bluuebunny/crossref_metadata_2025_split huggingface dataset:
SAT608 Gonadotrope-specific Deletion Of Icer Results In Increased Lh Pulsatility But Reduced Fsh Levels In Mice
Authors: Boris Natalia P , Pereira Sidney A , Stamatiades George A , Hausken Krist N , Kim Han Kyeol , Carroll Rona S , Kaiser Ursula B 
Published: October 2023

Abstract
Disclosure: N.P. Boris: None. S.A. Pereira: None. G.A. Stamatiades: None. K.N. Hausken: None. H. Kim: None. R.S. Carroll: None. U.B. Kaiser: None.
Background: The hypothalamic-pituitary-gonadal (HPG) axis is regulated by pulsatile secretion of hypothalamic GnRH, which acts on anterior pituitary gonadotropes to control synthesis and secretion of LH and FSH. High and low GnRH pulse frequencies preferentially stimulate Lhb and Fshb expression, respectively, through mechanisms that are not completely understood. The mouse Fshb gene promoter contains a half-AP-1/half-cAMP response element (CRE) motif; we have shown previously that this element is bound by CRE-binding protein (Creb) in vitro to increase expression in response to low GnRH pulse frequencies, but is antagonized by inducible cAMP early repressor (Icer) at higher GnRH pulse frequencies, resulting in a lower level of Fshb transcription. In this study, we aimed to identify the role of Icer in gonadotropin regulation in vivo in mice. We hypothesized that gonadotrope-specific deletion of Icer may influence pubertal timing and fertility due to an increase in Fshb expression. Methods and Results: Gonadotrope-specific deletion of Icer (GnrhrGRIC/+/Icerfl/fl; Icer KO) and control (Icerfl/fl) mice were generated, and pubertal and reproductive phenotypes were evaluated. There was no difference in body weight or in pubertal timing, evaluated by age of preputial separation in males and by vaginal opening and first estrus in females. In post-pubertal male mice, neither basal LH and FSH levels nor the LH or FSH response to acute GnRH stimulation were significantly different in Icer KO mice, compared to littermate Icerfl/fl controls. Male Icer KO mice 14 days post-gonadectomy (GDX) had significantly more LH pulses within a three-hour period than controls (Icer KO 5.83 ± 0.4 pulses vs Icerfl/fl 4.66 ± 0.3 pulses; p=0.049), but no differences in basal LH or LH pulse amplitude. Interestingly, serum FSH levels were significantly lower in Icer KO mice compared to Icerfl/fl controls 2 days post-GDX (Icer KO 20.0 ± 1.0 vs Icerfl/fl 26.0 ± 0.8; p=0.003) and 7 days post-GDX (Icer KO 18.0 ± 0.4 vs Icerfl/fl 22.5 ± 0.8, p=0.002). There were no significant differences in pituitary Fshb, Lhb, or Gnrhr mRNA levels between Icer KO and Icerfl/fl control mice 14 days post-GDX. Conclusions: Deletion of Icer from pituitary gonadotropes in mice did not affect body weight or timing of pubertal onset. However, in GDX male mice, LH pulse frequency was increased, whereas the post-GDX increase in serum FSH levels was blunted, in Icer KO mice compared to controls. These findings support a role for Icer in both LH and FSH regulation in vivo and highlight the importance of extending in vitro observations to in vivo models.
Presentation: Saturday, June 17, 2023
SAT614 Clinical, Laboratory And Imaging Features Associated With Central Diabetes Insipidus (Arginine Vasopressin Deficiency) In Erdheim-Chester Disease (ECD)
Authors: Vaid Sonal , Estrada-Veras Juvianee , Gahl William , Nicholas Patronas , Dave Rahul , Gochuico Bernadette , O'Brien Kevin , Hannah-Shmouni Fady , Shekhar Skand 
Published: October 2023

Abstract
Disclosure: S. Vaid: None. J. Estrada-Veras: None. W. Gahl: None. P. Nicholas: None. R. Dave: None. B. Gochuico: None. K. O'Brien: None. F. Hannah-Shmouni: None. S. Shekhar: None.
Background: Erdheim-Chester disease (ECD) is a rare, non-Langerhans, histiocytic multisystemic disorder commonly associated with somatic pathogenic variants in the BRAF or MAPK pathways. In ECD, diabetes insipidus (DI) is among the most common endocrinopathies and is often the presenting feature. We analyzed the prevalence and the genetic, biochemical, and imaging features associated with DI in subjects with ECD. Methods: A cross-sectional descriptive study of subjects with biopsy-confirmed ECD was conducted from January 2011 to December 2018 at the National Institutes of Health Clinical Center. Subjects underwent molecular genetics, baseline biochemical and pituitary endocrine function studies, and dedicated pituitary MRI. DI was diagnosed based on clinical and biochemical features. Other endocrinopathies were diagnosed based on standardized criteria. Continuous data were analyzed using t-tests or nonparametric tests between subjects with and without DI. Categorical data were analyzed via Fisher's exact tests. Results: Sixty-one subjects with ECD [23 females (37.7%) and 38 males (62.3%)] were evaluated. Twenty-three subjects (38%) had DI, with a higher percentage of males (87%) vs females (13%). DI subjects compared to those without DI were younger [mean (SD):50.1(10.4) vs 57.5 (14.5) years; p=0.01] and had a higher prevalence of BRAF V600E pathogenic variants [76.19% vs 39.47%; p&lt;0.01], lower IGF-1 [mean (SEM):136.5 (13.87) vs 161.67(10.22) ng/mL; p=0.02], and lower urine osmolality [466.6 (±260.18) vs 641.05 (±179.7) mOsm/kg; p&lt;0.01]. DI subjects also had a higher prevalence of central hypogonadism [78% vs 34%; p&lt;0.01], a higher prevalence of panhypopituitarism [39% vs 0%; p &lt;0.01] and a higher number of anterior pituitary deficits [mean (SEM):1.23 (1.15) vs 0.56 (0.67); p =0.01] than non-DI subjects. Subjects with DI had a higher frequency of absent posterior pituitary bright spots [61% vs 21%; p&lt;0.01] compared to those without DI. There were no differences in BMI, serum prolactin, vasopressin, serum osmolality, serum sodium, total cholesterol or hsCRP. The frequencies of central adrenal insufficiency, central hypothyroidism and abnormal pituitary imaging were similar between the two groups. Conclusion: DI is among the most common endocrinopathies in Erdheim-Chester disease. In DI subjects, a higher burden of anterior pituitary endocrinopathies, BRAF V600E pathogenic variants and absence of the posterior pituitary bright spot was noted, which may allow for early stratification and targeted clinical management.
Presentation: Saturday, June 17, 2023
SAT618 Uncovering The Role Of O-glcnacylation In Pituitary Adenoma Pathogenesis: Insights From Corticotroph Tumors
Authors: Massman Logan J , Gonzalez Roel , Laing Brandon , Coss Dylan , Ioachimescu Adriana Gabriela , Zwagerman Nathan , Stichelen Stephanie Olivier-Van 
Published: October 2023

Abstract
Disclosure: L.J. Massman: None. R. Gonzalez: None. B. Laing: None. D. Coss: None. A.G. Ioachimescu: None. N. Zwagerman: None. S. Olivier-Van Stichelen: None.
Functioning corticotroph pituitary adenomas are associated with high mortality, morbidity, and a high propensity of biochemical recurrence postoperatively. Silent corticotroph adenomas cause mass-effect manifestations and have an increased risk for tumor regrowth. The pathogenetic mechanisms responsible for the clinical course of corticotroph PA are poorly understood. In this study, we investigated the role of the O-GlcNAc posttranslational modification in their pathophysiology. O-GlcNAcylation is involved in protein signaling pathways and deregulated in cancers and diabetes. First, we performed RNA-sequencing in functioning and silent corticotroph and gonadotroph adenomas (n=25). We discovered that O-GlcNAc enzymes were upregulated in ACTH-secreting corticotroph tumors and correlated with larger, more invasive tumors. Also, an in vitro mechanistic analysis of corticotroph tumor cells (ATt-20) demonstrated that O-GlcNAcylation was essential for their proliferation and secretory ability. Specifically, O-GlcNAcylation affected Proopiomelanocortin mRNA splicing and stability, suggesting a new mechanism of fast hormonal response in corticotropes. Overall, our study indicates a key role for O-GlcNAcylation in corticotroph adenomas’ cellular proliferation and hypersecretion.
Presentation: Saturday, June 17, 2023
THU131 Functional Hypogonadotropic Hypogonadism And Failure To Thrive In A Poorly Controlled Type 1 Diabetes Patient
Authors: Rakhra Pavandeep , Wright Victoria , Athanassaki Ioanna 
Published: October 2023

Abstract
Disclosure: P. Rakhra: None. V. Wright: None. I. Athanassaki: None.
Background: Multiple reports exist of obese males with type 2 diabetes linked to hypogonadotropic hypogonadism. We report a rare case of poorly controlled type 1 diabetes leading to functional hypogonadotropic hypogonadism as well as failure to thrive. Clinical Case: A 16-year-old Caucasian male with type 1 diabetes, antibody positive, diagnosed at 3 years of age presented in severe diabetic ketoacidosis. Patient had been lost to follow-up and had not had a clinic visit in over three years. He had reportedly been using a family member’s Tresiba and over the counter Humulin in the interim. Upon presentation, his hemoglobin A1c was found to be 11.8%. It was last documented at greater than 14%. He was also at less than the first percentile for height and weight, with a BMI of 16 kg/m2. His mid-parental height was 68.5 inches (25 – 50th percentile). His physical exam was remarkable for Tanner III pubic hair with 12 cc testicular volume bilaterally. Biochemical analysis revealed LH was in pubertal range of 0.5 mIU/mL (0.2 – 2.3 mIU/mL), low FSH &lt;0.7 mIU/mL (0.7 – 6.2 mIU/mL), and low testosterone 7.7 ng/dL (200 – 1036 ng/dL). IGF-1 was low at 49 ng/mL (230 – 769 ng/mL) and low IGF-BP3 at 2.6 mg/L (3.1 – 8.9 mg/L). Bone age per the standards of Greulich and Pyle was delayed at 14 years with a predicted adult height of 68 inches. Associated conditions known to cause failure to thrive in patients with diabetes, such as adrenal insufficiency, hyperthyroidism, and celiac disease were ruled out. ACTH stimulation test revealed cortisol peak of 24.6 ug/dL (&gt;18.0 ug/dL). TSH was normal 2.474 mIU/mL (0.5 – 3.4 mIU/mL) and normal Free T4 0.8 ng/dL (0.8 – 2 ng/dL). Mauriac syndrome was considered however, patient lacked any Cushingoid features, did not have hepatomegaly on exam, and had normal liver function tests. A brain/pituitary MRI was performed prior to discharge and was found to be normal, ruling out concerns for a central lesion causing delayed puberty. Patient was able to gain weight during the admission with intensive insulin management. However, he remains less than the first percentile for height and weight. A growth hormone stimulation test (with clonidine and arginine) was performed outpatient. Patient was primed with estrace prior to the test and results revealed a peak of 15.0 ng/mL (&gt;10 ng/mL) ruling out concerns for growth hormone deficiency. Conclusion: We report this case to highlight that although uncommon in the developed world, delayed puberty and growth failure are known but rare complications of poorly controlled type 1 diabetes.
Presentation: Thursday, June 15, 2023
THU609 Timeline For Undetectable Mitotane Plasma Levels In Adrenocortical Carcinoma Patients After Stopping Treatment
Authors: Younes Nada , Hétu Pierre-Olivier , Lacroix André , Bourdeau Isabelle 
Published: October 2023

Abstract
Disclosure: N. Younes: None. P. Hétu: None. A. Lacroix: None. I. Bourdeau: None.
Background: Mitotane (o,p’DDD) is an adrenolytic steroidogenesis inhibitor recommended in the treatment of adrenocortical carcinoma (ACC) with a high risk of recurrence. Mitotane has a long plasma elimination half-life, because of its highly lipophilic properties. Objectives: To further explore time to reach undetectable mitotane plasma levels (UM) in treated ACC patients after stopping the medication. Methods: We retrospectively analyzed the medical files of 13 adult patients with ACC who were treated with mitotane during at least 24 months, between 2006 and 2020, in our center. We calculated the duration in months for plasma concentrations of mitotane to be undetectable, from the time of cessation of mitotane in all 13 patients. Baseline demographic characteristics of patients and baseline tumor characteristics were recorded, along with the maximal dose of mitotane used. We also explored the time it took patients to be able to stop glucocorticoid and/or mineralocorticoid replacement therapy following mitotane cessation. Results: The mean age at diagnosis of ACC was 48.2 ± 14.9 years and 69.2% of patients were female. Patients weighted 78.2 ± 27.2 Kg. The mean tumor size and proliferation index Ki67 were 8.1 ± 4.3 cm and 13.3 ± 7.3%. None of the patients had metastasis at diagnosis. They were treated with a mean of 4 ± 2 g of mitotane daily, for 33.5 ± 9 months. Only one patient never had documented therapeutic mitotane range (between 14 and 20 mg/L) during treatment. The time to UM from the time of mitotane cessation was 13.2 ± 7.1 months. All 13 patients were taking glucocorticoid replacement therapy and 5 were able to completely withdraw hydrocortisone 39 ± 14.5 months after stopping mitotane treatment. Only 2 patients out of the 6 patients that were on mineralocorticoid replacement therapy, were able to stop after 34.2 and 59.7 months, respectively. There was no significant relationship found between the duration of exposure to mitotane and the time to UM (p=0.82). On simple linear regression, patients’ weight explained 80% of variance of time to UM. There was a positive relationship between patients’ weight and time to UM (standardized coefficient beta 0.89, p &lt;0.0001). On multiple linear regression, patients’ weight was an independent predictor of time to UM. Conclusion: Mitotane can take up to 13 months to become undetectable in patients’ plasma after cessation. In our cohort, it is mainly influenced by increased weight but not by duration of exposure to the drug.
Presentation: Thursday, June 15, 2023
THU180 Evaluation Of Factors Affecting Changes In Body Mass Index In Childhood Brain Tumor Survivors
Authors: Chatila Dana , DiMeglio Linda A , Runco Daniel , Haddad Nadine G 
Published: October 2023

Abstract
Disclosure: D. Chatila: None. L.A. DiMeglio: None. D. Runco: None. N.G. Haddad: None.
Introduction Excessive weight gain in childhood brain tumor (CBT) survivors has been documented. We characterized changes in body mass index (BMI) in CBT survivors and studied possible risk factors for excessive weight gain. Objectives 1) Compare BMI z-score at CBT diagnosis to that at time of last clinical follow up, and 2) Correlate BMI and BMI z-score changes with age at diagnosis; tumor location; treatment including radiation therapy (RT), chemotherapy (CT), or both; presence of endocrinopathies. Methods Following IRB approval, we conducted a retrospective chart review of children with CBTs diagnosed between 2005 and 2017. We excluded children with craniopharyngiomas due to their known high risk of obesity. Results 311 patients (177 female) were identified (median age at diagnosis 6y [range 0-18 y], median follow-up duration 6y [range 1-15 y]. Gliomas were the most common CBT type (69%) then medulloblastomas (18%) and germinomas (6%). 77 (25%) of CBTs were suprasellar. 137 patients received RT, 167 had CT, 110 had both, 7 had only surgery. 95 (30%) of children were ultimately diagnosed with a concomitant endocrinopathy. Baseline BMI and BMI z-scores (18.6 ± 4.8; 0.45 ± 1.52) correlated with mean BMI and BMI z-scores at last follow up [22.5 ± 6.4 (r=0.15, p=0.005); 0.67 ± 1.26, (r=0.11, p=0.048)]. BMI z-scores increased significantly over time. Age at diagnosis was not correlated with change in BMI or BMI z-scores. There were no differences in BMI z-scores at last follow-up or change in BMI z-scores between patients who had suprasellar tumors vs those with other tumor locations (BMI z-scores 0.94 ± 1.53 vs 0.60 ± 1.17, p=0.06; change in BMI z-score 0.36 ± 1.95 vs 0.18 ± 1.84, p=0.47). However, patients with a suprasellar tumor location had a lower mean age at diagnosis (5.6 ± 4.2 years vs 7.2 ± 4.2 years p=0.01). There were no differences in BMI z-scores at last follow-up or change in BMI z-score by type of treatment (CT, RT, or surgery alone) nor were there differences in BMI z-scores at last follow-up or change in BMI z-score between patients who did and did not have endocrinopathies (BMI z-score 0.61 ± 1.29 vs 0.70 ± 1.25, p=0.57; change in BMI z-score 0.03 ± 1.95 vs -0.33 ± 1.817, p=0.11) although children with endocrinopathies were older at CBT diagnosis (8.1 ± 4.9 years vs 6.3 ± 4.5 years, p=0.002) and had a longer duration of follow up than patients without endocrinopathies (7.5 ± 3.4 vs 5.7± 3.0 years, p&lt; 0.001). Conclusions In CBT survivors, BMI z-scores increased over time however this change did not correlate with age at diagnosis of CBT, tumor location, type of intervention received, or presence of endocrinopathies. Future studies are needed to evaluate additional risk factors underlying increases in BMI.
Presentation: Thursday, June 15, 2023
THU193 Clinical Usefulness Of Repetitive GnRH Stimulation Test For The Diagnosis Of Central Precocious Puberty
Authors: Heo Seung , Shim Young Suk , Lee Hae Sang , Hwang Jin Soon , Lim Jung Sub 
Published: October 2023

Abstract
Disclosure: S. Heo: None. Y. Shim: None. H. Lee: None. J. Hwang: None. J. Lim: None.
Objective In girls, breast development under 8 years of age and peak serum luteinizing hormone (LH) is 5 IU/L or higher in gonadotropin releasing hormone (GnRH) stimulation tests is a standard method for diagnosing central precocious puberty (CPP). Although breast development and bone age progress rapidly compared to chronological age, repeated GnRH stimulation tests do not exceed 5 IU/L in some cases. We aimed to analyze the clinical characteristics of girls who repeatedly examined the GnRH stimulation test. Methods We retrospectively reviewed the medical records of 988 girls under 9 years of age who visited our hospital due to breast development more than Tanner stage II and whose bone age was more than a year advanced than the chronological age and examined GnRH stimulation test twice or more. According to peak luteinizing hormone (LH) at first GnRH stimulation test, patients were divided into 5 groups that &lt; 1.0 IU/L (group 1, n=34), ≥1.0 to &lt; 2.0 IU/L (group 2, n=219), ≥2.0 to &lt; 3.0 IU/L (group 3, n=297), ≥3.0 to &lt; 4.0 (group 4, n=252) and ≥4.0 to &lt; 5.0 (group 5, n=186). We analyzed the incidence of CPP through the repetitive GnRH stimulation test and factors associated with the outcomes using a Cox proportional hazard model. Results Mean age of total of 988 girls was 7.68 ± 0.67 years and the period between the first and last GnRH stimulation test was 216.40 ± 145.14 days. CPP was diagnosed in 138 patients. Incidence of CPP were differed by groups that 0%, 1.4%, 6.1%, 20.6%, 34.9% each groups. When group 1 and each groups were compared using the Cox proportional hazard regression model, difference between bone age and chronological age (95% CI, 1.27-2.35, p&lt;0.001) (BA-CA) and basal follicle-stimulating hormone (95% CI, 1.01-1.48, p=0.039) showed a statistically significant positive correlation when stratifying the peak LH at GnRH stimulation test. Conclusion In the diagnosis of CPP, the GnRH stimulation test is gold standard. But the lower the peak LH in GnRH stimulation test, the more other factors such as difference between bone age and chronological age, basal FSH should be considered in the possibility of CPP.
Presentation: Thursday, June 15, 2023
THU194 Growth Pattern And Related Predictors Of Gonadotropin-releasing Hormone Analog Treatment In Girls With Precocious Puberty
Authors: Ouyang Lixue , Yang Fan 
Published: October 2023

Abstract
Disclosure: L. Ouyang: None. F. Yang: None.
Purpose: The purpose of this study was to analyze the height growth pattern during gonadotropin-releasing hormone analog (GnRHa) treatment in girls with central precocious puberty (CPP) and early and fast puberty (EFP), calculate the incidence of prominent height deceleration and explore the relevant predictors of prominent height deceleration, which may provide useful information for the application of GnRHa as treatement and other adjunctive treatments such as growth hormone (GH). Methods: Ninety-nine girls diagnosed with CPP and 47 girls with EFP were enrolled in this retrospective analysis, they were treated with GnRHa from 6 months to 2 years. Clinical indicators such as hormone levels, bone age (BA), and B-ultrasound indicators were included and shown every 6 months. The growth velocity (GV) of height and the change of height standard deviation score (SDS) were shown every 6 months and once a year. The incidence of height deceleration was calculated in both the first and second years of GnRHa treatment. Multivariate logistic regression analysis was used to explore the predictive indicators of height deceleration. Results: There was a statistically significant difference between girls with CPP and EFP in physical growth indicators, hormone levels, BA, BA advancement, and B-ultrasound indicators at the time of diagnosis (P &lt; 0.05); however, these statistical differences gradually disappeared as treatment progressed. The treatment of GnRHa decreases the GV, BA, and levels of hormones in girls with CPP and EFP. The GV during GnRHa treatment in two groups reached a trough at 18 months, followed by a gradual rebound, but the rebound was significantly greater in CPP than in girls with EFP. The GV of girls with CPP was higher than that of girls with EFP, and the decrease in height-SDS of girls with EFP was more than girls with CPP during the entire of GnRHa treatment. The incidence of growth deceleration in CPP in the first and second year of treatment was 17.35% (17/98) and 42.86% (24/56), and EFP was 25.53% (12/47) and 76.92% (10/13), respectively. No significant indicators predicted the occurrence of growth deceleration (P&lt;0.05). Conclusions: GnRHa is effective in slowing the GV of height, the maturation of BA, and hormone levels in patients with precocious puberty, and the treatment time of 2 years or more can lead to an adult height benefit. The girls with EFP seem to suffer more damage in GV, which might affect AH, so the use of GnRHa in treating EFP should be done with more caution than in CPP. An adequate period of observation in CPP is needed before adjunctive treatments such as GH are used due to the height ascent in the later stage of treatment (18 months to 24 months). None of the factors we studied predicted the incidence of height deceleration during the period of GnRHa treatment.
Presentation: Thursday, June 15, 2023