bluuebunny/crossref_metadata_2025 huggingface dataset:
SAT346 Empty Sella Syndrome And Hypopituitarism In A Childhood Cancer Survivor
Authors: Akhter Wajeeha , Gilden Janice L
Published: October 2023

Disclosure: W. Akhter: None. J.L. Gilden: None.

Introduction: It has been reported that 50% of childhood cancer survivors develop an endocrinopathy and require life-long monitoring. Hypopituitarism is common in patients who have been treated with radiotherapy and is progressive and irreversible. We present the case of a young cancer survivor, referred for evaluation of secondary amenorrhea and hyperprolactinemia., who was diagnosed with empty sella syndrome and hypopituitarism. Clinical Case: A 29-year-old female with past history of right maxillary rhabdomyosarcoma at age 15, treated with chemotherapy and radiation, was referred to the endocrinology clinic for evaluation of secondary amenorrhea and hyperprolactinemia. Menarche was at age 13, and stopped when starting chemotherapy and radiation. She had not been treated with hormone replacements or dopamine agonists. Upon evaluation, she had fatigue, lethargy, generalized muscle weakness, but denied headaches, fractures, abdominal pain, galactorrhea, and vaginal dryness. Laboratory revealed hypopituitarism with low estradiol <15 (nl=30-400 pg/ml premenopausal women, <10 pg/ml postmenopausal women) with inappropriately low FSH 0.82 (nl=1.5-12.4 mIU/ml), and low LH 0.22 (nl=5-25 IU/L premenopausal female), high prolactin 41.3 (nl=non-pregnant female <25 ng/mL, pregnant female 80-400 ng/mL), negative HCG, low cortisol 3.4 (nl=5-25 mcg/dL), low ACTH 9.7 (nl= 10-60 pg/mL), normal TSH 2.446 (nl=0.27-4.20 uIU/mL) and Free T4 0.54 (nl=0.5-1.6 ng/dL), negative thyroglobulin <1 (nl=0-4 IU/mL) and thyroid peroxidase AB 0.46(n=0-9 IU/mL), normal HbA1C 5.2(nl<5.7 %). MRI pituitary with contrast done 11 yrs. earlier showed a 1.5 mm focus of relative delayed and nonenhancement between anterior and posterior pituitary gland, as well as an overall volume of the pituitary smaller than expected for age. However, recent repeat MRI of brain and sella revealed a partially empty sella without evidence of macro or microadenoma. Conclusion: Patients with childhood malignancies have a greater chance of survival, as observed in the past 30 years. It is now recognized that disorders of the hypothalamic-pituitary axis can occur at any time in patients who have undergone radiation therapy. We should be aware that empty sella syndrome, which can be caused by radiation, can also be associated with hormonal abnormalities. Studies have reported that 50 % of patients with empty sella syndrome had endocrine dysfunction, with the most common endocrine abnormality being hyperprolactinemia. Therefore, amenorrhea in our patient could be from hypopituitarism caused by radiation and empty sella, as opposed to hyperprolactinemia. When evaluating amenorrhea our focus should not be entirely on hyperprolactinemia, but a diagnosis of empty sella syndrome can be missed, thus delaying appropriate hormonal replacement therapy.

Presentation: Saturday, June 17, 2023
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

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

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<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<0.01]. DI subjects also had a higher prevalence of central hypogonadism [78% vs 34%; p<0.01], a higher prevalence of panhypopituitarism [39% vs 0%; p <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<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

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

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 <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 (>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 (>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

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 <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

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< 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

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 < 1.0 IU/L (group 1, n=34), ≥1.0 to < 2.0 IU/L (group 2, n=219), ≥2.0 to < 3.0 IU/L (group 3, n=297), ≥3.0 to < 4.0 (group 4, n=252) and ≥4.0 to < 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<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

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 < 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<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
THU233 Reduction Of Overutilization Of 1,25-Dihydroxyvitamin D
Authors: Brown Jeremy , Dewan Maya , Courter Joshua , Spooner Andrew , Treasure Jennifer , Kaplan Kyle , Crimmins Nancy Abigail
Published: October 2023

Disclosure: J. Brown: None. M. Dewan: None. J. Courter: None. A. Spooner: None. J. Treasure: None. K. Kaplan: None. N.A. Crimmins: None.

Unnecessary testing may lead to patient harm, inappropriate treatments, and/or increased cost. Per the Endocrine Society, in conjunction with Choosing Wisely, 1,25-dihydroxyvitamin D (1,25-OH D) should not be measured unless a patient has hypercalcemia or decreased kidney function. This study sought to evaluate overutilization of 1,25-OH D at Cincinnati Children's Hospital Medical Center. We queried EPIC for all 1,25 OH vitamin D tests drawn in all patients (inpatient and outpatient) between 01/01/2021 and 12/31/2021. We then cross-referenced each test with all patient ICD10 codes associated with each patient’s chart. Appropriate ordering was defined as the patient having an ICD10 code related to calcium disorders or renal disease (531 codes included, data not shown). Out of a total of 1,057 1,25-OH D tests ordered, we found that only 19.4 percent were in patients whose chart contained a code that clinically would indicate testing. Further analysis showed most of these tests were obtained by psychiatry (22.7%) and community general pediatricians (14.6%) and not by endocrinology (12.5%) or nephrology (2.2%) providers. We will use this as baseline data to design quality improvement interventions to reduce unnecessary ordering of 1,25 OH vitamin D, including an ordering pathway in Epic to provide point of care education and guidance regarding appropriate Vitamin D test selection. In summary, inappropriate ordering of 1,25 vitamin D is common, likely due to misunderstanding of the best test to determine vitamin D sufficiency.

Presentation: Thursday, June 15, 2023
THU621 Mifepristone In Exogenous Cushing's Syndrome
Authors: Priyadarshan Swetha , Blavo Delali Ohui
Published: October 2023

Disclosure: S. Priyadarshan: None. D.O. Blavo: None.

Introduction: Cushing’s syndrome is characterized by elevated cortisol levels in the body and is associated with significant morbidity and mortality. It can be broadly divided into endogenous and exogenous Cushing’s depending on etiology. Endogenous (body-produced) Cushing’s is diagnosed using Late Night Salivary Cortisol(LNSC), Dexamethasone Suppression Test(DST), or 24-hr Urinary-Free Cortisol(UFC) and after ruling out exogenous glucocorticoid administration. Hyperglycemia and weight gain are two of the many manifestations of Cushing’s that have hitherto proven to be a challenge to treat. Mifepristone is a glucocorticoid receptor antagonist that was recently FDA-approved for treating endogenous Cushing’s syndrome following the breakthrough SEISMIC trial. Literature regarding the utility of Mifepristone in exogenous Cushing’s has been limited since its approval. This case aims to fill that void. Case: A 35-year-old female with past medical history of rheumatoid arthritis was referred to endocrinology for further evaluation due to complaints of weight gain, dorso-cervical fat pad, abdominal striae, bruising of her right breast, and hirsutism requiring her to shave twice a week. She had previously been on prednisone 10mg-20mg daily for 2-3years for rheumatoid arthritis and was later weaned off due to her developing bruising, perioral abscess and dorsocervical fat pad. She was hospitalized for pneumonia later that year and discharged with dexamethasone. Her baseline weight at the time had been around 380lbs and she had a rapid weight gain over the next few weeks with a peak of 467lbs, associated with facial swelling and shortness of breath. For this, a DST was done per her primary provider among other labs and showed a cortisol level of 0.5mcg/dL(n<2mcg/dL). At the endocrine clinic, she had an extensive workup done including renin, aldosterone, plasma metanephrines, LH/FSH levels which all returned within normal limits. A1c was elevated at 6.7%(n <5.7%) and she was started on Metformin 1000mg BID. She had a repeat DST which suppressed cortisol appropriately however her midnight salivary cortisol was elevated. She was diagnosed with exogenous Cushing’s syndrome and started treatment with Mifepristone at 300mg daily. Her only side effect was mild nausea that later resolved. In 4 months, she had already lost 50lbs since her initial visit and HbA1c was down to 5.8. The dose was subsequently increased in increments up to 1200mg. In 7 months since starting Mifepristone, her weight was down to 312lbs, a total of 164lbs down from her initial weight. Her HbA1C was 4.6, down from her initial value of 6.7. Conclusion: This case is an excellent example of the effectiveness of Mifepristone in achieving glycemic control and weight reduction in Cushing’s syndrome with minimal side effects. More specifically, it serves to illustrate its utility in exogenous Cushing’s syndrome.

Presentation: Thursday, June 15, 2023
OR21-05 Low-dose Infigratinib, An Oral Selective Fibroblast Growth Factor Receptor (FGFR) Tyrosine Kinase Inhibitor, Demonstrates Activity In Murine Models Of Achondroplasia And Hypochondroplasia
Authors: Muslimova Elena , Demuynck Benoit , Loisay Léa , Paull Morgan , Legeai-Mallet Laurence
Published: October 2023

Disclosure: E. Muslimova: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. B. Demuynck: None. L. Loisay: None. M. Paull: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. L. Legeai-Mallet: None.

Background: FGFR3 is a negative regulator of bone growth and gain-of-function mutations in the FGFR3 gene result in different skeletal osteochondrodysplasias, including achondroplasia (ACH) and hypochondroplasia (HCH). ACH is the most common form of rhizomelic short stature, affecting between 1 in 15,000 and 1 in 30,000 live births worldwide. The incidence of HCH is thought to be approximately the same as ACH. Currently, there is only one approved therapy for ACH and no approved therapies for HCH. Previously we demonstrated that the oral, selective FGFR 1-3 tyrosine kinase inhibitor (TKI) infigratinib has preclinical activity in a mouse model mimicking ACH (Fgfr3Y367C/+). We hypothesized that infigratinib could improve defective endochondral ossification and ameliorate the phenotype in a mouse model of HCH (Fgfr3N534K/+), which is the first and only HCH mouse model that expresses the most frequent human heterozygous mutation p.Asn540Lys.Methods:Fgfr3N534K/+ mice were given subcutaneous injections of infigratinib or vehicle control every 3 days (1 mg/kg) or daily (1 mg/kg) for 15 days (post-natal day [PND] 4-19) or 21 days (PND 3-24), respectively. Results:Fgfr3N534K/+ mice treated with 1 mg/kg infigratinib daily for a total of 21 days showed a statistically significant increase in appendicular and axial skeleton (tibia +3.18%, femur +3.16%, humerus +3.04%, ulna +2.94%, radius +3.01%). Treatment with infigratinib modified skull shape, length of the mandible, and foramen magnum length (+3.72%). Cartilage growth plate organization, in particular the hypertrophic chondrocyte area, was modified, indicating that chondrocyte differentiation is improved. These results, although of a lower magnitude, are in line with those previously reported from the Fgfr3Y367C/+ mouse model of ACH, which showed a statistically significant improvement in upper limbs (humerus +7.3%, ulna +11.1%, radius +14.2 %), lower limbs (femur +10.4%, tibia +16.8%), and foramen magnum length (+3.76%), when infigratinib was administered at a dose of 0.5 mg/kg. Conclusions: Low-dose treatment with infigratinib in the Fgfr3N534K/+ HCH mouse model ameliorated the clinical hallmarks of human pathology and significantly lengthened the axial skeleton, the appendicular skeleton and improved foramen magnum length. Development of infigratinib in ACH is currently ongoing. These latest findings with infigratinib in this mouse model of HCH support the rationale for targeting FGFR3 with a specific TKI such as infigratinib for the treatment of children with HCH.

Presentation: Saturday, June 17, 2023
THU626 Impact Of Body Mass Index On Clinical And Endocrinological Characteristics Of Indian PCOS Population
Authors: Pandey Seema , Ojha Kamal , Jayprakasan Kanna , Khanduri Kanishk
Published: October 2023

Disclosure: S. Pandey: None. K. Ojha: None. K. Jayprakasan: None. K. Khanduri: None.

The prevalence of polycystic ovarian syndrome (PCOS), defined based on the Rotterdam criteria, in Indian women is about 10% and the clinical characteristics can be different compared to western PCOS population. The objectives of this study are to evaluate the baseline clinical characteristics of PCOS women and to compare the characteristics in different population categorised based on body mass index (BMI). Material & Methods: In this observational study done at a tertiary fertility unit in Northern India, all PCOS women, defined based on the Rotterdam criteria, attended the clinic during 2018-2022 were included (n=554). Women with known endocrine issues were excluded. The baseline characteristics - age, BMI, blood pressure (BP), hirsutism assessed by Ferriman-Galleway (FG) score, acanthosis nigricans, AMH, prolactin, TSH- were assessed. Results: While the mean (±standard deviation) age of patients the study population was found to be 27.2 ±4.1 years, the mean BMI was 25.8±4.4 Kg/m2 and Acanthosis nigricans was observed in 87 (17.51%) women. The mean B.P. was 116/76 (±9/8) mmHg and the mean FG score was 3±1. The mean AMH, TSH and prolactin were 7.26±4.39ng/mL, 3.42±5.21mIU/mL and 17.07±15.92ng/mL respectively. BMI was classified in four categories- ≤22.9 (normal, n=121), 23-24.99 (overweight, n=111), 25-29.99 (pre-obese, n=182) and ≥30.0 (obese, n=76). The mean age across the four BMI groups were 26.1±3.9, 27.5±3.9, 27.2±4.2 and 29.0±4.0 years respectively (P<.001). The BP increases as the BMI increases (114/74 (±8/8), 116/76 (±8/8), 117/76 (±9/8) & 120/77 (±11/8) Kg/m2 respectively; P= <0.05). There was no difference in FG scores across the four BMI groups (3±1, 3±1, 3±2, 3±2, respectively; P=0.8). While the AMH (7.42±4.66, 6.99±4.30, 7.49±4.43, 6.87±3.95ng/mL, respectively; P=0.644) and prolactin (17.38±19.02, 17.84±14.92, 17.55±16.22, 14.27±9.62ng/mL, respectively; P=0.42) were similar across the four BMI groups, the TSH tend to be higher in the higher BMI groups (2.77±1.70, 3.09±1.93, 3.45±4.07, 4.88±11.23mIU/mL respectively; P=0.038). The prevalence of Acanthosis nigricans (12(9.4%), 20(18%), 29 (15.9%), 26 (34.2%), respectively; P=<0.001) was also found higher in the higher BMI groups. After conducting post-hoc analysis, it was found out that obese (≥30) group has highest mean of TSH (4.88±11.23) level, Age (28.97±4.04), B.P. count (120/77 (±11/±8)) and prevalence of acanthosis nigricans (34.2%). Discussion-While the mean (±SD) age of the study population was 27±4.1 years, the mean BMI was 25±4 Kg/m2. When categorized based on BMI (n=182; 32.9%) fell into the pre-obese group. While BMI showed a positive correlation with age, B.P., TSH and Acanthosis nigricans, nevertheless, the mean AMH, prolactin and FG score were similar across the 4 BMI groups.

Presentation: Thursday, June 15, 2023
THU628 Causal Relationship Between The Menstrual Cycle Length And Basal Metabolic Rate: A Two-sample Mendelian Randomization Study
Authors: Kazemi Maryam , Parry Stephen A
Published: October 2023

Disclosure: M. Kazemi: None. S.A. Parry: None.

Long or irregular menstrual cycles, as a hallmark reproductive trait in polycystic ovary syndrome (PCOS), have been associated with aberrant energy expenditure, obesity, and cardiometabolic comorbidities. However, current observational studies addressing the contributions of energy expenditure to menstrual cyclicity have generated conflicting results and have not utilized the full extent of known single nucleotide polymorphisms associated with basal energy expenditure. Whether the relationship is causal is uncertain. We conducted a two-sample Mendelian Randomization study to interrogate the causal relationships between basal metabolic rate and length of menstrual cycles. The (MR) analyses were performed using publicly released genome-wide association studies (GWAS) statistics from 2 separate European cohorts using the UK Biobank database. The inverse-variance weighted (IVW) method was used as the primary analysis. We applied four complementary methods, including weighted median, weighted mode, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO), to detect and correct the effect of horizontal pleiotropy. The result of the IVM method revealed that genetically determined basal metabolic rate has an inverse causal effect on the length of the menstrual cycle (β, -0.13, SE, 0.03; P=2.17 E-05). The results of MR-Egger regression, weighted median, and weighted mode methods were consistent with those of the IVW method. Sensitivity analyses revealed that horizontal pleiotropy was unlikely to distort the causal estimates. Collectively, our MR analysis revealed that basal metabolic rate appears to be causally affecting the length of menstrual cycles. Our findings reflect novel insights into the role of energy metabolism on menstrual disturbances. However, the molecular mechanisms should be investigated. Future MR analysis is warranted to confirm our findings by controlling for potentially relevant confounders, including obesity and age. Nevertheless, our findings have perturbations to elucidate causal pathways explaining obesity in relevant conditions, including PCOS.

Presentation: Thursday, June 15, 2023
THU639 17α-Estradiol Signals Primarily Through Nongenomic Mechanisms: Implications For Its Beneficial Longevity Effects
Authors: Cooke Paul S , Sirohi Vijay K , Zomer Helena D , Graceli Jones B , Mesa Ana , Medrano Theresa
Published: October 2023

Disclosure: P.S. Cooke: None. V.K. Sirohi: None. H.D. Zomer: None. J.B. Graceli: None. A. Mesa: None. T. Medrano: None.

Recent work indicates that exogenous 17α-estradiol (17α-E2), a stereoisomer of 17β-E2, increases longevity 20% in male mice, despite previous literature that 17α-E2 is a weak estrogen with low affinity for nuclear (n)ESR1. This study aimed to obtain mechanistic insights into uterine 17α-E2 actions in vivo. We hypothesized that 17α-E2 signals preferentially through membrane (m)ESR1 to affect target tissues and promote longevity. To test this, we treated pre-pubertal (postnatal day 20) female CD-1 mice with 3 daily ip injections of vehicle or 10 mg/kg of 17α-E2 or 17β-E2. 17α-E2 treatment did not significantly increase uterine weight - a marker of nuclear (n)ESR1 signaling (20.3 ± 2.1 vs. vehicle 15.7 ± 2.0, p>0.05, n=4), while 17β-E2 strongly increased it to 41.4 + 1.1 mg; p<0.05). Accordingly, histological analysis revealed reduced cell proliferation in 17α-E2- vs. 17β-E2-treated uteri. Both 17α-E2 and 17β-E2 produced robust and similar epithelial p-ERK and p-AKT expression, the active phosphorylated forms of these protein kinases. Western blotting and immunofluorescence showed that 17α-E2 and 17β-E2 stimulated a strong and comparable stimulation of EZH2, a critical mediator of estrogen’s epigenetic effects linked to mESR1 signaling, as well as increases in NRF2 and CBP signaling. Progesterone pre-treatment blocks both the 17α-E2- and 17β-E2-mediated increases in p-ERK. In conclusion, despite limited actions through nESR1, 17α-E2 robustly signals through mESR1 to activate uterine protein kinase cascades and epigenetic effects. Thus, 17α-E2 acts preferentially through mESR1, which may explain its powerful longevity effects despite limited effects on classical markers of estrogen action such as uterine weight.

Presentation: Thursday, June 15, 2023
THU641 Single-cell Transcriptomic Analysis Reveal Dysregulated Immune Modulation In The Pituitaries Of Letrozole-induced Mouse Model Of PCOS
Authors: De Robles Gabriela
Published: October 2023

Disclosure: G. De Robles: None.

The most common endocrine disorder, affecting both the reproduction and metabolism of females, is polycystic ovary syndrome (PCOS). Characterizations of the heterogeneous disorder include anovulation, biochemical hyperandrogenemia, insulin resistance, and obesity, which can be recapitulated with a letrozole-induced PCOS mouse model. Immune abnormalities have also been reported in PCOS human patients, including pro-inflammatory factor secretion imbalance and endothelial cell dysfunction. The extent to which the letrozole-induced mouse model for PCOS can represent these immune dysregulations remain unclear, specifically its relevance to disrupting hormone-regulating centers, such as the pituitary gland. Using a PCOS mouse model developed via letrozole induction, we performed single-cell mRNA sequencing on the pituitaries to study impairment in hormone activity and immune regulation. We also carried out a multiplexed immunoassay on stimulated splenocytes to profile cytokines under different immune cell activations. We identified B cells, neutrophils, microglia, T memory cells, and interestingly, sub-populations of macrophages in the pituitary. Differential expression analysis revealed affected genes in the total macrophages of PCOS mice, such as the up-regulation of Pf4, Il1a, and Ccl7. Differentially expressed genes, such as Lyz2, Ctss, Apoe, and H2-Aa, were also down-regulated in the T memory cells of PCOS mice. Pituitary cell types also exhibited dysregulated expressions, including lactotropes, corticotropes, gonadotropes, and somatotropes. Differences in cytokine expression from the multiplex immunoassays also allowed the mice to be distinct from those treated with letrozole or not via principal component analysis. Altogether, the letrozole-treated mice presented disrupted immune responses and hormonal imbalances in their transcription and cytokine profiles that further strengthens their ability to model PCOS.

Presentation: Thursday, June 15, 2023
FRI373 Effect Of Neonatal R115866 Injection On Ovary Development In Mice
Authors: Akroush Mike , Urbanowski Audrey , Edwards Abigail , Kipp Jingjing
Published: October 2023

Disclosure: M. Akroush: None. A. Urbanowski: None. A. Edwards: None. J. Kipp: None.

The active metabolite of vitamin A, retinoic acid, is vital to several physiological functions and is most notably associated with vision and organ development. Its role in the male reproductive system is well understood, but studies on female reproduction are lacking. Recent studies show that Cyp26b1, a retinoic acid degrading enzyme, is expressed highly in the day 1-10 mouse ovary. This time point correlates with the establishment of the primordial follicle pool. In vitro studies show that both retinoic acid and R115866, a Cyp26b1 inhibitor that blocks retinoic acid metabolism, increase cell proliferation. Therefore, we hypothesize that retinoic acid plays a critical role in the early development of the ovary. To test this hypothesis, we injected neonatal mice with R115866 at either 0.5 or 1.0 mg/kg during the first 7 days after birth when the levels of Cyp26b1 expression are high. At day 19, week 7, and week 15, ovaries were harvested for morphological, immunohistochemical, and RT-PCR studies. Our results showed that animals injected with R115866 showed dose-dependent decreases in body weight in day 19 and week 7 mice, while week 15 mice appeared to recover. Neonatal R115866 injection increased the number of multi-nucleic oocytes at day 19 and bursa cysts at week 15. Cyp26b1 mRNA and protein levels were both increased by R115866 treatment in Day 19 ovaries, as confirmed by real-time RT PCR and immunohistochemical studies, consistent with the effect of these inhibitors in increasing RA levels which in turn induce Cyp26b1 expression. Neonatal R115866 injection also increased the expression of proliferative markers, including Ki67, Cyclin E1, and PCNA. Currently, we are completing studies on follicle classification and count. Overall, our results suggest that retinoic acid plays an important role in the development of the mouse ovary and that balanced retinoic acid levels in early development are needed for the health of ovaries.

Presentation: Friday, June 16, 2023
FRI406 Maternal Biomarkers Of Adiposity And Stress For Preterm Birth
Authors: Mayne Gabriella , DeWitt Peter E , Wen Jennifer , Christians Uwe , Dabelea Dana , Schulkin Jay , Joseph Hurt K
Published: October 2023

Disclosure: G. Mayne: None. P.E. DeWitt: None. J. Wen: None. U. Christians: None. D. Dabelea: None. J. Schulkin: None. K. Hurt: None.

Background: Adiponectin is a potent uterine tocolytic and decreases with gestational age, so it could be a maternal metabolic quiescence factor during pregnancy. Maternal stress can influence risk for preterm birth, and adiponectin may be inversely related to cortisol. Therefore, we characterized a potential mechanistic link between preterm birth, adiponectin, and cortisol. In this pilot study, we hypothesized maternal plasma adiponectin and cortisol concentrations are inversely related and that lower adiponectin and higher cortisol associate with spontaneous preterm birth. Methods: We performed a nested case-control study using biobank morning fasting plasma samples, taken twice in pregnancy for the Healthy Start pre-birth cohort. We included low-risk women with singleton pregnancies and excluded mothers with major medical illness, preeclampsia, chronic hypertension, or prior preterm birth. We matched preterm cases with term controls (1:3) by gestational age at first blood sample and least variation in time between blood samples (16 preterm, 46 term). We quantified high (HMW), low molecular weight (LMW), and total adiponectin using an ELISA assay. We also quantified cortisol and five related steroid hormones from the same specimens using HPLC/mass spectrometry. We used generalized estimating equations and additive models to compare group means and associations between adiponectin and cortisol. We used machine learning with gradient boosting for predictive modeling. Results: Contrary to our hypothesis, total, HMW, and LMW adiponectin positively associated with cortisol across gestation (P<0.001 for all), however the association was reduced in the preterm compared with term group and significantly so for LMW (P=0.044). In predictive modelling, HMW adiponectin, maternal pre-pregnancy BMI, maternal age, and cortisol were the four most highly relevant predictors for preterm birth (AUROC=0.704). Conclusion: In healthy low-risk patients, we found associations between adiponectin and cortisol differ across gestation for pregnancies ending with term or preterm delivery and have some predictive value in this cohort. This suggests a possible mechanistic link between maternal metabolism and stress for pregnancy maintenance. These biomarkers may prove useful as predictors in larger studies and might indicate possible maternal metabolic therapies for preterm birth prevention.

Presentation: Friday, June 16, 2023