT-qPCR and western blot validation. Serum GH and IGF-1 levels significantly increased from week 3 and remained elevated throughout the study in the rhGH-treated group. Acneiform lesions, including epidermal hyperkeratosis, sebaceous gland hyperplasia, and dermal thickening, were observed. Immunohistochemical analysis revealed upregulation of IGF-1, IGF-1R, SREBP1, and IL-1β. Transcriptomic and proteomic analyses identified 1,112 differentially expressed genes and 440 differentially expressed proteins, underscoring the activation of inflammation, extracellular matrix (ECM) remodeling, epithelial-mesenchymal transition (EMT), and cell proliferation through PI3K/Akt pathways. Significant upregulation of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase 1 (TIMP-1) was observed in both transcriptomic and proteomic analyses. Chronic GH stimulation leads to persistent IGF-1 elevation, promoting acne by increasing IGF-1R expression and disrupting ECM remodeling via PI3K/Akt-regulated MMPs and TIMP-1. These findings help clarify the link between acromegaly and acne and provide mechanistic insights into the role of IGF-1 in acne pathogenesis.

The aim of this study was to assess the impact of acromegaly and excessive growth hormone on ocular tissues using swept-source optical coherence tomography (SS-OCT). Subfoveal retinal thickness (SRT), subfoveal choroidal thicknesses (SCT), peripapillary retina nerve fiber layer (pRNFL), macular ganglion cell-inner plexiform complex (GCIPL), and scleral thickness were evaluated in this prospective study. Scleral thickness was evaluated in four quadrants at 2, 4, and 6 mm posterior to the scleral spur. Right eyes of 50 acromegaly (Group 1) and 50 healthy individuals (Group 2) were enrolled. SRT was significantly higher in Group 1 (P = 0.036). SCT measurements showed no difference (P = 0.31). There was no difference between the groups in terms of pRNFL and GCIPL measurements (P = 0.30, P = 0.26). Thickness measurements from all scleral quadrants and all distances were significantly thicker in Group 1 than in Group 2 (P < 0.001). The study suggests the sclera may be a target tissue in acromegaly, with increased scleral thickness. No differences were found in choroidal, optic disc, or GCIPL parameters compared to controls.

Background: Acromegaly is a rare endocrine disorder. It results from excess growth hormone (GH) secretion, predominantly due to pituitary adenomas. Endoscopic trans-nasal transsphenoidal (ETT) resection remains the primary treatment modality. Adjunctive medical and radiotherapeutic interventions are required for incomplete remission. This study evaluates the surgical outcomes and complications in patients with acromegaly managed at Hamad General Hospital (HGH), Qatar.Methods: This retrospective study includes patients diagnosed with acromegaly and managed at HGH between January 2010 and May 2025. Only patients with confirmed acromegaly and available preoperative and postoperative hormonal assessments and imaging were included. Hormonal remission rates, extent of tumor resection, and postoperative complications were the key outcomes.Results: A total of 45 patients were included; 23 underwent surgery at HGH. The median patient age was 43 years, with a total of 39 males. ETT resection was the sole surgical modality. Postoperatively sustained biochemical remission was observed in most cases at 12-month follow-up with lowered insulin-like growth factor-1 levels (IGF-1). Lower recurrence rates (17.3% vs. 8.88%) and a higher proportion of complete tumor resection were evident in the group of patients operated at HGH. Postoperative pituitary function was preserved in 73.9% of patients with a low incidence of complications such as cerebrospinal fluid (CSF) leaks, diabetes insipidus, and infections. Histopathology revealed a predominance of densely granulated somatotroph adenomas in the HGH group, associated with improved surgical outcomes.Conclusion: ETT surgery remains an effective primary treatment for acromegaly. Favorable biochemical remission rates and tumor resection outcomes are observed in patients managed at HGH. The predominance of densely granulated somatotroph adenomas in this cohort may have contributed to the observed favorable surgical outcomes. Further large multicenter studies are warranted to validate these conclusions.

IntroductionAcromegaly is a rare condition caused by excess growth hormone after skeletal maturity, leading to abnormal soft tissue and bone growth. These changes raise the risk of obstructive sleep apnea (OSA) due to craniofacial abnormalities.ObjectiveThe study aims to determine the correlation between the occurrence and severity of OSA and craniofacial anthropometric parameters in patients with newly diagnosed acromegaly.Study designObservational, cross-sectional study.SettingSingle-center study involving patients diagnosed with acromegaly.MethodsThe research included 30 patients ranging from 25 to 81 years old (mean age 48) who were diagnosed with acromegaly. The diagnosis of OSA relied on polygraphy with the SOMNO check micro device. MRI provided the necessary craniofacial and upper airway measurements. Each patient received an ear, nose, and throat examination followed by a fiberoptic evaluation of the upper airway.ResultsOSA was diagnosed in 76.67% of patients. The analysis revealed that moderate to severe OSA affected 46% of patients, while women developed the condition at twice the rate of men. The research established a statistically relevant link between the severity of OSA and tongue base hypertrophy. The study failed to detect meaningful relationships concerning OSA severity and palatine uvula hypertrophy on MRI and between OSA severity and palatine tonsil size and middle pharyngeal airway width.ConclusionOur study found a high OSA prevalence (76.67%) in newly diagnosed acromegaly patients and a significant association between tongue base hypertrophy (FTP scale) and OSA severity (p < 0.001), while other anatomical parameters showed no significant correlation with AHI. The high prevalence of OSA in patients with newly diagnosed acromegaly highlights the importance of including sleep apnea screening in the initial diagnostic workup.

Introduction and purpose Acromegaly is an endocrine disorder resulting from an excess of growth hormone (GH), most often caused by a pituitary adenoma. In addition to typical somatic symptoms, a key clinical aspect is its complications (particularly metabolic). Chronic exposure to GH and insulin - like growth factor (IGF-1) significantly affects lipid and carbohydrate metabolism. This paper presents the current state of knowledge on acromegaly, including the most common metabolic disorders occurring during its course. The aim of this review is to deepen the understanding of acromegaly as a systemic disease, with particular emphasis on its metabolic complications. Material and methods The paper analyzes scientific publications on acromegaly and its metabolic complications published between 2008 and 2024. To gather relevant data, the literature available on PubMed was used, utilizing the following keywords: acromegaly, metabolic disorders, complications. Results The analysis of available scientific publications revealed the presence of metabolic disorders in the majority of patients with acromegaly. Lipid disturbances affect as many as 74% of patients. These individuals typically exhibit hypercholesterolemia, hypertriglyceridemia, and decreased HDL-C levels. Equally significant are disturbances in glucose metabolism, affecting more than 50% of patients. The data confirm that prolonged excess of GH and IGF-1 significantly disrupts the body’s homeostasis, requiring monitoring and comprehensive treatment. Conclusions Acromegaly is a potentially fatal disease whose effects extend far beyond the endocrine system. Its complications significantly increase cardiovascular risk, worsen patient prognosis, and negatively impact their quality of life (QoL). To improve treatment outcomes, a holistic approach to patient care, appropriate metabolic monitoring, and individualized treatment are essential.

McCune-Albright Syndrome (MAS) is a non-inherited disorder caused by missense point mutations in the GNAS1 gene located on the long arm of chromosome 20. It is a sporadic disease characterised by polyostotic Fibrous Dysplasia (FD), café-au-lait lesions, and a variety of endocrine disorders, including gonadal hyperfunction, hyperfunction of the thyroid and adrenal cortex, as well as excessive Growth Hormone (GH) secretion. The diagnostic triad includes polyostotic FD, precocious puberty, and café-au-lait lesions. When at least two of these are present, the diagnosis of MAS is confirmed. We present a case of an 18-year-old girl who presented with abdominal distension and a history of ovarian cystectomy. A detailed history revealed precocious puberty with vaginal bleeding at age three. Imaging showed a large, well-defined ovarian cyst with no solid component or septation. Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) revealed multiple expansile lytic lesions with a ground-glass matrix in the pelvic bones, skull, and sphenoid, suggestive of polyostotic FD. Café-au-lait macules and hormonal findings pointed towards MAS. This case highlights the importance of considering MAS in young females with recurrent ovarian cysts, skeletal abnormalities, and early pubertal changes, as ovarian cysts with bony lesions do not always indicate metastasis and require careful evaluation to avoid misdiagnosis.