Normal Insulin-like Growth Factor Research Articles

8209 Silent Somatotroph Adenoma Unmasked as Pituitary Apoplexy, Disguised as Subarachnoid Hemorrhage

Abstract Disclosure: P. Vemparala: None. S. Challagulla: None. Introduction - Pituitary apoplexy is a rare and potentially life-threatening complication associated with pituitary adenomas, particularly in cases of nonfunctioning macroadenomas. Silent somatotroph adenomas, characterized by the presence of growth hormone (GH) immunoreactivity without manifesting signs and symptoms of acromegaly, are uncommon. This case report presents a distinctive instance where pituitary apoplexy served as the initial manifestation of a GH-immunoreactive tumor. CASE PRESENTATION- A 45-year-old male with a medical history of hypertension, sleep apnea, and hypogonadism sought emergency medical attention following a syncopal episode. Post-syncope, he reported severe headache and neck pain, with no other associated symptoms. Imaging revealed a subarachnoid hemorrhage and a sellar/suprasellar mass measuring approximately 2.8 x 3.6 x 4.2 cm. CT angiography ruled out an aneurysm or vascular malformation. The subarachnoid hemorrhage was attributed to hemorrhage within the sellar mass. Treatment with Nimodipine and levetiracetam was initiated. Laboratory investigations indicated normal insulin-like growth factor 1 (IGF-1) levels. Brain MRI revealed a 4.2 x 2.3 x 2.6 cm heterogeneous enhancing cystic sellar/suprasellar lesion causing mass effect on the hypothalamus and third ventricle. The patient underwent endoscopic transsphenoidal hypophysectomy, revealing a tumor that was diffusely positive for GH and synaptophysin immunostaining and negative for prolactin and ACTH. Ki67 was less than 5%, with no apparent mitotic activity, atypia, or tumor necrosis. The postoperative course was uneventful, and the patient was discharged on oral steroids. Conclusion- Silent somatotroph adenomas constitute a small percentage (2-4.2%) of pituitary adenomas. In contrast to silent gonadotroph adenomas, these tumors are more prevalent in women, tend to present earlier and exhibit higher recurrence rates. This case emphasizes the potential of silent somatotroph adenomas to manifest initially as pituitary apoplexy. It underscores the importance of vigilant post-surgical follow-up due to the possibility of recurrence. Additionally, recognizing pituitary apoplexy as subarachnoid hemorrhage is crucial for timely intervention and appropriate management. Presentation: 6/2/2024

6937 A Rare Case of Pembrolizumab-induced Multiple Endocrinopathies Presenting with Acute Adrenal Crisis Secondary to Isolated ACTH Deficiency - A Case Report

Abstract Disclosure: R. Abdelmasih: None. W. Pan: None. Introduction: Pembrolizumab is an immune checkpoint inhibitor (ICI) that blocks programmed cell death receptor 1 (PD-1) which took a massive leap in the oncology world. However, we are still understanding more about its immune-related adverse events (irAEs). Here we report a case of adrenal crisis due to pembrolizumab-induced hypophysitis and adrenalitis. Case Description: A 74-year-old male with a history of left renal cell carcinoma post left nephrectomy 5 years ago, complicated with lung metastasis for which Pembrolizumab was started. 5 months after, patient developed hypothyroidism and was started on Levothyroxine. 3 months later, Patient presented with lethargy and hypotension. Physical exam revealed hypotension (MAP of 55), fever, and acute encephalopathy. AM cortisol 4.2 ug/dL, Patient was started on IV pressors and a stress dose of Hydrocortisone. Hemodynamics improved, and Hydrocortisone was tapered down. ACTH stimulation test revealed a subnormal response of cortisol 0.2, 1.7, and 2.7 ug/dL at 0, 30, and 60 minutes respectively in the setting of very low ACTH of < 1.5 pg/ml, other pituitary hormones were checked, revealing normal insulin-like growth factor was 116 ng/mL, LH 15.29 mIU/mL, and FSH 27.45 mIU/mL. TSH was high 15 mIU/mL and free T4 was 1.4 ng/dl, levothyroxine dose was increased, and hydrocortisone was maintained at 10 in am and 5 in pm with excellent response. Discussion:ICIs inhibit the immunological pathways that control T-cell activation, leading to multiple immune-related endocrinopathies. Thyroiditis is the most reported one (30%), though anti-PD1-induced hypophysitis is exceptionally rare (< 1%). To date, the pathophysiology of pembrolizumab-induced central AI is not clearly understood, it’s presumed that it causes lymphocytic hypophysitis often presenting with isolated ACTH deficiency. Also, Pembrolizumab-induced primary adrenal insufficiency has seldom been reported and not yet understood, interestingly, anti-steroidogenic enzyme antibodies were absent in those few most reported cases which suggests a different mechanism compared to traditional primary AI. We suggest that our patient had combined primary and secondary adrenal insufficiency based on ACTH stim test result with very low cortisol responses in the setting of very low ACTH, which we believe is what led to such severe presentation of adrenal crisis. Diagnosis of PD1-induced AI can be challenging due to the overlapping of advanced malignancy and AI presentation. A higher level of suspicion is prompted especially in patients who experienced other endocrine irAEs (as our patient who had PDL-1-induced hypothyroidism). We present this case to shed light on this rare yet potentially fatal endocrine adverse event that can be reversed by prompt diagnosis and timely management due to the increasing use of pembrolizumab. More cases are needed for a better understanding of such a rare adverse event. Presentation: 6/2/2024

6983 Pembrolizimab Induced Hypophysitis: Uncommon Side Effect Leading To Late Diagnosis

Abstract Disclosure: T. Chaudhary: None. O. Syed: None. A. Shridar: None. R. Kaur: None. O. Chaudhary: None. M.S. Zubair: None. Background: Pembrolizumab, an immune checkpoint inhibitor, has shown efficacy inducing remission in various malignancies. Associated immune-related adverse effects (irAEs) have been recorded but cases of concomitant hypophysitis and thyroiditis are rare. Clinical case: The patient is a 41-year-old male with a past medical history significant for metastatic melanoma of the left calf, status post sentinel lymph node biopsy and left inguinal lymph node dissection, treated with pembrolizumab for one year. He initially presented with a severe headache that was preceded by two months of fatigue and impaired concentration. CT and MRI head were both unremarkable while lab work was significant for cortisol 0.2 ug/dL and adrenocorticotropic hormone (ACTH) 1.1 pmol/L. A full hormone panel was ordered which showed normal insulin-like growth factor-1 (IGF-1), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Free testosterone was at the lower end of normal. Prolactin was elevated at 27.3 ng/mL. The thyroid function tests showed primary hypothyroidism with elevated thyroid stimulating hormone (TSH) at 109 uIU/mL, low T4 at 1.5 ug/dL, and low free T4 at 0.4 ng/dL. There were no signs or symptoms of posterior pituitary dysfunction. The patient was diagnosed with hypophysitis and started on hydrocortisone 20 mg once daily along with levothyroxine 175 mcg once daily. DEXA scan showed normal bone mineral density. Subsequently, the patient presented to our care and reported symptom improvement after taking the prescribed medication however he continued to develop fatigue by the end of the day. Therefore, hydrocortisone prescription was switched to 15 mg in the morning and 10 mg at noon. A repeat thyroid function panel, sex hormone binding globulin, and LH were ordered, to be followed up at the patient's next visit. The patient was also advised to wear a medical alert bracelet at all times moving forward. Conclusion: Due to non-specific symptoms at onset, hypophysitis can be undiagnosed or misdiagnosed therefore it is important to have a high clinical suspicion with patients on PD-1 inhibitors presenting with such symptoms. It is also imperative to order a full set of hormones as this patient had concomitant primary hypothyroidism. Presentation: 6/1/2024

Early postoperative growth hormone measurement as a predictive marker for acromegaly remission.

Growth hormone (GH) has a short half-life and declines abruptly following somatotropinoma surgery, enabling its prompt measurement as an indicator of surgical success. This study assesses the predictive value of early postoperative GH levels for 3-month and >1-year remission of acromegaly. We conducted a retrospective search in our database of patients who had undergone transsphenoidal surgery of GH-secreting pituitary adenoma from January 2011 to June 2022. Only the patients who underwent the first pituitary surgery and had GH measurements on the fifth postoperative day were included. The 3-month and >1-year remission of acromegaly was defined as achieving the GH nadir of <0.4 μg/L during an oral glucose tolerance test and maintaining normal insulin-like growth factor 1 levels at the initial follow-up visit 3 months after surgery and throughout at least the first year postoperation. We included 63 patients in the analysis, with a median follow-up of 51.8 (13-155) months. The 3-month remission was achieved in 42 (66.7%) patients, and >1-year remission without additional therapy in 38 (60.3%) patients. Those who achieved >1-year remission had significantly lower fifth-day postoperative GH levels (0.59 [0.09-8.92] vs. 2.63 [0.25-24.64] μg/L, p < .001). Receiver-operating characteristic analysis revealed a significant value of fifth-day postoperative GH levels regarding the prediction of 3-month (area under the curve [AUC], 0.834; p < .0001) and >1-year (AUC, 0.783; p < .0001) acromegaly remission. The GH threshold of ≤1.57 μg/L yielded a sensitivity of 90.5% and a specificity of 71.4% at 3 months and 89.5% sensitivity and 60% specificity at the >1-year remission, respectively. Notably, all patients with fifth-day postoperative GH levels ≤0.23 μg/L exhibited remission of acromegaly throughout the follow-up period. Early postoperative GH measurement could be a reliable predictor of both 3-month and >1-year remission of acromegaly.

Suspected silent pituitary somatotroph neuroendocrine tumor associated with acromegaly-like bone disorders: a case report

BackgroundGrowth hormone (GH) positive pituitary neuroendocrine tumors do not always cause acromegaly. Approximately one-third of GH-positive pituitary tumors are classified as non-functioning pituitary tumors in clinical practice. They typically have GH and serum insulin-like growth factor 1 (IGF-1) levels in the reference range and no acromegaly-like symptoms. However, normal hormone levels might not exclude the underlying hypersecretion of GH. This is a rare and paradoxical case of pituitary tumor causing acromegaly-associated symptoms despite normal GH and IGF-1 levels.Case presentationWe report a case of a 35-year-old woman with suspicious acromegaly-associated presentations, including facial changes, headache, oligomenorrhea, and new-onset diabetes mellitus and dyslipidemia. Imaging found a 19 × 12 × 8 mm pituitary tumor, but her serum IGF-1 was within the reference, and nadir GH was 0.7ng/ml after glucose load at diagnosis. A thickened skull base, increased uptake in cranial bones in bone scan, and elevated bone turnover markers indicated abnormal bone metabolism. We considered the pituitary tumor, possibly a rare subtype in subtle or clinically silent GH pituitary tumor, likely contributed to her discomforts. After the transsphenoidal surgery, the IGF-1 and nadir GH decreased immediately. A GH and prolactin-positive pituitary neuroendocrine tumor was confirmed in the histopathologic study. No tumor remnant was observed three months after the operation, and her discomforts, glucose, and bone metabolism were partially relieved.ConclusionsGH-positive pituitary neuroendocrine tumors with hormonal tests that do not meet the diagnostic criteria for acromegaly may also cause GH hypersecretion presentations. Patients with pituitary tumors and suspicious acromegaly symptoms may require more proactive treatment than non-functioning tumors of similar size and invasiveness.

Long-term pasireotide-LAR treatment in the personalized therapy of patients with complex acromegaly: a collection of clinical experiences.

Pasireotide-LAR is recommended as a second-line treatment for patients with acromegaly. Although the effects of pasireotide-LAR have been well characterized in clinical studies, real-practice evidence is scant, especially in the long term and within the individualization of therapy in patients with comorbidities. To provide additional insight on the individualized approach to acromegaly management, six clinical cases of complex acromegaly treated with pasireotide-LAR for more than 5 years were reported. Pasireotide-LAR allowed the normalization of insulin-like growth factor 1 (IGF1) values in all patients and reduced tumour residue volume where present. A good safety profile and long-term tolerability were also reported.

Pseudoacromegaly-A challenging entity in the endocrine clinic: A systematic review.

Pseudoacromegaly encompasses conditions with features of acromegaly/gigantism, but no growth hormone (GH) or insulin-like growth factor-1 (IGF-1) excess. We aimed to review published pseudoacromegaly cases evaluated due to clinical suspicion of acromegaly. PubMed/Medline search was conducted to identify reported pseudoacromegaly cases, which were systematically reviewed to ensure they met eligibility criteria: (1) presentation suggestive of acromegaly; (2) acromegaly excluded based on normal GH, IGF-1 and/or GH suppression on oral glucose tolerance test (OGTT-GH); (3) diagnosis of the pseudoacromegaly condition was established. Data were retrieved from each case and analysed collectively. Of 76 cases, 47 were males, mean ages at presentation and at first acromegaloid symptoms were 28 ± 16 and 17 ± 10 years, respectively. Most common conditions were pachydermoperiostosis (47%) and insulin-mediated pseudoacromegaly (IMP) (24%). Acromegaloid facies (75%) and acral enlargement (80%) were the most common features. Measurement of random GH was reported in 65%, IGF-1 in 79%, OGTT-GH in 51%. GH excess was more frequently excluded based on two tests (53%). Magnetic resonance imaging (MRI) was performed in 30 patients, with pituitary adenoma or hyperplasia being reported in eight and three patients, respectively. Investigations differed between cases managed by endocrine and non-endocrine specialists, the former requesting more often IGF-1, OGTT-GH and pituitary MRI. Pseudoacromegaly is a challenging entity that may be encountered by endocrinologists. Pachydermoperiostosis and IMP are the conditions most often mimicking acromegaly. Adequate assessment of GH/IGF-1 is crucial to exclude acromegaly, which may be better performed by endocrinologists. Pituitary incidentalomas are common and require careful judgement to prevent unnecessary pituitary surgery.

THU070 Randomized, Placebo-controlled Phase 3 Trial Protocol Assessing The Efficacy And Safety Of Octreotide Subcutaneous Depot (CAM2029) In Patients With Acromegaly

Abstract Disclosure: D. Ferone: Advisory Board Member; Self; Recordati, Novartis-AAA, Sandoz, Camurus. Grant Recipient; Self; Bristol-Myers Squibb, Novartis-AAA, Ipsen, Camurus. Research Investigator; Self; Camurus. P. Freda: Research Investigator; Self; Camurus. L. Katznelson: Advisory Board Member; Self; Recordati, Camurus, Amryt. Research Investigator; Self; Camurus. F. Gatto: Research Investigator; Self; Camurus. A. Gilis-Januszewska: Research Investigator; Self; Camurus. M.B. Gordon: Advisory Board Member; Self; Camurus, Crinetics, HRA Pharma, Novo Nordisk, Recordati. Grant Recipient; Self; Amryt, Ascendis, Camurus, Corcept, Crinetics, Ipsen, Novartis Pharmaceuticals, Novo Nordisk, Opko, Pfizer, Inc., Strongbridge. Research Investigator; Self; Camurus. P. Kadioglu: Research Investigator; Self; Camurus. P. Maffei: Research Investigator; Self; Camurus. J.R. Seufert: Research Investigator; Self; Camurus. J. Silverstein: Advisory Board Member; Self; Amryt, Recordati. Research Investigator; Self; Camurus. J.L. Spencer-Segal: Grant Recipient; Self; Camurus. Research Investigator; Self; Camurus. M. Harrie: Employee; Self; Camurus. A. Svedberg: Employee; Self; Camurus. F. Tiberg: Employee; Self; Camurus. Extended-release formulations of the somatostatin analogues (SSAs), octreotide and lanreotide, are first-line medical therapies for patients with acromegaly who have contraindications for, or are not cured by, surgical intervention and/or radiotherapy. Treatment goals, regardless of modality, include biochemical normalization of insulin-like growth factor 1 (IGF-1) and growth hormone (GH), symptom relief, tumor control, and maintenance of pituitary function. From the patient perspective, treatment satisfaction, autonomy, and quality of life may be as important as biochemical control. Constraints of current SSA formulations include incomplete biochemical and symptom control, and a lack of convenient self-administration options. Octreotide subcutaneous (SC) depot (CAM2029) is a novel FluidCrystal® formulation of octreotide designed for easy administration by patients, in a ready-to-use prefilled syringe or injection pen. In previous clinical trials, CAM2029 provided more than five-fold higher bioavailability compared to the currently marketed long-acting octreotide formulation.The efficacy and safety of CAM2029 in acromegaly is being evaluated in a 6-month, randomized, double-blind, placebo-controlled phase 3 trial (NCT04076462). 72 patients were randomized 2:1 to monthly SC doses of CAM2029 20 mg or placebo, with the option for self-administration. Key inclusion criteria included a biochemical and clinical diagnosis of acromegaly due to a pituitary adenoma with persistent or recurrent disease, treatment with a stable dose of octreotide long-acting release or lanreotide Autogel for at least 3 months as monotherapy, and controlled disease with IGF-1 ≤1 x upper limit of normal (ULN). Key exclusion criteria included GH ≥2.5 μg/L at screening, pituitary surgery within 6 months of screening, prior pituitary irradiation, and recent treatment with pasireotide, pegvisomant, or dopamine agonists. The primary endpoint is the proportion of patients with normalized IGF-1 (≤1 x ULN) after 6 months of treatment. Other endpoints include change from baseline of IGF-1, GH and patient-reported outcomes (Treatment Satisfaction Questionnaire for Medication, Self-Injection Assessment Questionnaire, Acromegaly Quality of Life Questionnaire, EQ-5D-5L), safety and tolerability, clinical signs and symptoms of acromegaly, use of rescue medication and octreotide pharmacokinetics. The estimated primary completion date for the trial is May 2023. After completing study treatment, patients may switch to open-label treatment in a phase 3 long-term safety and extension trial of CAM2029 (NCT04125836). Presentation: Thursday, June 15, 2023

Dysregulation of insulin-like growth factor-1 signaling in postnatal bone elongation.

Insulin-like growth factor-1 (IGF-1) is a critical modulator of cell growth and survival, making it a central part of maintaining essentially every biological system in the body. Knowledge of the intricate mechanisms involved in activating IGF-1 signaling is not only key to understanding basic processes of growth and development, but also for addressing diseases, such as cancer and diabetes. This brief review explores how dysregulation of normal IGF-1 signaling can impact growth by examining its role in postnatal bone elongation. IGF-1 actions are dysregulated in autoimmune diseases, such as juvenile idiopathic arthritis and chronic kidney disease, which results in growth stunting. Conversely, childhood obesity results in growth acceleration, premature growth cessation, and ultimately, diminished bone quality, while systemic IGF-1 levels remain normal. Understanding the role of IGF-1 signaling in normal and dysregulated growth can add to other studies that address how this system regulates chronic diseases.

Somatropin for Short Stature

&#x0D; For children with short stature who were born small for gestational age, 1 guideline suggests increasing human growth hormone dose when treatment response is unsatisfactory, while aiming for normal insulin-like growth factor 1 levels.&#x0D; For children with idiopathic short stature, 1 guideline recommends against the routine use of growth hormone. It suggests initiating growth hormone therapy on a case-by-case basis, with a starting dose ranging from 0.24 mg/kg/week to 0.47 mg/kg/week, as well as conducting an assessment 12 months after initiation to optimize dosage.&#x0D; The development of recommendations from guidelines included in this report was challenged by limited relevant evidence, as well as heterogeneity of growth hormone dose and frequency and treatment response found in available literature. Future guidelines should also consider patient perspectives, resource implications, and the facilitators of and barriers to therapy within the context of health care systems in Canada.&#x0D;

Endocrinologic Outcome Following Endonasal Transphenoidal Excision of Growth Hormone Secreting Pituitary Adenomas

Background: Endonasal Transphenoidal Approach for excision of pituitary adenomas has been gaining popularity over the traditional microsurgical approach. The objective of this study is to assess the rate of hormonal recovery following endonasal transphenoidal excision of growth hormone secreting pituitary macroadenoma in out center. Methods: In this prospective observational study all cases subjected to endonasal transphenoidal excision of growth hormone secreting pituitary adenoma, during the study period from January 2019 to December 2020 at National Neurosurgical Referral Center, Bir Hospital, Kathmandu were included in this study. Preoperative and postoperative patient characteristics were recorded. Hormonal remission was defined as normal insulin-like growth factor-1 level at 3 months follow-up. Results: A total of 24 cases were included. The mean age of acromegaly cases was 39.42±10.41 years (24-56 years), with male to female ratio of 0.71:1. Majority (9) of cases had a Knosp grade 1.Thirteen cases had a Wilson-Hardy Extension Grade 0. Majority (11) of cases had a Wilson-Hardy Invasion Grade I. Three cases developed post-operative CSF leak, which recovered after lumbar drainage with no sequel. Five cases developed epistaxis which resolved with nasal packing. Sixty three percent (15 cases) had normal IGF-1 levels at 3 months follow up. Conclusion: Endoscopic endonasal transphenoidal approach to excision of growth hormone secreting pituitary adenomas is a safe and effective modality at achieving hormonal control in our setting.

Association of Body Mass Index with Insulin-like Growth Factor-1 Levels among 3227 Chinese Children Aged 2–18 Years

Insulin-like growth factor-1 (IGF-1) levels are affected by nutritional status, yet there is limited research exploring the association between body mass index (BMI) and IGF-1 levels among children. This cross-sectional study included 3227 children aged 2-18 years without specific diseases, whose height, weight, and pubertal stages were measured and assessed by pediatricians. BMI standard deviation scores (BMISDS) were used to categorize children as underweight (BMISDS < -2); normal-weight (-2 ≤ BMISDS ≤ 1); overweight (1 < BMISDS ≤ 2); and obese (BMISDS > 2). Children were divided into low-level (<-0.67 SD) and nonlow-level (≥-0.67 SD) groups based on IGF-1 standard deviation scores (IGF-1SDS). The association between IGF-1 and BMI as categorical and continuous variables was explored by Binary logistic regression, the restrictive cubic spline model, and the generalized additive model. Models were adjusted by height and pubertal development. Recursive algorithm and multivariate piecewise linear regression were further utilized to assess the threshold of the smooth curve. IGF-1 levels varied by BMI categories, with the highest levels observed in the overweight group. The proportion of low IGF-1 levels in underweight, normal-weight, overweight, and obese groups was 32.1%, 14.2%, 8.4%, and 6.5%, respectively. The risk odds of low IGF-1 levels in underweight children were 2.86-, 2.20-, and 2.25-fold higher than in children with normal weight before adjustment, after adjustment for height, and after adjustment for height and puberty, respectively. When analyzing the association between BMI and low IGF-1 levels, dose-response analysis demonstrated an inverted J-shaped relationship between BMISDS and low IGF-1 levels. Lower or higher BMISDS increased the odds of low IGF-1 levels, and significance was retained in underweight children but not in obese children. When BMI and IGF-1 levels were used as continuous variables, the relationship between the BMISDS and IGF-1SDS followed a nonlinear inverted U shape. IGF-1SDS increased with the increase of BMISDS (β = 0.174, 95% CI: 0.141 to 0.208, p < 0.01) when BMISDS was less than 1.71 standard deviation (SD) and decreased with the increase of BMISDS (β = -0.358, 95% CI: -0.474 to -0.241, p < 0.01) when BMISDS was greater than 1.71 SD. The relationship between BMI and IGF-1 levels was found to depend on the type of variable, and extremely low or high BMI values could result in a tendency toward low IGF-1 levels, emphasizing the importance of maintaining a normal BMI range for normal IGF-1 levels.

Growth hormone deficiency in adult survivors of childhood brain tumors treated with radiation.

Growth hormone deficiency (GHD) is the most common endocrine late effect in irradiated survivors of childhood brain tumors. This study aimed to determine the prevalence of GHD in adults treated with proton or photon irradiation for a brain tumor in childhood and to detect undiagnosed GHD. This study is a cross-sectional study. We investigated GHD in 5-year survivors from two health regions in Denmark treated for childhood brain tumors with cranial or craniospinal irradiation in the period 1997-2015. Medical charts were reviewed for endocrinological and other health data. Survivors without a growth hormone (GH) test at final height were invited to a GH stimulation test. Totally 41 (22 females) survivors with a median age of 21.7 years (range: 15.1-33.8 years) at follow-up and 14.8 years (range: 5.1-23.4 years) since diagnosis were included; 11 were treated with proton and 30 with photon irradiation; 18 of 21 survivors were previously found to have GHD; 16 of 20 survivors with no GH test at final height were tested, 8 (50 %) had GHD. In total, 26 of 41 patients (63%) had GHD. Insulin-like growth factor-1 (IGF-1) is associated poorly with the insulin tolerance test (ITT). This study identified a high prevalence of undiagnosed GHD in survivors with no GH test at final height. The results stress the importance of screening for GHD at final height in survivors of childhood brain tumors with prior exposure to cranial irradiation, irrespective of radiation modality and IGF-1. This cross-sectional study reports a prevalence of 63% of GHD in irradiated childhood brain tumor survivors. Furthermore, the study identified a considerable number of long-term survivors without a GH test at final height, of whom, 50% subsequently were shown to have undiagnosed GHD. Additionally, this study confirmed that a normal serum IGF-1 measurement cannot exclude the diagnosis of GHD in irradiated survivors. This illustrates the need for improvements in the diagnostic approach to GHD after reaching final height in childhood brain tumor survivors at risk of GHD. In summary, our study stresses the need for GHD testing in all adult survivors treated with cranial irradiation for a brain tumor in childhood irrespective of radiation modality.

A systematic literature review to evaluate extended dosing intervals in the pharmacological management of acromegaly

PurposeThis systematic literature review investigated whether extended dosing intervals (EDIs) of pharmacological acromegaly treatments reduce patient burden and costs compared with standard dosing, while maintaining effectiveness.MethodsMEDLINE/Embase/the Cochrane Library (2001–June 2021) and key congresses (2018–2021) were searched and identified systematic literature review bibliographies reviewed. Included publications reported on efficacy/effectiveness, safety and tolerability, health-related quality of life (HRQoL), and patient-reported and economic outcomes in longitudinal/cross-sectional studies in adults with acromegaly. Interventions included EDIs of pegvisomant, cabergoline, and somatostatin receptor ligands (SRLs): lanreotide autogel/depot (LAN), octreotide long-acting release (OCT), pasireotide long-acting release (PAS), and oral octreotide; no comparator was required.ResultsIn total, 35 publications reported on 27 studies: 3 pegvisomant monotherapy, 11 pegvisomant combination therapy with SRLs, 9 LAN, and 4 OCT; no studies reported on cabergoline, PAS, or oral octreotide at EDIs. Maintenance of normal insulin-like growth factor I (IGF-I) was observed in ≥ 70% of patients with LAN (1 study), OCT (1 study), and pegvisomant monotherapy (1 study). Achievement of normal IGF-I was observed in ≥ 70% of patients with LAN (3 studies) and pegvisomant in combination with SRLs (4 studies). Safety profiles were similar across EDI and standard regimens. Patients preferred and were satisfied with EDIs. HRQoL was maintained and cost savings were provided with EDIs versus standard regimens.ConclusionsClinical efficacy/effectiveness, safety, and HRQoL outcomes in adults with acromegaly were similar and costs lower with EDIs versus standard regimens. Physicians may consider acromegaly treatment at EDIs, especially for patients with good disease control.

PSUN314 Severe Insulin Resistance Impacts the Growth Hormone-Insulin-Like Growth Factor-I Axis and Linear Growth

Abstract Diabetes and insulin resistance (IR) may impact growth hormone (GH), insulin-like growth factor 1 (IGF-1), and linear growth. Poorly controlled diabetes impairs growth, while high insulin may increase growth. To understand relationships between diabetes, IR, and growth, we examine height, body mass index (BMI), glucose, GH, and IGF- in patient populations with IR, including (in order of increasing IR): congenital generalized lipodystrophy (CGL), heterozygous pathogenic variants of the insulin receptor INSR (+/-), homozygous INSR variants (INSR-/-), and autoantibodies to the insulin receptor (Type B IR). Patients with CGL and INSR +/- have less IR, lower glucose, higher BMI, and higher IGF-1 vs patients with INSR -/- and Type B INSR. Patients with INSR -/- have short stature, while those with CGL have tall stature. GH is comparable in all groups. After remission of Type B IR, patients had normalization of insulin resistance, glucose, and IGF-1, supporting the idea that IR or elevated glucose caused low IGF-1. Our findings suggest that severe IR causes elevated blood glucose with inadequate glucose reaching cells mimicking a starvation state and causing low IGF-1. If this occurs during childhood growth (as in INSR -/-, but not in Type B IR), it leads to short stature. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

PMON117 IGF-1 Testing: Diagnostic Pitfalls

Abstract Introduction Acromegaly is a rare endocrine disorder, with an incidence of 5.3/million/year, that results from persistent hypersecretion of growth hormone (GH), which stimulates hepatic secretion of insulin-like growth factor-1 (IGF-1). The best single test for the diagnosis of acromegaly is measurement of serum IGF-1; however, the result must be interpreted with caution, with understanding of potential pitfalls. Here we present a case of falsely elevated IGF-1 levels. Case Description A 43-year-old female with medical history of prediabetes, sleep apnea, and headaches was referred to endocrine clinic for evaluation of possible acromegaly. Patient had been evaluated by her primary care physician for frequent headaches, unintentional weight gain, and bilateral leg and hand swelling. Patient endorsed being unable to wear her wedding ring for a few years. Initial laboratory evaluation by primary care physician 3 months prior revealed normal thyroid function, prolactin, FSH, LH, random cortisol, but elevated IGF-1 of 310 ng/mL (normal 71-258 ng/mL), with negative pregnancy test. Brain MRI at that time revealed a pineal gland cyst but no pituitary abnormality. During her initial endocrine visit, IGF-1 was repeated, which was again elevated but improved to 283 ng/mL (normal 71-258 ng/mL). Other pertinent labs included a normal random ACTH of 18 pg/mL (normal &amp;lt;47 pg/mL), and pm cortisol of 2.4 mcg/dL (normal 2.9-17.3 mcg/dL). Physical examination was notable for a few light purple striae on abdomen, acanthosis nigricans, and mild limb edema, but no macrognathia, enlarged hands or feet. Given patient's lack of typical features of acromegaly, normal pituitary imaging, and spontaneous IGF-1 improvement, it was decided to postpone GH measurements with oral glucose tolerance test but repeat IGF-1 in 6 months. Patient was able to follow up 11 months after initial visit at which patient denied any worsening symptoms. At that time, repeat laboratory study showed normal IGF-1 of 231. Given spontaneous normalization of IGF-1 levels, no further laboratory testing or imaging studies were recommended, and patient was instructed to follow up in 11-12 months. Discussion Prompt diagnosis of acromegaly is crucial. However, it is important to note IGF-1 could be falsely elevated. A retrospective review by Erickson et. al of 2747 unique patients with IGF-1 elevation, 117 (4%) were found to have false-positive results following a review of the clinical data. In addition to acromegaly, other causes of elevated IGF-1 levels include high protein and high glycemic-index diet, pregnancy, hyperthyroidism, IGF-1 assay problems, and some rare tumors (carcinoids) secreting IGF-1. Discovery of "falsely" elevated IGF-1 may lead to unnecessary testing and physician visits. Therefore, clinicians should consider retesting patients after some time interval if spurious IGF-1 is suspected, before aggressively pursuing more extensive investigations. Presentation: No date and time listed

Association of pre- and postoperative αKlotho levels with long-term remission after pituitary surgery for acromegaly

Soluble αKlotho (sKl) is a disease-specific biomarker that is elevated in patients with acromegaly and declines after surgery for pituitary adenoma. Approximately 25% of patients do not achieve remission after surgery, therefore a risk stratification for patients early in the course of their disease may allow for the identification of patients requiring adjuvant treatment. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) have been assessed as biomarker for disease activity, however the value of sKl as a predictive biomarker of surgical success has not been evaluated yet. In this study, we measured serum biomarkers before and after transsphenoidal pituitary surgery in 55 treatment-naïve patients. Based on biochemical findings at follow-up (7–16 years), we divided patients into three groups: (A) long-term cure (defined by normal IGF-1 and random low GH (< 1 μg/l) or a suppressed GH nadir (< 0.4/μg/l) on oral glucose testing); (B) initial remission with later disease activity; (C) persistent clinical and/or biochemical disease activity. sKl levels positively related to GH, IGF-1 levels and tumor volume. Interestingly, there was a statistically significant difference in pre- and postoperative levels of sKl between the long-term cure group and the group with persistent disease activity. This study provides first evidence that sKl may serve as an additional marker for surgical success, decreasing substantially in all patients with initial clinical remission while remaining high after surgery in patients with persistent disease activity.

Treatment of Short Stature in Aggrecan-deficient Patients With Recombinant Human Growth Hormone: 1-Year Response.

Patients with aggrecan (ACAN) deficiency present with dominantly inherited short stature, often with advanced skeletal maturation and premature growth cessation. There is a paucity of information on the effects of growth-promoting interventions. The aim of this study was to evaluate the efficacy and safety of recombinant human growth hormone (rhGH) therapy on linear growth in children with ACAN deficiency. Open-label, single-arm, prospective study at Cincinnati Children's Hospital Medical Center. Ten treatment-naïve patients were recruited. Inclusion criteria were a confirmed heterozygous mutation in ACAN, age ≥2 years, prepubertal, bone age (BA) ≥chronological age (CA), and normal insulin-like growth factor I concentration. Treatment was with rhGH (50 µg/kg/day) over 1 year. Main outcomes measured were height velocity (HV) and change in (Δ) height SD score (HtSDS). Ten patients (6 females) were enrolled with median CA of 5.6 years (range 2.4-9.7). Baseline median HtSDS was -2.5 (range -4.3 to -1.1). Median baseline BA was 6.9 years (range 2.5-10.0), with median BA/CA of 1.2 (range 0.9-1.5). Median pretreatment HV was 5.2 cm/year (range 3.8-7.1), increased to 8.3 cm/year (range 7.3-11.2) after 1 year of therapy (P = .004). Median ΔHtSDS after 1 year was +0.62 (range +0.35 to +1.39) (P = .002). Skeletal maturation did not advance inappropriately (median ΔBA/CA -0.1, P = .09). No adverse events related to rhGH were observed. Treatment with rhGH improved linear growth in a cohort of patients with short stature due to ACAN deficiency.

Cost-Utility of Acromegaly Pharmacological Treatments in a French Context.

ObjectiveEfficacy of pharmacological treatments for acromegaly has been assessed in many clinical or real-world studies but no study was interested in economics evaluation of these treatments in France. Therefore, the objective of this study was to estimate the cost-utility of second-line pharmacological treatments in acromegaly patients.MethodsA Markov model was developed to follow a cohort of 1,000 patients for a lifetime horizon. First-generation somatostatin analogues (FGSA), pegvisomant, pasireotide and pegvisomant combined with FGSA (off label) were compared. Efficacy was defined as the normalization of insulin-like growth factor-1 (IGF-1) concentration and was obtained from pivotal trials and adjusted by a network meta-analysis. Costs data were obtained from French databases and literature. Utilities from the literature were used to estimate quality-adjusted life year (QALY).ResultsThe incremental cost-utility ratios (ICUR) of treatments compared to FGSA were estimated to be 562,463 € per QALY gained for pasireotide, 171,332 € per QALY gained for pegvisomant, and 186,242 € per QALY gained for pegvisomant + FGSA. Pasireotide seems to be the least cost-efficient treatment. Sensitivity analyses showed the robustness of the results.ConclusionFGSA, pegvisomant and pegvisomant + FGSA were on the cost-effective frontier, therefore, depending on the willingness-to-pay for an additional QALY, they are the most cost-effective treatments. This medico-economic analysis highlighted the consistency of the efficiency results with the efficacy results assessed in the pivotal trials. However, most recent treatment guidelines recommend an individualized treatment strategy based on the patient and disease profile.

Characteristics and treatment responsiveness of patients with acromegaly and a paradoxical GH increase to oral glucose load.

We aimed to investigate the clinical, biochemical, histological and radiological characteristics as well as the response to somatostatin analogs (SSA) in a large cohort of acromegaly patients with a paradoxical GH response (PR) to oral glucose tolerance test (OGTT). Retrospective study. Of 110 patients with acromegaly included in our study, 30 (PR+; 27%) had a paradoxical GH increase of more than 25% relative to basal GH levels during OGTT. At diagnosis, PR+ patients were older than PR- patients (52 ± 16 years vs 44 ± 14 years, P < 0.05) and had smaller pituitary tumors (40% microadenomas vs 19%, P < 0.05), which were less often invasive (17% vs 35%, P < 0.05), overall more secreting (insulin-like growth factor-1 (IGF-1)/tumoral surface: 2.35 ULN/cm2 (0.28-9.06) vs 1.08 (0.17-7.87), P = 0.011), and more often hypointense on T2-weighted MRI (92% vs 48%, P = 0.001). While the rate of remission after surgery was similar in the two groups (69%), a better response to SSA treatment was observed in PR+ patients, either before (IGF-1 reduction of > 50% after 3-6 months in 77% vs 49%, P = 0.023) or after surgery (normalization of IGF-1 in 100% vs 44%, P = 0.011). Our study demonstrates that in acromegaly, a paradoxical GH increase during OGTT is associated with particular features of somatotroph adenomas and with a better prognosis in terms of response to SSA.