IGF-I Levels Research Articles

Chronic psychosocial stress affects insulin-like growth factor 1 and its receptors in mouse ovaries.

Context Chronic psychosocial stress negatively affects folliculogenesis and oogenesis. Intraovarian mechanisms mediating these effects are poorly understood. Aims This work aimed to find out how chronic psychosocial stress affects ovarian IGF1 and its receptor (IGF1R), as well as Igf1 and Igf1r gene expression in cumulus-oocyte complexes (COCs). It also aimed to address possible protective effects of gonadotropin stimulation on IGF1 ovarian signalling. Methods Female CD1 mice experienced chronic psychosocial stress of 11-day isolation followed by overcrowding for 10days. To verify the model, blood corticosterone levels and the quality of oocytes were evaluated in stressed females. The levels of IGF1/IGF1R, blood IGF1 concentration, and expression of Igf1 /Igf1r in the ovaries were compared in stressed and unstressed females. Key results Psychosocial stress caused an elevation of corticosterone level, which was alleviated by gonadotropin treatment. The stressed mice showed a decreased IGF1 level in the ovaries and a decreased expression of Igf1 and Igf1r in COCs. In the unstressed females, gonadotropin injection decreased the expression of Igf1 and Igf1r ; in the stressed females, the same treatment increased Igf1r expression. Neither stress nor ovarian stimulation with gonadotropins affected the serum IGF1 level. Conclusions Psychosocial stress suppresses IGF1 signalling in the ovaries. Gonadotropin treatment modulates these effects differently in stressed and unstressed animals. Implications The results may have translational value for human reproduction. Ovarian IGF1 can be considered a candidate for further improvement of IVF results in women under conditions of chronic stress.

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

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

Causal associations between the insulin-like growth factor family and sarcopenia: a bidirectional Mendelian randomization study

ObjectiveInsulin-like growth factor (IGF) is closely associated with sarcopenia, yet the causal relationship of this association remains unclear. This study aims to explore the potential causal relationship between members of the IGF family and sarcopenia from a genetic perspective through bidirectional Mendelian randomization (MR) analysis using two-sample datasets.MethodsFive genetically predicted factors of the IGF family (IGF-1, IGF-1R, IGF-2R, IGFBP-3, IGFBP-7) as one sample, while four relevant features of sarcopenia (low hand grip strength, appendicular lean mass, whole body fat-free mass, and walking pace) as another sample, in conducting a two-sample MR analysis.ResultsThe forward MR results of the relationship between IGF and sarcopenia showed that elevated levels of IGF-1 reduced the risk of low hand grip strength (OR = 0.936, 95% CI=0.892-0.983, P = 0.008) and increased appendicular lean mass of the extremities and whole body fat-free mass (OR = 1.125, 95% CI=1.070-1.182,P = 0.000; OR =1.076, 95% CI=1.047-1.106, P=0.000), reduced the risk of sarcopenia. Elevated IGF-1R also favored an increase in whole body fat-free mass (OR=1.023, 95% CI=1.008-1.038, P =0.002), and the appendicular lean mass trait was more pronounced with elevated IGFBP-3 and IGFBP-7 (OR=1.034, 95% CI=1.024-1.044, P =0.000; OR=1.020, 95% CI=1.010-1.030, P=0.000). Inverse MR results of the effect of sarcopenia on IGF showed that decreased hand grip strength may elevate IGF-1 levels (OR=1.243, 95% CI=1.026-1.505,P =0.027), whereas improvements in appendicular lean mass, whole body fat-free mass traits, and increased walking pace decreased IGF-1 levels (OR=0.902, 95% CI: 0.877-0.927, P = 0.000; OR=0.903, 95% CI=0.859-0.949,P = 0.000; OR=0.209, 95% CI=0.051-0.862,P = 0.045). Also decreased hand grip strength may elevate IGF-1R levels (OR=1.454, 95% CI=1.108-1.909, P =0.007), and appendicular lean mass stimulated high expression of IGFBP-1 (OR=1.314, 95% CI=1.003-1.722, P =0.047). Heterogeneity and pleiotropy were not detected in all results, and the results were stable and reliable.ConclusionThere is a bi-directional causal association between IGF family members and the risk of sarcopenia, which provides a more adequate basis for early biological monitoring of sarcopenia and may provide new targets for early intervention and treatment of sarcopenia.

Endometrial Dysbiosis: A Possible Association with Estrobolome Alteration

Background/Objectives: Microbiota modification at the endometrial level can favor gynecological diseases and impair women’s fertility. The overgrowth of pathogen microorganisms is related to the contemporary alteration of estrogen-metabolizing bacteria, including β-glucuronidase, thereby enhancing estrogen-related inflammatory states and decreasing anti-inflammatory cells. The possible connection between estrobolome impairment and gynecological diseases has been suggested in animal models. Nevertheless, in humans, coherent evidence on the estrobolome alteration and functionality of the female reproductive tract is still lacking. The objective of this study was to explore alterations in estrogen-related signaling and the putative link with endometrial dysbiosis. Methods: Women with infertility and repeated implantation failure (RIF, N = 40) were enrolled in order to explore the putative link between estrogen metabolism and endometrial dysbiosis. Endometrial biopsies were used to measure inflammatory and growth factor molecules. β-glucuronidase enzyme activity and estrogen receptor (ER) expression were also assessed. Results: Herein, increased levels of inflammatory molecules (i.e., IL-1β and HIF-1α) and decreased levels of the growth factor IGF-1 were found in the endometrial biopsies of patients presenting dysbiosis compared to eubiotic ones. β-glucuronidase activity and the expression of ERβ were significantly enhanced in patients in the dysbiosis group. Interestingly, Lactobacilli abundance was inversely related to β-glucuronidase activity and to ERβ expression, thus suggesting that an alteration of the estrogen-activating enzyme may affect the expression of ERs as well. Conclusions. Overall, these preliminary data suggested a link between endometrial dysbiosis and estrobolome impairment as possible synergistic contributing factors to women infertility and RIF.

Effect of Bypass Fat on Genital Status and Blood Biochemical Profiles in Pubertal Swamp Buffalo Heifers and Puerperal Swamp Buffalo Cows

Background: The interaction between nutrition and reproduction has long been known to have important implications for the reproductive performance in animal.The present study highlights the effect of by-pass fat supplementation on genital changes and blood biochemical profile in pubertal swamp buffalo heifers and puerperal swamp buffalo cows. Methods: 24 heifers of 2-2.5 years of age and 24 puerperal cows on the day of parturition, irrespective of parity were used as experimental animal. The analytical method was based on the treatment protocols of 3 groups in both heifers and cows (n=8 in each group) viz., treated with oral bypass fat alone (I), oral bypass fat, mineral mixtures and injectable phosphorus (II) and control (III) respectively. Genital status, metabolic hormone (leptin, Ghrelin and IGF-1), reproductive hormone (estrogen and progesterone) and mineral constituents (calcium, phosphorus, zinc and copper) were analyzed on day 0, day 15 and day 30 in heifers and day 15, day 30 and day 45 in cows respectively. Result: Feeding of bypass fat alone or bypass fat fortified with minerals and injectable phosphorus was not found to induce significant genital changes in heifers and cows. The serum leptin and IGF-1 levels were increased significantly (p less than 0.05) in heifers at day 30 in Group I and II. However, a significant rise (p less than 0.05) of leptin was recorded at day 45 in group I and II cows. IG1-1 level was recorded increased significantly only in cows treated with fortified bypass fat (Group II). With the progression of treatment the serum phosphorus level was increased significantly (p less than 0.05) in Group I and II cows. Serum estrogen levels were increased in both heifers and cows with progression of treatment in both Group I and II. However, serum progesterone levels were increased significantly only in heifers of Group I and II with progression of treatment.

Effect of Time-Restricted Eating on Circulating Levels of IGF1 and Its Binding Proteins in Obesity: An Exploratory Analysis of a Randomized Controlled Trial

Obesity is associated with alterations in circulating IGF1, IGF1-binding proteins (IGFBPs), insulin, inflammatory markers, and hormones implicated in cardiovascular disease, diabetes, cancer, and aging. However, the effects of 4 and 6 h time-restricted eating (TRE) on circulating IGF1 and IGFBPs is uncertain. Objective: This study aimed to investigate the effects of TRE on plasma IGF1, IGFBP1, IGFBP2, and IGFBP3, and whether these effects were mediated by weight loss or body composition changes. Insulin sensitivity, glucose control, adipokines, and inflammatory markers were also examined. Design: An exploratory analysis of an 8-week randomized controlled trial implementing a daily TRE intervention was carried out. Participants/Setting: This study was conducted at the University of Illinois at Chicago in 2019. Participants with obesity were randomized to 4 or 6 h TRE (n = 35) or a control (n = 14) group. Plasma biomarkers were measured by ELISA at baseline and week 8. In a sub-analysis, participants were stratified into higher- (>3.5%) and lower- (≤3.5%) weight-loss groups. Intervention: Participants fasted daily from 7 p.m. to 3 p.m. in the 4 h TRE group (20 h) and from 7 p.m. to 1 p.m. in the 6 h TRE group (18 h), followed by ad libitum eating for the remainder of the day. Controls received no dietary recommendations. Main outcome measures: IGF1, IGFBPs, hsCRP, and adipokines were the main outcome measures of this analysis. Statistical Analysis: Repeated measures ANOVA and mediation analysis were conducted. Results: Body weight significantly decreased with TRE (−3.6 ± 0.3%), contrasting with controls (+0.2 ± 0.5%, p < 0.001). Significant effects of TRE over time were observed on plasma IGFBP2, insulin, HOMA-IR, and 8-isoprostane levels, without affecting other biomarkers. In the sub-analysis, IGFBP2 increased while leptin and 8-isoprostane decreased significantly only in the “higher weight loss” subgroup. Changes in insulin and HOMA-IR were related to TRE adherence. Conclusions: Eight-week daily 4 to 6 h TRE did not affect IGF1, IGFBP1, or IGFBP3 levels but improved insulin, HOMA-IR, and 8-isoprostane. IGFBP2 increased and leptin decreased when weight loss exceeded 3.5% of baseline.

Improvement of Bone Metabolism in Prepubertal Girls with Turner Syndrome Following Long-term Pegylated Growth Hormone Treatment.

The study aims to assess the improvement in bone metabolism in prepubertal girls with Turner Syndrome (TS) after long-term polyethylene glycol recombinant human Growth Hormone (PEG-rhGH) treatment. A 12-month longitudinal prospective study was conducted with 28 prepubertal girls diagnosed with TS. Participants were divided into two groups: 18 received PEG-rhGH therapy (0.1-0.25 mg/kg/week) and 10 did not. Anthropometric measurements, bone turnover markers (BTMs), and serum levels of IGF-1, calcium, and phosphate were collected at baseline and after 12 months. BTMs included bone alkaline phosphatase (BAP), Type I collagen propeptide (CICP), Type I collagen telopeptide (CTX), and fibroblast growth factor 23 (FGF23). After 12 months of PEG-rhGH therapy, the treatment group showed significant increases in growth velocity (GV) and height standard deviation scores (HtSDS). Serum IGF-1 levels increased rapidly within one month and remained elevated. BTMs indicated enhanced bone formation, significantly increasing BAP and CICP, while CTX levels remained low. FGF23 levels initially rose slightly but declined below baseline by 12 months. Elevated blood phosphate levels were observed. PEG-rhGH therapy in children with TS significantly improves linear growth and enhances bone formation markers, benefiting bone metabolism.

Predictive value of IGF-1/IGFBP-3 ratio for thyroid nodules in type 2 diabetic mellitus.

To explore the predictive value of the IGF-1/IGFBP-3 ratio for the presence of thyroid nodules in patients with type 2 diabetes mellitus (T2DM). This observational study prospectively enrolled patients with T2DM at the Second Hospital of Jilin University between May 2021 and January 2022. Thyroid nodule (TN) status was determined by ultrasonography. Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive value of the serum IGF-1/IGFBP-3 molar ratio for TNs. Multivariable logistic regression analysis was conducted to identify risk factors for thyroid nodules in patients with T2DM. A total of 122 patients (mean age ± standard deviation: 52.57 ± 11.71 years; 74 males) were enrolled. 37.7% (n=46) of patients did not have TNs, while 62.3% (n=76) had TNs. The duration of diabetes, age, and HDL-C level were significantly higher in the T2DM group with TNs compared to the group without TNs (all P < 0.05). The area under the ROC curve (AUC) for the combination of IGF-1, IGFBP-3, and the serum IGF-1/IGFBP-3 molar ratio in predicting TNs in T2DM patients was 0.619 (P < 0.001). Additionally, multivariable logistic regression analysis revealed that the duration of diabetes, age, fasting plasma glucose (FPG), fasting insulin (FINS), thyroid-stimulating hormone (TSH), IGF-1, and IGFBP-3 levels were independent risk factors for thyroid nodules, while the serum IGF-1/IGFBP-3 molar ratio level was an independent protective factor for thyroid nodules in patients with T2DM (all P < 0.05). The combination of IGF-1, IGFBP-3, and the serum IGF-1/IGFBP-3 molar ratio may have a better predictive value for TNs in T2DM patients than using any single marker alone. The duration of diabetes, age, FPG, FINS, TSH, IGF-1, IGFBP-3, and the serum IGF-1/IGFBP-3 molar ratio levels were independently associated with thyroid nodules in patients with T2DM.

An intensified trans-sectoral nutritional intervention in malnourished patients with chronic pancreatitis improves diseases prognosis and identifies potential biomarkers of nutritional status.

Malnutrition is a common complication in chronic pancreatitis and associated with reduced quality of life and life expectancy. Nutritional support is considered mandatory in malnourished patients with chronic pancreatitis but there is only scarce evidence on optimal treatment modalities and the efficacy of nutrition therapy. Here, we investigated the feasibility and efficacy of an intensified nutritional intervention in malnourished patients with chronic pancreatitis and aimed to identify suitable indicators for monitoring nutritional status. We performed a single-arm feasibility study, in which malnourished patients with chronic pancreatitis received an intensified trans-sectoral nutritional intervention for 6 months. Multimodal treatment comprised face-to-face dietary counseling, oral nutritional supplementation, and a complementary telephone-based nutrition and exercise coaching. Patients underwent follow-up examinations after 28, 90, and 180 days, when we assessed changes in anthropometric and body composition measures, muscle function, Chronic Pancreatitis Prognosis Score (COPPS), as well as blood parameters and intestinal microbiota composition. Eleven out of 73 patients initially screened for study participation were enrolled in the trial of which 9 subjects (age (mean ± SD): 56.2 (±14.8) years; male: 67%; alcoholic etiology: 44%) underwent the complete intervention. Patients gained a median of 5.3 kg (8.6%) body weight, including 1.6 kg skeletal muscle mass, and significantly increased gait speed (p < 0.001). Ameliorated nutritional status and muscle function were associated with increased blood levels of IGF-1 and cholinesterase as well as altered gut microbiota composition on the phyla and genera level. Moreover, significant improvements in COPPS indicated reduced disease severity after 90 and 180 days. Malnourished patients with chronic pancreatitis benefit from intensified nutritional therapy. Besides ameliorated nutritional status, a multimodal intervention can improve muscle function as well disease prognosis. Future studies are needed to prove superiority to standard-of-care and to validate potential biomarkers for prospective monitoring of nutritional status. https://clinicaltrials.gov/study/NCT04476056, NCT04476056.

6545 Weekly Somapacitan Reduces Serum C-reactive Protein Levels in Adult Patients with Growth Hormone Deficiency

Abstract Disclosure: Y. Seki: None. S. Morimoto: None. M. Ikemoto: None. N. Takano: None. K. Yamashita: None. K. Bokuda: None. D. Watanabe: None. A. Ichihara: None. Background: Adult growth hormone deficiency (GHD) is known to be associated with increased inflammation. Our previous research revealed a significant association between GHD and elevated serum C-reactive protein (CRP) levels. Limited studies have demonstrated a significant association between GH replacement therapies and CRP levels; only two reports showed a significant reduction in serum CRP levels with daily somatropin. This study aimed to investigate the effects of weekly somapacitan on serum CRP levels in adult patients with GHD. Methods: We prospectively observed serum CRP levels as the primary outcome before and 6 months after somapacitan treatment in adult patients with GHD with no history of GH supplementation therapy within the past 6 months. Secondary outcomes included anthropometric data, IGF-1 levels, and kidney and liver functions. The somapacitan dose was titrated based on IGF-1 levels during the 6-month treatment period. Results: Eight adult patients (mean age 50±17, male 4 [50%]) with GHD received weekly somapacitan treatment. Of the patients, 2 (25%) had ACTH deficiency, 2 (25%) had TSH deficiency, and 2 (25%) had gonadotropin deficiency. Two patients (25%) were on glucocorticoid replacement. The somapacitan dose at 6 months was 1.9 (1.5-2.6) mg/week. Weekly somapacitan significantly increased serum IGF-1 level (48 [29-122] to 125 [63-205] ng/mL, P = 0.001) and IGF-1 SD score (-3.3 [-5.3-0.9] to -0.7 [-3.0-0.8], P = 0.008) and significantly decreased serum CRP level (0.243 [0.056-0.464] to 0.093 [0.036-0.290] ng/mL, P = 0.008). However, it did not affect body weight (80.6±11.6 to 79.8±10.5 kg, P = 0.67) or serum creatinine (0.74±0.13 to 0.68±0.21 mg/dL, P = 0.35) and alanine aminotransferase (60 [20-99] to 48 [21-85] U/L, P = 0.23) levels. Changes in CRP levels were significantly correlated with changes in IGF-1 levels (rs = -0.83, P = 0.010) and IGF-1 SD scores (rs = -0.79, P = 0.021). Conclusion: GH supplementation therapy with weekly somapacitan reduced serum CRP levels in adult patients with GHD without affecting body composition or kidney and liver functions. Presentation: 6/3/2024

6530 A Case of Lymphocytic Hypophysitis Followed by Acromegaly

Abstract Disclosure: L. Medina Mora: None. S. Htoo: None. A. Sanchez Ruiz: None. M. Harshan: None. M. Liu: None. Introduction: Acromegaly, a disorder with an estimated incidence of 0.28-0.4 cases per 100,000 individuals, is characterized by overproduction of growth hormone. Features include acral enlargement, frontal bossing, macrognathia, headaches, and hyperhidrosis. Comorbidities include hypertension, sleep apnea, type 2 diabetes, and cardiomyopathies. Hypophysitis, with an incidence of 1 in 9 million individuals, is an even rarer condition that involves pituitary gland inflammation. It can often lead to hormonal dysfunction and compression of surrounding structures. It is extremely rare for both acromegaly and hypophysitis to occur in the same individual. In this case report, we present a patient who developed lymphocytic hypophysitis followed by acromegaly. Case Report: A 58-year-old woman with a history of hypertension and lymphocytic hypophysitis (discovered during a workup of headaches without hormone derangement) returned to the clinic two years after complaining of progressive enlargement of her hands and feet, fragmented sleep, insomnia, and coarsening of facial features. She was found to have elevated IGF-1 (886 ng/mL; reference range: 48-235 ng/mL) and growth hormone levels (86.9 ng/mL; reference range: 0.12-9.88 ng/mL). An MRI showed a 2.9 x 3.2 x 3.8 cm suprasellar/sellar mass causing pressure on the optic chiasm, hypothalamus, third ventricle and midbrain. The patient underwent transsphenoidal resection (TSR), which was incomplete because the tumor was located behind the pituitary gland, followed by a right craniotomy to remove the remaining tumor. The tumor specimen stained positive for GH and PIT 1, exhibiting elevated proliferative indices (&amp;gt;2 mitotic figures per 10HPF, Ki-67 20%) and p53 labeling (5%). After the surgery, the patient's IGF-1 and GH levels normalized. However, her postoperative course was complicated by third cranial nerve palsy, diabetes insipidus, hypothyroidism, and secondary adrenal insufficiency. Discussion: Although TSR is the first-line treatment for most patients with acromegaly, it may not always result in a complete cure, as almost 50% of patients with macroadenomas do not achieve full surgical recovery. For persistent disease, medical therapy or transcranial surgery may be required. The tumor in this case was atypically proliferative, which was likely why GH and IGF-1 levels rose rapidly, manifesting in acromegalic symptoms in our patient two years after diagnosis of lymphocytic hypophysitis. The natural history of hypophysitis typically progresses from inflammation to fibrosis and subsequently to atrophy of the pituitary cells. This atrophy may cause changes in regulatory hormones that promote tumorigenesis. Therefore, hypophysitis may stimulate adenoma formation leading to acromegaly. More research is needed to characterize the relationship between these two rare entities. Presentation: 6/2/2024

8524 Pituitary Hormone Dysregulation In Symptomatic Long COVID: A Multi-Center Observational Study

Abstract Disclosure: S.L. Sims: None. A. Labadzhyan: None. Z. Chen: None. S. Kim: None. J. Brathwaite: None. L. Cullen: None. M. Koga: None. U. Cheliadinova: None. V. Hwe: None. D. Gomez: None. C. Andriakos: None. T. Melnik: None. E. Puig-Wong: None. S. Whelan: None. S. Cheng: None. S. Joung: None. Z. Abelev: None. C. Le: None. R. Zabner: None. Y. Kawakami: None. T. Araki: Consulting Fee; Self; Chiesi. Objective: Pituitary hormone dysregulation has been reported in symptomatic long COVID, but it has not been rigorously studied. We conducted a multicenter observational cross-sectional study to assess pituitary hormone levels in long COVID patients and a longitudinal study to follow patients with abnormal results. Methods: Male and female adults with confirmed symptomatic long COVID were recruited from post COVID clinics at Mount Sinai in New York, Cedars-Sinai in Los Angeles, and the University of Minnesota, as well as nationwide physician referrals. Pituitary hormone levels were measured, and because fatigue is common in long COVID, patients completed the QoL-AGHDA survey. Those who exceeded pre-determined survey cutoffs or demonstrated any hormone abnormality were invited to the longitudinal study to repeat surveys and blood work every 3 months. A separate cohort with banked serum samples from before and 3, 6, and 9 months after subacute COVID was used as a comparator. Correlation analysis examined associations between QoL-AGHDA scores and pituitary hormone levels. Results: 246 patients were enrolled in the cross-sectional study after a median of 17.0 months (range, 1-39) since the most recent SARS-CoV2 infection prior to the onset of long COVID symptoms. 56% were enrolled in the longitudinal study due to a high questionnaire score and/or pituitary hormone abnormalities. Current mean follow-up period is 7.95 ± 3.2 months. Mildly elevated prolactin levels were most frequent, observed in 12.7% of patients (males 14.0%, females 12.2%). These patients presented post-COVID with galactorrhea, irregular menses, erectile dysfunction, and nonspecific symptoms of hyperprolactinemia. On follow-up, mild hyperprolactinemia tended to persist. Mildly low IGF1 levels (Z-score &amp;lt;-1.0) were observed in 9.0% of patients (males 6.3%, females 10.0%); on follow-up, IGF1 levels recovered in only 15% of these patients. 2.0% of the entire cohort showed transiently elevated IGF1 levels (Z-score &amp;gt;2.0). Low morning cortisol (&amp;lt;5.0 µg/dL) was observed in 3.3% of patients, but response to cosyntropin stimulation was normal. Mild secondary hypothyroidism was observed in 3.7% of all patients, and mild hypogonadism was observed in 7.8% of males. There was no correlation between QoL-AGHDA score and level of each pituitary hormone. After excluding pre-COVID hormone abnormalities in the post subacute COVID cohort, the rate of hyperprolactinemia was lower than that seen in the long COVID cohort (1% vs 12.7%). The rate of low IGF1 levels was higher in the subacute COVID cohort (22% vs 9.0), but unlike with long COVID, low IGF1 levels after subacute COVID recovered in 3-6 months. Conclusion: Abnormalities in pituitary hormone levels in symptomatic long COVID are frequent, with persistent hyperprolactinemia in &amp;gt;10%. Pituitary hormone screening may be important in patients with prolonged symptomatic long COVID. Presentation: 6/3/2024

6459 A Novel Long-Acting GH Receptor Antagonist Optimizing Therapeutic Efficacy and Duration

Abstract Disclosure: C. Ku: None. C. Kang: None. J. Oh: None. E. Wang: None. H. Song: None. K. Park: None. B. Kim: None. K. Kim: None. S. You: None. S. Park: None. E. Lee: None. Background: Forty to sixty percent of acromegalic patients undergo medical treatment, utilizing somatostatin analogues, dopamine agonists, and GH receptor (GHR) antagonists. The GHR antagonist, pegvisomant exhibits the most robust efficacy in reducing IGF-1 levels in acromegalic patients. However, pegvisomant faces several clinical limitations, such as poor compliance due to the necessity of daily injections. This study aimed to develop a novel, long-acting fusion GHR antagonist with optimized therapeutic efficacy and duration. Method: Twelve mutant proteins with alterations in the C-terminal and N-terminal regions of GHR were generated to confirm the GHR binding affinity and inhibitory potency compared with pegvisomant, which was evaluated with STAT5b luciferase reporter assay. Several carriers were engineered into selected mutant GHRs to increase the therapeutic duration. For in vivo experiments, single or repetitive injection of GHR antagonists were applied to acromegalic mouse model (somatotroph specific Aip knock out (sAIPKO) mice). Pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated in New Zealand White (NZW) rabbits. Result: Four out of the 12 GHR mutants exhibited higher affinity and stronger inhibitory potency toward human GHR when compared to pegvisomant. Specifically, three GHR mutants significantly reduced serum IGF-1 levels in sAIPKO mice following daily injections of 20 mg/kg for 7 days (52.3±6.0 to 5.9±1.3, 50.3±3.5 to 32.3±2.3, and 49.8±3.7 to 13.9±4.3 ng/mL; all p &amp;lt; 0.05). Among them, S4020N exhibited the lowest EC50 value for GHR binding affinity in in vitro analysis containing human GHR (0.594 nM) and mouse GHR (0.891 nM). Following fusion with each long-acting carrier, S4020N with the Fc carrier protein (ALT-B5) demonstrated the highest binding affinity and the strongest inhibitory potency toward human GHR, surpassing pegvisomant by 14 and 25 times, respectively. Administration of ALT-B5 (80 mg/kg) and pegvisomant (24 mg/kg) at a 3-day interval revealed the superior efficacy of ALT-B5 over pegvisomant (1879±219.4 vs. 3800±355.9 ng*hr/mL IGF-1 AUC for 5 days in ALT-B5 and pegvisomant, respectively; p &amp;lt; 0.01). In PK/PD studies, ALT-B5 was administered at doses of 3 mg/kg and 10 mg/kg in NZW rabbits, and PK/PD parameters were compared with the same molar concentration of pegvisomant. ALT-B5 exhibited the longest therapeutic duration and the highest efficacy compared to pegvisomant. Conclusion: ALT-B5 exhibited the longest duration and highest effectiveness in lowering IGF-1 levels. ALT-B5 emerges as a potential novel therapeutic option for acromegaly. Presentation: 6/1/2024

12526 Acromegaly Secondary to Sparsely Granulated Adenoma

Abstract Disclosure: D. John: None. M. Kinaan: None. J. Titus: None. K. Lamar: None. The most common pathological finding in acromegaly is a densely granulated adenoma which is composed of large round eosinophilic cells with prominent nucleoli and spherical nuclei that closely resemble a somatotroph cell. Less common finding is a sparsely granulated adenoma that is composed of sheets of poorly cohesive, pleiomorphic nuclei, chromophobic cells. We present a case of a 58-year-old gentleman presenting to our endocrine clinic for evaluation of a pituitary macroadenoma. The patient was hospitalized for nausea, vertigo, headaches, and blurring of vision. CT brain at that time showed a pituitary mass measuring 2.4 x 1.6 x 1.7 cm centered in the right cavernous sinus and inseparable from the pituitary gland. Hormonal work-up in the hospital was remarkable for high GH level. IGF-1 level was not done. Patient was advised to follow-up with neurosurgery as outpatient and no emergent surgery was planned. In the clinic, patient denied symptoms of DI, adrenal insufficiency or hypothyroidism. He has history of hypogonadotropic hypogonadism and was on testosterone therapy, but he stopped it since his hospitalization. On physical examination, he was noted to have macroglossia, deep voice, prominent jawbone, and soft tissue swelling in the hands and feet. Patient did not have any visible joint swelling. He stated he did not notice these changes personally and that he’s always been a “big guy” and always had a deep voice since he was a teenager. Repeat hormonal workup (done at 8 AM) showed: normal CMP, ACTH, cortisol, prolactin, TSH, T4, and T3. Testosterone was low with LH and FSH inappropriately within the normal reference range consistent withhypogonadotropic hypogonadism. IGF-I was elevated at 628ng/mL with a Z score of 3.9. These findings were consistent with acromegaly. He underwent surgery for tumor resection and pathology report showed that about 40% of the cells demonstrated weak immunoreactivity for GH, and rare (less than 1%) prolactin-positive cells were present within the tumor. The specimen was negative for TSH, ACTH, FH, and LH immunostains. Immunostain for CAM5.2 showed predominantly perinuclear dot-like immunoreactivity. The *MIB1 proliferation index is about 1%. The findings were consistent with a sparsely granulated gonadotrophic adenoma, which may demonstrate aggressive behavior. Postoperative MRI showed postoperative changes with residual pituitary tissue (normal gland vs. residual tumor). Postoperative cortisol &amp;gt;16. Postoperative GH dropped from 4.39 to 2.69 after 1 month. After 3 months, patient was doing well with no symptoms. However, IGF1 level (&amp;gt;400) showing that surgery was not curative. Currently he is awaiting gamma knife radiation therapy with possible medical therapy afterwards. Our case will provide an overview of the specific management considerations for these tumor and how they differ from densely-granulated tumors. Presentation: 6/3/2024

6712 Intractable Hypoglycemia: A Clue to Tumor Diagnosis

Abstract Disclosure: N. Kharkongor Chengappa: None. E.I. Krug: None. Background: Non-Islet Cell Tumor Hypoglycemia (NICTH) known as Doege-Potter syndrome, is a rare paraneoplastic syndrome of hypo-insulinemic hypoglycemia caused by excessive production of partially processed IGF-II from a solitary fibrous tumor (SFT).We present a case of a patient admitted with intractable hypoglycemia leading to the diagnosis and treatment of a large pelvic SFT. Clinical Case: A 59-year-old male with type 2 Diabetes Mellitus on metformin mono therapy, was admitted after he collapsed at work and was found to have blood glucose (BG) of 22 mg/dl. He was previously in his usual state of health except for an increase in his shoe size over the past year. Physical examination revealed coarse thick skin, large coarse bullous nose, enlarged fingers and a non-tender, firm abdomen with no obvious organomegaly. Laboratory results including CBC, CMP and thyroid function were normal. ACTH stimulation test revealed normal adrenal function. Hypoglycemic drug screen and insulin antibodies were negative. During a hypoglycemic event (BG of 45mg/dl) he had C-peptide level &amp;lt; 0.1ng/ml, beta-hydroxybutyrate levels of &amp;lt;0.05 and insulin level &amp;lt;0.4uIU/ml, indicating non-insulin mediated hypoglycemia. IGF-I and IGF-II levels were ordered. Due to a concern for paraneoplastic etiology of hypoglycemia. CT scan revealed a 20 cm solid mass, filling most of the pelvis and extending into the lower abdomen. Further investigations revealed normal PSA, CEA, CA19-9 and undetectable hCG and AFP levels. MRI confirmed a presence of 23 cm pelvic mass with few areas of central necrosis, extending into the lower abdomen. CT-guided biopsy revealed spindle cell neoplasm consistent with SFT. The patient underwent pelvic mass resection. Postoperatively, hypoglycemia resolved with BG readings of 138mg/dl to 178mg/dl. Surgical pathology results confirmed malignant SFT with positive STAT 6 and CD34 markers. IGF-II level obtained prior to surgery was markedly elevated at 2029 ng/ml (38-267 ng/mL). Conclusion: NICTH was described in 1930 by KW Doege and RP Potter. Less than 5% of patients with SFTs develop NICTH. Diagnosis requires manifestation of Whipple's triad, low insulin, pro-insulin and C-peptide levels, elevated IGF-II levels, or an IGF-I/IGF-II ratio&amp;gt;2, and the identification of the tumor. Positive immunohistochemical stain of the tumor for STAT6 confirms the diagnosis. Management involves resection of the tumor when feasible or debulking. For higher-risk tumors, radiation therapy may be considered. In inoperable cases, glucocorticoids, recombinant hGH and glucagon are recommended for palliation of hypoglycemia. Octreotide and Diazoxide are ineffective in NICTH.

6667 IGF1 Induces The Expression of CYR61 In Metastatic Prostate Cancer

Abstract Disclosure: G.L. Ortiz Hernández: None. M. Walker: None. L. Woods-Burnham: None. R.A. Kittles: None. C.A. Casiano: None. S.L. Neuhausen: None. The cysteine-rich angiogenic inducer 61 (CYR61) is a member of the cellular communication network (CCN) protein family that can be induced by growth factors. CYR61-specific functions are dependent on cellular context. In prostate cancer (PCa), CYR61 contributes to cell growth and survival through its interactions with extracellular ligands, such as integrins avb3 and a6b4, in the extracellular matrix space. CYR61 contains an insulin-like growth factor-binding protein domain suggesting that it may interact with insulin-like growth factor-I (IGF1). High serum levels of IGF1 are directly linked to PCa development and recently have been studied as a predictor of metastatic disease. Given the important roles that IGF1 and CYR61 play in PCa and their potential interaction, it is critical to investigate their molecular interplay. The correlation between PCa aggressiveness and circulating levels of CYR61 and IGF1 is poorly studied. Our goal was to assess the contribution of the interaction of CYR61-IGF1 to PCa cell proliferation. Their combined role may explain a proportion of aggressive PCa. This study was designed to characterize the role of IGF1-induced expression of CYR61 in metastatic PCa cellular models and to determine if this interaction contributes to aggressive tumor properties (e.g., proliferation, migration, tumorsphere formation). Using immunoblotting, we demonstrated that CYR61 is upregulated in the metastatic cell line PC3. Furthermore, optimized knockdown of CYR61 using siRNA significantly reduced PC3 cell proliferation, viability, and prostasphere formation. To examine the underlying mechanisms associated with IGF1 signaling, we assessed the activation of either the PI3/Akt and MAPK pathways in PC3 cells with CYR61 silencing. CYR61 siRNA-mediated knockdown decreased activation of the PI3/Akt pathway but did not affect the MAPK pathway. In addition, we found that IGF1 induces protein expression of CYR61 in a time-dependent manner, validated by both immunoblotting and confocal microscopy. PC3 cell lines are androgen receptor negative (AR-) and glucocorticoid receptor positive (GR+), which is characteristic of aggressive, advanced metastatic castration-resistant prostate cancer (mCRPC). Currently, we are conducting the same experiments in LNCaP cells, which are AR+/GR-, to determine if the CYR61-IGF1 interplay also occurs in PCa cells capable of AR signaling. In conclusion, we found that CYR61 expression is induced by IGF1 and its inhibition decreased the capacity of metastatic PCa cells to proliferate. Our results suggest that CYR61 inhibition may have the potential for treating metastatic PCa. Presentation: 6/1/2024

12562 Extraocular Muscle Enlargement With Proptosis In A Patient With Non Thyroidal Disease

Abstract Disclosure: S.S. Bantu: None. P.N. Kabir: None. A. Gondhi: None. T.B. Vaughan: None. Extraocular muscle enlargement with proptosis in a patient with Nonthyroidal disease Introduction: Majority of cases with extraocular muscle enlargement (EOME) is due to Graves’ disease, commonly in about 95% cases and another 5% make up other causes including inflammatory, neoplastic, vascular, infectious and acromegaly. We present a patient with sudden loss of vision, retroorbital pain with visual field deficits found to have EOME and subsequently a pituitary macroadenoma on imaging. Case: We present a 54-year-old male with history of hypertension, obstructive sleep apnea and morbid obesity who presented to us with complains of left sided vision loss. Patient was evaluated by ophthalmology and noted to have unilateral, left-sided, change in visual acuity. Physical exam was notable for macrognathia, skin tags, enlarged hands, excessive sweating. MRI brain revealed bilateral EOME with proptosis and a pituitary macroadenoma measuring 1.5x1.7x1.3cm, abutting the pre-chiasmatic left optic nerve. On biochemical evaluation he was noted to have elevated IGF1 of 979 confirming the diagnosis of acromegaly. ((hemoglobin A1C of 5.5%, prolactin 5.1, FT4 0.89, TSH 0.692, total testosterone 61, IGF1 level was 979)). He underwent transsphenoidal resection of the pituitary macroadenoma. Pathology showed sparsely granulated somatotroph adenoma. Discussion: Acromegaly has an incidence of 3-4 cases per million per year. The characteristics of the disease are due to chronic growth hormone hypersecretion resulting in the excessive growth of tissue due to the stimulation of insulin-like growth factor 1 (IGF-1). EOME with proptosis in acromegaly is seen rarely. Visual symptoms may manifest as visual field deficits due to compression of the optic pathway in 18-25% cases, increased intraocular pressure, increase in corneal thickness and a diffuse symmetrical enlargement of the extraocular muscles which cannot be distinguished from thyroid orbitopathy on imaging. The degree of enlargement appears to correlate with the duration of the disease rather than the levels of IGF1. EOME improves with the treatment of acromegaly. Although visual symptoms may be a rare presentation of acromegaly, if the clinical suspicion exists, one may consider obtaining an IGF-1 level to complete the evaluation of EOME if the thyroid levels are normal. Presentation: 6/3/2024

6667 IGF1 Induces the Expression of CYR61 in Metastatic Prostate Cancer

Abstract Disclosure: G.L. Ortiz Hernández: None. M. Walker: None. L. Woods-Burnham: None. R.A. Kittles: None. C.A. Casiano: None. S.L. Neuhausen: None. The cysteine-rich angiogenic inducer 61 (CYR61) is a member of the cellular communication network (CCN) protein family that can be induced by growth factors. CYR61-specific functions are dependent on cellular context. In prostate cancer (PCa), CYR61 contributes to cell growth and survival through its interactions with extracellular ligands, such as integrins avb3 and a6b4, in the extracellular matrix space. CYR61 contains an insulin-like growth factor-binding protein domain suggesting that it may interact with insulin-like growth factor-I (IGF1). High serum levels of IGF1 are directly linked to PCa development and recently have been studied as a predictor of metastatic disease. Given the important roles that IGF1 and CYR61 play in PCa and their potential interaction, it is critical to investigate their molecular interplay. The correlation between PCa aggressiveness and circulating levels of CYR61 and IGF1 is poorly studied. Our goal was to assess the contribution of the interaction of CYR61-IGF1 to PCa cell proliferation. Their combined role may explain a proportion of aggressive PCa. This study was designed to characterize the role of IGF1-induced expression of CYR61 in metastatic PCa cellular models and to determine if this interaction contributes to aggressive tumor properties (e.g., proliferation, migration, tumorsphere formation). Using immunoblotting, we demonstrated that CYR61 is upregulated in the metastatic cell line PC3. Furthermore, optimized knockdown of CYR61 using siRNA significantly reduced PC3 cell proliferation, viability, and prostasphere formation. To examine the underlying mechanisms associated with IGF1 signaling, we assessed the activation of either the PI3/Akt and MAPK pathways in PC3 cells with CYR61 silencing. CYR61 siRNA-mediated knockdown decreased activation of the PI3/Akt pathway but did not affect the MAPK pathway. In addition, we found that IGF1 induces protein expression of CYR61 in a time-dependent manner, validated by both immunoblotting and confocal microscopy. PC3 cell lines are androgen receptor negative (AR-) and glucocorticoid receptor positive (GR+), which is characteristic of aggressive, advanced metastatic castration-resistant prostate cancer (mCRPC). Currently, we are conducting the same experiments in LNCaP cells, which are AR+/GR-, to determine if the CYR61-IGF1 interplay also occurs in PCa cells capable of AR signaling. In conclusion, we found that CYR61 expression is induced by IGF1 and its inhibition decreased the capacity of metastatic PCa cells to proliferate. Our results suggest that CYR61 inhibition may have the potential for treating metastatic PCa. Presentation: 6/1/2024

7673 Genetic Analysis and Clinical Characterization of Patients with Congenital Hypopituitarism Due to Gene Defects

Abstract Disclosure: T.M. Sasson: None. I.J. Arnhold: None. B.B. Mendonca: None. L.R. Carvalho: None. Introduction: Congenital hypopituitarism is characterized by the deficiency of one or more hormones secreted by the anterior pituitary gland. The genetics of this pathology is complex, and the molecular diagnosis is established in approximately 13% of cases. Objectives: The aim of the present study is to characterize the phenotype harboring pathogenic variants causing congenital hypopituitarism. Methods: Among 393 subjects with congenital hypopituitarism followed up at a tertiary health center, 57 subjects (14,5%) were selected due to a confirmed molecular diagnosis by exome in 9 subjects or by gene panel or Sanger sequencing in 48 subjects. This was a retrospective study where data from medical records, clinical, laboratory and radiological characteristics were analyzed. Results: The most frequent variants identified by sequencing analyzes were in the following genes: PROP1 (29.8%), GH1 (22.8%), GHRHR (15.7%), followed by GLI2, OTX2, HESX1, POU1F1, TGIF1, GHRS, CDH2, SATB1, SOX3 e LZTR1. Consanguinity was reported in 50% of cases, and there was the presence of familial cases of short stature in 60%. The average age at the start of follow-up was 11.1 years (11 SD), 40% of them were male and 52.3% had physical stigmata typical of GH deficiency. Regarding hormonal deficiencies, 27 (47%) had isolated Growth Hormone Deficiency (DGHI) and the others, multiple deficiencies. MRI study of the pituitary gland showed some alteration in 66%, 54% of whom had adenohypophysis hypoplasia and 31% had an ectopic or non-visualized neurohypophysis. From 29 patients with IGF-1 levels available, 28 were below the reference range for sex and age. The serum GH peak after the stimulus test was on average 1.28 ng/mL (1.4SD), of these, only 4 cases had GH peak between 3.3 and 5.0 ng/mL and 1 patient with low IGF-1 and an ectopic neurohypophysis had GH peak of 6.0 ng/mL in a glucagon test. Regarding growth, the initial height in z-score was -4.8 and the average growth at the end of the first year of treatment was 10.7cm, with the average height after this period of Z-3.35. The average of final delta target height (final height Z-score minus the target height Z-score) of patients who underwent hormonal treatment was -0,53 (good response = delta &amp;lt;-1.5). Conclusion: In subjects with congenital hypopituitarism and an established molecular diagnosis, the most frequently affected genes were PROP1 and GH1, the great majority presented a stimulated GH peak &amp;lt; 3.3 ng/mL (only one patient had GH &amp;gt; 5), low basal serum IGF-1 and good increase in growth speed at the end of the first year of treatment with recovery of final height at the end of GH therapy. Presentation: 6/3/2024

6367 Growth gone Awry: A Rare Case of Acromegaly in a 16-Year-Old Female with Panhypopituitarism Secondary to Craniopharyngioma on Low Doses of Growth Hormone with Low IGF-1 levels

Abstract Disclosure: L.M. Ayala Castro: None. J. Ye Tay: None. A. Diaz: None. This report highlights a rare case of a 16-year-old female with panhypopituitarism due to craniopharyngioma, where GH replacement therapy triggered acromegaly features despite having low IGF-1 levels. Background: Craniopharyngiomas are the most common tumors causing acquired pituitary deficiencies in children. Various mechanisms contribute to acromegaly, and hypersensitivity to hormonal treatment in this benign tumor emerges as a plausible avenue for investigation. Case Presentation: A 16-year-old female diagnosed with craniopharyngioma at age 5 developed secondary panhypopituitarism. Baseline hormonal profiles indicated markedly reduced levels of IGF-1 and insulin growth factor–binding protein 3 (IGF-BP3). Despite the established condition, GH treatment was initiated at age 8 for potential growth and development benefits. Before commencing GH therapy, a bone age assessment revealed normal skeletal development. However, GH replacement therapy led to an unexpectedly robust response, resulting in physical changes consistent with acromegaly. Paradoxically, laboratory evaluations showed low IGF-1 levels. Imaging studies, including pituitary MRI, ruled out new abnormalities or tumors. As the patient approached peak adult height at 16, having been on adult GH therapy since age 13, a decision was made to discontinue GH replacement therapy and address acromegaly symptoms. Frequent follow-up visits were planned to assess growth velocity, monitor hormonal levels, and evaluate potential adverse effects. Discussion: This case demonstrates an unusual sensitivity to exogenous GH, resulting in an exaggerated response contrary to expected IGF-1 elevation. Atypical IGF-1 levels may suggest alterations in liver physiology, GH receptor signaling pathways (e.g., Laron Syndrome), or downstream defects in IGF-1 synthesis. Further research is crucial to elucidate the underlying mechanisms. Conclusion: Only 3 cases of acromegaly as a side effect of GH replacement therapy have been reported in the literature. We report a further case that underscores the complexity of managing hormonal imbalances, especially in unique patient populations with panhypopituitarism secondary to craniopharyngioma. The unexpected response to GH treatment emphasizes the need for individualized approaches and vigilant monitoring.