bluuebunny/crossref_metadata_2025 huggingface dataset:
8234 Composite Pheochromocytoma-Ganglioneuroma: Two Clinical Cases Presenting To St. Elizabeth’s Medical Center
Authors: El Najjar Mayssam , Naous Elie , Blake Caroline , Teresa Sweeney Ann
Published: October 2024

Disclosure: M. El Najjar: None. E. Naous: None. C. Blake: None. A.T. Sweeney: None.

Introduction: Pheochromocytomas (PCCS) are rare catecholamine producing tumors that originate from the chromaffin cells of the adrenal medulla. In 3-9% of cases, they may be accompanied by other tumors. Ganglioneuromas are the most encountered tumor type that occur with PCC and are termed composite PCC-GN. The entity is very rare with < 35 cases reported. Herein, we present 2 cases of composite PCC-GN. Case Presentation: Patient 1 (Pt1) & Patient 2 (Pt2): were 35- & 54-year-old obese females. Pt1 had controlled hypertension and symptoms of anxiety along with palpitations, diaphoresis and flushing. Pt2 had type 2 diabetes and complained of abdominal pain. Metabolic studies showed elevated total plasma fractionated metanephrines(MNs). MNs in Pt1 and Pt2 were: 76 and 61pg/ml respectively (normal <57 pg/ml) and normetaneprines levels were 161 and 116pg/ml respectively (normal <148 pg/ml). Abdominal computed tomography (CT) scans demonstrated right adrenal masses in both cases with Pt1 having a 2.3 x 2.3 x 2.6 cm mass (Figure1) with smooth margins measuring 36 Hounsfield units (HU) on non-contrast(NC) CT imaging with 0% washout on delayed imaging after IV contrast. Pt2 on NCCT had a 4.5 x 3.5 cm right adrenal mass measuring 73 HU and a subsequent abdominal MRI(Figure2) demonstrated the mass to have heterogenous signal intensity. Both patients were prepared with pre-operative a and b blockade and underwent laparoscopic robotic adrenalectomies without complications. Pathological analyses in both cases revealed composite PCC-GN. Pt2 underwent genetic testing which did not reveal any known mutations. Surveillance in both patients demonstrated no recurrence. Clinical lesson: The clinical presentation of PCC-GNs is indistinguishable from isolated PCCs. The definitive diagnosis is through histopathological analysis. Histologically the composite tumor is composed of two distinct patterns with PCC showing angular cells with granular, basophilic cytoplasm, arranged in nests, while GNs show ganglion cells in fibrous stroma. Immunohistochemistry show the PCCs staining for chromogranin A and synaptophysin while GNs stain for S-100 protein and neurofilament antibody. Most cases occur in patients between 40 - 60 years old. Most PCC-GNs are functional, with increased MNs. PCC-GN composite tumors may occur sporadically but have also been described as part of syndromes such as MEN2A and NF1. The definitive treatment for PCC-GN is complete surgical excision which is associated with an excellent prognosis. The probability of recurrence is low though distant metastases have rarely been reported. Therefore, lifetime surveillance is critical.

Presentation: 6/3/2024
7447 Rare KSR2 Variants: The Effect of Glycine and N-acetylcysteine (GlyNAC) Supplementation
Authors: Youn Ji Youn , Carcamo-Bahena Yareli , Lartigue Elecia , Sisley Stephanie
Published: October 2024

Disclosure: J. Youn: None. Y. Carcamo-Bahena: None. E. Lartigue: None. S. Sisley: None.

Kinase suppressor of ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Of note, disruption of the kinase domain of KSR2 in humans and mice causes obesity by reducing metabolic rate, suggesting its important role in energy homeostasis. In the present study, we identified two variants (P189L, T290A) with mutations located in the proximal CA2 region from children with severe, early-onset obesity. Since variants in this region have not been confirmed to cause obesity, we generated plasmid constructs containing these KSR2 mutations by site directed mutagenesis. The HEK293 cells transfected with KSR2 plasmid construct containing P189L or T290A had reduced binding affinity with AMPK and phosphorylation of AMPK without affecting KSR2 protein integrity. These variants also significantly reduced cellular metabolic rates measured by Seahorse analysis in C2C12 cells, suggesting that KSR2 variants in the proximal CA2 region can result in impaired KSR2 function, subsequently leading to a decrease in cellular metabolic rate. In addition, these KSR2 variants decreased protein levels of NRF-2, a transcription factor of cytoprotective genes regulating the antioxidant glutathione (GSH) pathway compared to wild type KSR2 which augmented NRF2 levels. We also observed lower levels of total GSH and GSH/Glutathione disulfide (GSSG) ratio and higher levels of thiobarbituric acid reactive substances (TBARS), an indicator of oxidative stress, indicating an imbalance of antioxidant and oxidant with proximal KSR2 variants. However, treatment of cells with Glycine and N-acetylcysteine (GlyNAC) reversed the detrimental effects of KSR2 variants by normalizing protein expression levels of NRF-2, GSH/GSSG ratios and TBARS levels. Taken together, we show strong evidence that two new KSR2 variants, P189L and T290A, cause disruption of KSR2 function. Additionally, we also report a novel role of KSR2 in maintaining redox homeostasis suggesting that increased oxidative stress following GSH deficiency may play an important role in the development of obesity from KSR2 variants.

Presentation: 6/1/2024
6866 Real-world implications and limitations of GLP-1 prescriptions in adolescents
Authors: Castano Gabriel , Sisley Stephanie
Published: October 2024

Disclosure: G. Castano: None. S. Sisley: None.

Background: Glucagon-like-peptide-1 agonists (GLP1), approved for adolescents ≥ 10 years in 2019 for type 2 diabetes (T2D) and ≥ 12 years in 2020 for obesity, require adequate dose titration and have known side effects. There is little information on insurance approval, adherence to titration regimens, or the side effects of liraglutide in clinical practice. Methodology: We performed a retrospective review of all patients <18 years old who were prescribed GLP-1 at a large children’s hospital. We collected demographic information, prescription orders, insurance approval, and drug initiation dates. For individuals who completed at least 26±8 weeks of treatment, we also collected dose titration, side effects, and insulin doses. Results:599 patients were prescribed GLP-1 from 2019 to 2023, with a mean age of 14.99±2.1 years, 58% female, 58% public insurance, and 74% (n=442) with T2D. The cohort was comprised of 63% White, 30% Black, and 2.3% Asian individuals, with 52% of Hispanic ethnicity. 90% of prescriptions were for liraglutide, and 10% for other GLP1 analogs, including exenatide, dulaglutide, and semaglutide. Insurance denied 41% (n=244) of prescriptions, with more denials in those without T2D, 64% vs 32% in patients with T2D.Whereas private insurance denied more prescriptions than Medicaid in patients with T2D (54% vs 27%), the reverse was true for patients without T2D ( 55% private vs 69% Medicaid). Patients lost to follow-up in the first 3 months accounted for 22% (n=135) of the cohort, even though 48% (n=66) of those patients had insurance approval.Those who had insurance approval and took liraglutide for at least 26 weeks accounted for 34% (n=204) of the cohort. Of the patients with T2D, 50% (n=95) titrated to 1.8mg by their first follow-up appointment (1-3 months after prescription start), 33% (n=62) by 6 months, and 17% (n=32) never reached 1.8mg. In patients prescribed a higher dose of liraglutide (3.0 mg daily), 42% (n=8) titrated to 3mg over 5 weeks as prescribed, and 52% (n=10) never reached 3mg, with only one of them not reaching 1.8 mg.Most patients (82%, n=169) had no side effects documented in their charts. From those with side effects reported, GI problems (nausea, vomiting, diarrhea) were noted in 12% (n=25), and 2% (n=4) reported injection site reactions. Side effects that required medication discontinuation included hypoglycemia (n=1), mild pancreatitis (n=1), and severe pancreatitis (n=2). Conclusion: In clinical practice, despite FDA approval, insurance coverage of liraglutide is limited. Almost half of the patients require extra time to reach full doses of liraglutide, with one-third never reaching full treatment doses. Severe pancreatitis may be a previously unpublished side effect. More research is needed to understand how real-world adherence and side effects of liraglutide affect clinical outcomes.

Presentation: 6/1/2024
8488 Sex-Specific Differences in an Alstrom Syndrome Mouse Model
Authors: Carcamo-Bahena Y , Youn J , Lartigue E , Sisley S
Published: October 2024

Disclosure: Y. Carcamo-Bahena: None. J. Youn: None. E. Lartigue: None. S. Sisley: None.

Background: Alström syndrome is a monogenic autosomal recessive disorder caused by loss of the ALMS1 gene that affects 1 in 1 million. Loss of a functional ALMS1 protein leads to global disorganization of microtubules. Patients are affected by progressive vision and hearing loss and are at risk of developing obesity and type 2 diabetes. Aside from reproductive system anomalies, no clinical reports have identified sex-specific difference in patients with Alström syndrome. Methods: Male and female Alms1tvrm[1]02/tvrm[1]02 (null), Alms1tvrm[1]02/+ (heterozygous) and wildtype littermate mice were weaned onto standard chow diet. At 16 weeks of age, they were changed to a 45% high fat diet (HFD). Weekly body weights were collected and intraperitoneal glucose tolerance tests (GTTs, 1.5 g/kg D20W) were performed at three different time points (11, 16, 25 weeks of age). Results:Alms1 null mice were heavier than wildtype and heterozygous mice on standard chow diet. In males, significant changes in weight gain in null mice occurred by 10 weeks compared to wildtype and heterozygous mice (p<0.05). In females, compared to null, this change was observed by 13 weeks (p<0.05). Although female mice are typically protected from diet-induced obesity, the null females weighed the same as the null males (65.0 ± 2.0 vs 67.7 ± 2.8 g) after 9 weeks on HFD. We observed sex and diet specific differences in GTT outcomes. On chow diet, Alms1 deficiency did not affect glucose levels during a GTT in female mice. However, after 9 weeks of HFD (25 weeks of age), baseline fasting glucose levels were higher in the null females compared to wildtype (p<0.05) and heterozygotes (p<0.01). Additionally, the GTT curve was monophasic, indicating onset of diabetes whereas wildtype and heterozygotes (p<0.0001) had normal curves. Null male mice showed an impaired glucose response at 11 weeks of age on chow diet compared to wildtype and heterozygous males (p<0.001) and by 16 weeks, the GTT glucose curve for Alms1 null mice was monophasic. After 9 weeks of HFD, no differences were observed in glucose levels during a GTT. Conclusions: We observed sex-specific differences in this Alms1 null mouse model related to body weight and glucose tolerance with male null mice exhibiting earlier obesity and impaired glucose tolerance and female mice showing more pronounced effects on a HFD. Future research should investigate if these sex-specific effects alter responses to dietary or pharmaceutical interventions.

Presentation: 6/1/2024
7345 Study on the correlation between the levels of myokines and metabolic abnormality in obese children
Authors: Ouyang L , Li M , Yang F
Published: October 2024

Disclosure: L. Ouyang: None. M. Li: None. F. Yang: None.

Objective: There are limited drug options to treat childhood obesity. Studies have found that myokines play an important role in the mechanism of exercise in the treatment of obesity. However, the correlation between myokines and metabolic abnormalities in obese children is still unclear. The purpose of this study is to analyze the correlation between the levels of myokines and metabolic abnormalities in obese children to provide the basis for the future application of myokines in childhood obesity. Methods: 41 obese children who visited the pediatric clinic of our hospital from March to October 2022 were enrolled, and 11 healthy non-obese children who had a regular physical examination in the pediatric clinic during the same period were enrolled. Basic information, anthropological indicators and biochemical indicators were collected. Human myokine magnetic bead panel was used to detect serum myokine levels including irisin, FGF21, BDNF, LIF, MSTN, IL 6, and IL 15. Difference analysis, rank sum test and Spearman analysis were used to conduct the correlation between the levels of myokines and metabolic abnormalities in obese children. Results: We found that the BMI-SDS and body fat rate of obese children with abnormal metabolism was higher than those with normal metabolism status(p<0.05). Children with abnormal glucose metabolism had an increased risk of abnormal lipid metabolism and hyperuricemia(p < 0.05), and children with abnormal lipid metabolism had an increased risk of hyperuricemia and hypertension(p<0.05). The obese children with abnormal glucose and lipid metabolism had an increased risk of abnormal purine metabolism. The levels of leukemia inhibitory factor and brain-derived neurotrophic factor in obese children were significantly higher than those in non-obese children (p<0.05), and the level of fibroblast growth factor 21 in obese children with abnormal metabolism was significantly higher than that in children with normal metabolism (p<0.05), respectively. There was a significant positive correlation between BMI-SDS and the levels of irisin, leukemia inhibitory factor and brain-derived neurotrophic factor (r=0.361, 0.368, 0.343, p=0.009, 0.007, 0.013, respectively). There was a significant positive correlation between irisin, BDNF, LIF, MSTN and IL 6, and between FGF21 and irisin, MSTN, IL 6 in children (p < 0.05). Conclusions: With the increase in BMI, the risk of metabolic abnormalities in obese children increases. Obese children with one kind of metabolic abnormality are prone to merge with other metabolic abnormalities. The levels of leukemia inhibitory factor, fibroblast growth factor 21, irisin, brain-derived neurotrophic factor, and other myokine in obese children and obese children with abnormal metabolism are different from those in non-obese children and obese children with normal metabolism respectively, and there is interaction between myokines.

Presentation: 6/1/2024
7237 Targeting IGF-I to Growth Plate Cartilage Augments Therapeutic Effects on Skeletal Growth and Reduces Hypoglycemic Effects in Mice
Authors: Tailor Krishma , Stowe Tim , van Ree Janine , Ventura Brit , van Deursen Jan , O’Brien Robert , Baron Jeffrey , Lui Julian
Published: October 2024

Disclosure: K. Tailor: None. T. Stowe: None. J. Ree: None. B. Ventura: None. J. Deursen: None. R. O'Brien: None. J. Baron: None. J. Lui: None.

Recombinant human growth hormone (GH) is commonly used to treat short stature in children but has limited efficacy in severe, non-GH-deficient conditions, such as skeletal dysplasias, and has adverse off-target effects. Because short stature is the result of reduced growth plate chondrogenesis, we hypothesized that targeting chondrogenic growth factors specifically to the growth plate might augment the therapeutic skeletal effect while diminishing adverse effects on non-target tissues. Toward this end, we previously developed fusion proteins conjugating insulin-like growth factor-1 (IGF-1) with a single-chain human monoclonal antibody fragment (ScFv) targeting matrillin-3 (1), a protein specifically expressed in cartilage matrix, and demonstrated increased on-target therapeutic efficacy at the growth plate and decreased off-target effects in a GH-deficient (lit) mouse model (2). In the current study, we established a second GH-deficiency model by administration of a GH antagonist, pegvisomant (PEG), in C57BL/6 wild-type male mice. Alternate-day injection of pegvisomant at 40 mg/kg for 7 days reduced body weight, serum IGF-1 levels, and growth plate height in mice. Using this model, we found that once-daily SQ administration of cartilage-targeted IGF-I (named CV1574-1) for five days increased body weight and growth plate height greater than an equimolar dose of IGF-I itself administered twice daily. Hypoglycemia is an adverse effect of recombinant IGF-1 treatment. Therefore, we also monitored blood glucose levels after a single SQ injection of CV1574-1 and found that this fusion protein showed a reduced hypoglycemic effect compared to injection of IGF-I itself. Lastly, to gain mechanistic insight into the role of matrillin-3 targeting on therapeutic efficacy, we assessed the ability of CV1574-1 to induce pAKT signaling in vitro. Transient exposure to CV1574-1 caused more prolonged induction of pAKT signal in wild-type rat chondrosarcoma (RCS) cells compared to matrillin-3-knockout RCS cells, suggesting that matrillin-3 targeting extends the duration of IGF-1 receptor activation. To summarize, the current findings demonstrate that CV1574-1, a fusion protein that targets IGF-1 to cartilage, improves efficacy at the growth plate, reduces hypoglycemic effects, and, in vitro, prolongs receptor activation. Our study provides further evidence that cartilage-targeted therapy has the potential to provide new pharmacological approaches for the treatment of childhood linear growth disorders, including skeletal dysplasias and growth failure due to systemic disease. Reference:(1) Cheung et al. Pharma Res 2015, 32(7):2439-49.(2) Lui et al. Molecular Therapy 2019, 27(3):673-680

Presentation: 6/3/2024
7338 Temporal Trend of Age at Menarche in Korean Adolescents: A Population-based Study
Authors: Kim Hwa Young , Kim Jaehyun
Published: October 2024

Disclosure: H.Y. Kim: None. J. Kim: None.

Background: The age at menarche has been decreasing worldwide. Previous studies in Korean adolescents also reported a downward trend of age at menarche. We investigated the current trends of age at menarche in Korean adolescents using nationally representative data. Methods: Data from the Korea National Health and Nutrition Examination Survey 2007-2021 were used in this study. A total of 50,730 females born between 1927 and 2004 with information on age at menarche were included in this study. The trend of age at menarche was analyzed according to 12 birth-year groups (with 5-year interval) using quantile regression analysis. Results: The mean age at menarche decreased over time, from 16.58±0.02 years for females born before 1950 to 12.45±0.04 years for females born between 2000 and 2004 (P <0.001). According to the percentiles group of age at menarche, the menarche age decreased by 0.073 years per year (95% confidence intervals [CIs], 0.072-0.074) in the 50th percentile group, 0.088 years per year (95% CI, 0.085-0.091) in the 97th percentile group, and 0.050 years per year (95% CI, 0.048-0.052) in the 3rd percentile group (P <0.001 for all). A decreasing trend of age at menarche was more prominent in the obese group (0.080 years per year, 95% CI, 0.078-0.082) compared to the non-obese group (0.069 years per year, 95% CI, 0.068-0.071) (P <0.001 for both). Conclusion: Ongoing downward trend in age at menarche was observed in Korean adolescents born until 2004, decreasing by 0.73 years per decade. A downward trend was faster in individuals in the higher percentile of age at menarche and in those with obesity.

Presentation: 6/1/2024
8764 A Unique Case of Infertility in a Patient with NCCAH
Authors: Paravastu Mounika , Patel Ruchita
Published: October 2024

Disclosure: M. Paravastu: None. R. Patel: None.

Background: Non-Classic Congenital Adrenal Hyperplasia (NCCAH) in women often presents with hirsutism, acne, menstrual dysfunction, or infertility. Subfertility in patients with NCCAH can be attributed to menstrual disorders including oligomenorrhea or secondary amenorrhea. We report a unique case in which a patient with NCCAH with consistently normal menstrual cycles is experiencing infertility. Case Description: A 31 y/o female with no PMH was referred to our Endocrinology Clinic for evaluation of Infertility and elevated 17-Hydroxyprogesterone levels (17OHP). Patient has been having trouble conceiving for the past 2 years, no prior successful pregnancies. She started menstrual cycles at age 17, she reports having regular menstrual cycles. Prior to our evaluation, she was seen in Reproductive Endocrinology who completed hormonal and imaging evaluation. Elevated 17OHP: 286ng/dL. Rest of hormonal workup within normal range. Normal Pelvic Ultrasound. Hormonal workup was repeated in our clinic. 17OHP is elevated at 617.01ng/dL. Rest of lab work returned normal with DHEAS:218.9mcg/dL, TSH: 2.826mcUnits/mL, Free Testosterone: 5.4pg/mL, Prolactin:11.7ng/mL, Beta HCG: negative, LH: 13.5mUnits/mL, FSH: 5.3mUnits/mL, Estradiol 79pg/mL. Cosyntropin stimulation test was completed. Baseline AM 17OHP:469.78ng/dL, Baseline Cortisol: 17.9mcg/dL. 17OHP 30 minutes-post:1216.4ng/dL, Cortisol 30 minutes-post: 18.5mcg/dL. 17OHP 60 min-post: 1051ng/dL, Cortisol 60 minutes post:16.4 mcg/dL. Given Inconclusive Cosyntropin stimulation test results, Genetic Testing was recommended. Genetic testing returned positive for NCCAH, patient’s husband is not a carrier of this gene. She was started on Hydrocortisone therapy for treatment of infertility. Shortly after she started on hydrocortisone therapy, patient did successfully conceive, however the pregnancy later resulted in a miscarriage. Conclusion: Subfertility in patients in NCCAH is thought to be due to menstrual irregularities including oligomenorrhea or secondary amenorrhea. We report the first case of a woman with diagnosis of NCCAH who is experiencing infertility despite having normal menstrual cycles.

Presentation: 6/1/2024
6681 Age and Sex Disparity in NASH and the Potential Role of Estradiol Treatment for NASH
Authors: Tripathi Madhulika , Sakthivel Suganya , Suzuki Ayako , Singh Brijesh K , Yen Paul M
Published: October 2024

Disclosure: M. Tripathi: None. S. Sakthivel: None. A. Suzuki: None. B.K. Singh: None. P.M. Yen: None.

Introduction: NAFLD (nonalcoholic fatty liver disease) and its more severe form, NASH (nonalcoholic steatohepatitis) are sexually dimorphic conditions that exhibit higher prevalence in men than women during reproductive ages but have similar prevalence after menopause. Reproductive age women are protected from hepatic fibrosis relative to men, although they lose this protection after menopause. These sex differences in NASH have been attributed, at least partly, to different circulating estrogen levels. However, the underlying mechanism(s) is not fully understood. We thus conducted animal experiments to investigate: 1) sex differences in the histologic severity of NASH, necroinflammatory and fibrogenic activities, and other relevant pathways in young and old male and female mice and 2) the effects of estradiol administration on these parameters in old male and female mice to evaluate the therapeutic potential of estradiol in NASH. Methodology: Young/reproductive age (12-weeks old) and old/post-reproductive age female and male (48∼50-weeks weeks old) C57BL/6J mice were fed control chow diet (NCD) or high-fat methionine/choline-deficient (MCD) diet for six weeks to induce NASH. The old mice were administered 200nM 17β-estradiol (physiological) in drinking water. We analyzed serum and hepatic NASH parameters, ER stress, and lysosome-autophagy defects. Results and Conclusion: Among reproductive age mice with NASH, females developed less severe histologic inflammation and fibrosis and decreased gene expression of Il1b, Il6, Tgfb, Col1a1, Ccl2, and Ccl5, and lower hepatic collagen than males. Females with NASH also had less inhibition of hepatic autophagy and lysosomal protein expression than males with NASH. Among old mice, post-reproductive age females fed NCD or MCD exhibited more severe hepatic inflammation and fibrosis and had higher gene expression of inflammatory and fibrogenic markers with comparable autophagic inhibition and lysosomal defects as similar age males. Physiological doses of estradiol significantly reduced hepatic gene expression of inflammatory and fibrogenic markers, ER stress and lysosomal-autophagic defects in post-reproductive age females. In conclusion, similar to clinical NASH, we observed marked sex and age-related differences in the severity of NASH. Furthermore, physiological doses of estradiol treatment improved the hepatic histology, lysosome-autophagy, inflammation, and fibrosis in post-reproductive age female mice with NASH and suggests that estradiol supplementation may decrease or reverse NASH progression in post-menopausal women with NASH.

Presentation: 6/2/2024
7299 An Eucaloric High-Fat Diet Suppresses Urinary Estrogen and Progesterone Metabolites, Mimicking Reprometabolic Syndrome in Normal Weight Women
Authors: Kuhn Katherine , Bradford Andrew P , Duffy Katelyn , Britton Olivia , Santoro Nanette F
Published: October 2024

Disclosure: K. Kuhn: None. A.P. Bradford: Consulting Fee; Self; Amazon. N.F. Santoro: Advisory Board Member; Self; Menogenix, Astellas, Que Oncology, Amazon. Consulting Fee; Self; Ansh.

Introduction: Reprometabolic syndrome is associated with relative hypogonadotropic hypogonadism, reduced fecundability, and increased pregnancy loss in women with obesity. We employed a eucaloric, high-fat diet (HFD) to attempt to reproduce the decreased urinary estrogen and progesterone metabolites, characteristic of this phenotype, in healthy women of normal BMI. Materials and Methods: 18 women with normal BMI (18-24.9kg/m²), mean age 29.1±6.3, were recruited for a four-month study including a prescribed 30-day, eucaloric, high-fat, dietary intervention (48% calories from fat). Women collected daily morning urine for 4 menstrual cycles. Daily urinary estrone conjugate (E1c) and pregnanediol-3-glucuronide (Pdg) levels were measured by immunoassay before, during and after the HFD. Paired t tests were used to compare average urinary E1c and Pdg levels and area under the curve (AUC) to determine the impact of the HFD. Cycles were aligned by LH peak (day 0). Results: Participants were weight stable throughout the 4 month study period with no change in BMI (pre-diet BMI 21.46±1.95 kg/m2 and post-diet BMI 21.35±1.81 kg/m2). Average mid cycle E1c peak was significantly lower during (32.4 ng/mg creatinine) and after the HFD (26.5 ng/mg creatinine), compared to pre-diet levels (43.2 ng/mg creatinine; p< 0.001). Post-diet urinary Pdg (AUC) was also significantly lower than pre-diet (p< 0.01). Follicular (days -14 to 0) and luteal phase (days 2-14) E1c AUC was significantly decreased post HFD (p< 0.05). Follicular and luteal phase Pdg levels were also significantly decreased post HFD (p<0.001, both). No significant changes in menstrual cycle length were observed throughout the study. Conclusion: Consumption of a high-fat diet for one month was sufficient to induce a significant reduction in E1c and Pdg, characteristic of Reprometabolic Syndrome of obesity, in normal weight, eumenorrheic women. This finding provides important insights regarding the mechanisms underlying reproductive dysfunction in obesity and indicates that a dietary intervention may be an effective strategy to mitigate sub-optimal reproductive hormone levels in women with obesity-related subfertility.

Presentation: 6/1/2024
7609 Androgen Receptor Positive DCIS in a Transmasculine Individual on Testosterone Therapy
Authors: Kelly J , Cohen B
Published: October 2024

Disclosure: J. Kelly: None. B. Cohen: None.

Introduction: The rate of breast cancer in transgender men is lower than in cisgender women, perhaps due to lower estrogen levels in the setting of suppression from exogenous testosterone, lack of clear guidelines on screening after top surgery, and increase in mastectomies. However, the impact of testosterone therapy on existing breast cancer is not known. Concerns regarding use of testosterone in patients with breast cancer include the potential for conversion of testosterone to estradiol, as well as direct androgen receptor (AR) stimulation. However, for some patients, hormone therapy is lifesaving and stopping gender affirming hormone therapy (GAHT) will negatively impact patient well-being. This creates a challenging clinical scenario when transgender patients on testosterone are diagnosed with breast cancer.Case Presentation: We present a case of a 29-year-old self-identified transmasculine nonbinary individual (assigned female at birth) who underwent chest reconstruction surgery after several months on daily transdermal testosterone therapy. A 4 cm DCIS ER+/AR+ with possible micro invasion was incidentally noted on pathology. They had no family history of breast cancer. The patient underwent chest MRI which was negative for persistent disease. The treating oncologist did not recommend Tamoxifen. The patient chose to discontinue testosterone therapy due to uncertainty regarding future breast cancer risk. However, due to worsening depression and fatigue, the patient chose to resume GAHT after receiving counseling of possible risk, though likely low, of cancer recurrence. Given that they had undergone bilateral mastectomy which, unlike chest reconstruction surgery where some breast tissue is left for contouring, all breast tissue was removed and given that chest MRI was negative for disease, cancer recurrence was felt to be low. Furthermore, though AR positivity was noted, the clinical implications are unclear and it is not known whether testosterone would stimulate tumor growth or potentially have antagonistic effects on ER signaling. Additionally, any stimulatory effects of AR signaling may be balanced by androgen suppression of gonadotroph production and reduction in estrogen production; this is more clearly associated with stimulatory effects on cancer growth. And finally, the potential risks of therapy must be weighed against the benefits provided to the patient’s well-being and mental health. Ultimately, the patient resumed testosterone therapy and has been doing well.Teaching Point: This case illustrates the uncertainties regarding the management of gender affirming testosterone therapy in patients with DCIS or breast cancer. It also highlights the need for a patient centered approach to decisions regarding changes to GAHT, to appropriately weigh the risks and benefits of continuing therapy.

Presentation: 6/2/2024
7641 Antimüllerian Hormone Levels by Phenotypes in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis
Authors: Schwenck-Carvalho Patricia , Simoes Ricardo , Maffaziolli Giovana , Soares-Jr José Maria , Baracat Edmund C , Maciel Gustavo Arantes
Published: October 2024

Disclosure: P. Schwenck-Carvalho: None. R. Simoes: None. G. Maffaziolli: None. J. Soares-Jr: None. E.C. Baracat: None. G.A. Maciel: None.

Objective: This study aims to comprehensively evaluate the levels of antimüllerian hormone (AMH) across the different phenotypes (A, B, C, D) of Polycystic Ovary Syndrome (PCOS) according to Rotterdam diagnostic criteria. Methods: In this systematic review and meta-analysis, two independent reviewers following PRISMA guidelines conducted a comprehensive search of PubMed, Embase, and Web of Science databases for studies published from inception up to December 2023. Studies reporting the AMH levels by PCOS phenotypes were considered for inclusion. The quality of studies was assessed using the ROBINS-E tool. The primary outcome of interest was the mean level of AMH among the PCOS phenotypes regardless of AMH assay used (tAMH). In a secondary analysis, AMH levels were converted into AMH Beckman Coulter Gen II assay (bcAMH). Secondary outcomes included age and BMI by phenotype. Random-effects models were applied to assess mean levels and SMD (standardized mean differences) with 95% confidence intervals (CI 95%). Results: Forty-nine studies were included in this review involving a total of 15 535 subjects. The meta-analysis showed that AMH levels vary according to the PCOS phenotype, being higher into the A phenotype followed by D, C and B: PCOS A tAMH=9.87ng/mL (SMD 2.97 CI 95% 9.29-10.48) bcAMH=11.49ng/mL (SMD 3.06 CI 95% 10.47-12.61), PCOS B tAMH 5.71ng/mL (SMD 0.98, CI 95% 4.96-6.57) bcAMH=6.25ng/mL (sd 1.36 CI 95% 5.20-7.51), PCOS C tAMH 6.91ng/mL (SMD 1.42 CI 95% 6.30-7.57) bcAMH=7.98ng/mL (SMD 1.52 CI 95% 7.16-8.90), PCOS D tAMH 7.80ng/mL (sd 2.27, CI 95% 7.20-8.45) bcAMH=8.97ng/mL (SMD 2.44 CI 95% 8.04-10.00). There were no significant differences between age and BMI through phenotypes - PCOS A age=26.17 years (SMD 4.02 CI 95% 24.29-28.30), BMI=26.11kg/m² (SMD 3.82 CI 95% 25.31-26.94); PCOS B age=27.22 years (SMD 3.75 CI 95% 26.16-26.95), BMI=25.89kg/m² (SMD 3.07 CI 95% 24.86-26.95); PCOS C age=27.46 years (SMD 4.12 CI 95% 26.49-28.46), BMI=25.19kg/m² (SMD 3.44 CI 95% 24.42-25.98); PCOS D age=27.57 years (SMD 4.01 CI 95% 26.68-28.49), BMI=24.78kg/m² (SMD 3.90 CI 95% 24.06-25.53). The heterogeneity among the studies was high, indicating that factors beyond phenotypic categories may be influencing AMH in PCOS. Conclusions: Our findings emphasize the need for phenotype-specific considerations in PCOS management and suggest that AMH levels could enhance the characterization of PCOS subtypes. Additionally, the variability observed in AMH assays across different studies highlights the future need for a universal standardization of AMH measurement techniques.

Presentation: 6/3/2024
6766 Cortisol Pumps: Hospitalizations And Quality Of Life
Authors: Tiwari Apoorv , Berry Ryan , Mokbel Ali , Abotouk Ammar , Rahman Alrifai Abdul , Waleed Jumana , Alzohaili Opada
Published: October 2024

Disclosure: A. Tiwari: None. R. Berry: None. A. Mokbel: None. A. Abotouk: None. A.R. Alrifai: None. J. Waleed: None. O. Alzohaili: None.

Introduction: Oral regimens of exogenous cortisol fail to mimic physiologic levels. The discrepancy leads to complications, notably nausea, hyperglycemia, and susceptibility to infection. Finer control over cortisol delivery may be achievable with infusion pumps. While international groups have published their experiences with cortisol pumps, these studies often include less than ten patients. We share the largest, single-center cohort ever documented and the first from an American clinic. Methods: We conducted a retrospective cohort study. Through chart review, we identified all patients who received a cortisol pump at a private clinic; these pumps were originally designed to deliver insulin, but we repurposed them for patients with adrenal insufficiency. Clinic notes allowed collection of cortisol dosing pre- and post-exposure to the cortisol pump. We supplemented this information with telephone and digital surveys on the frequency of hospitalization, symptoms, and quality of life; patients provided verbal consent before participation. A Wilcoxon signed rank test and Fisher exact test evaluated significant differences between groups. Results: We identified thirty patients who received a cortisol infusion pump. Our study revealed a statistically significant decrease in hospitalization rate after exposure to a cortisol pump (n=26, mean difference = -5.94 hospitalizations per year, p=0.003), a decrease in the frequency of fatigue (n=25, p=0.0001) and a decrease in the frequency of hypotension (n=25, p=0.005). A validated, quality of life survey corroborated these findings with improvement in twenty-seven out of twenty-eight questions (n=22, p<0.05). However, we did not detect a statistically significant difference in the frequency of eighteen other symptoms nor cortisol dosing between pre- and post-exposure groups. Conclusion: Infusion pumps can better mimic physiological variations in cortisol than oral dosing regimens. We show the extent to which cortisol dosing may reduce hospitalization rate - and therefore cost - as well as improve quality of life. We hope our findings encourage the availability of infusion pumps for adrenal insufficiency, a smaller market that may not otherwise attract commercial investment for a dedicated, randomized trial.

Presentation: 6/3/2024
7243 COVID-19 Associated Primary Autoimmune Adrenal Insufficiency: A New Clinical Entity
Authors: Naredo Rojas Jessica , Udegbe Beverly , Remba-Shapiro Ilan , Stockman Sara L , Nachtigall Lisa B
Published: October 2024

Disclosure: J. Naredo Rojas: None. B. Udegbe: None. I. Remba-Shapiro: None. S.L. Stockman: None. L.B. Nachtigall: None.

Background: The adrenal glands express angiotensin converting enzyme and transmembrane serine protease 2 receptors for SARS-CoV-2 protein S, facilitating viral entry. Cortisol levels are decreased in COVID-19 infection in correlation with disease severity. A number of potential mechanisms could relate autoimmune adrenal insufficiency (AI) to COVID-19, but whether or not SARS-CoV-2 infection plays a direct role in the autoimmune pathogenesis of primary AI is unknown. Furthermore, while single cases have been reported, autoimmune-mediated primary adrenal insufficiency following COVID-19 illness has not been formally studied. Purpose: To determine the association and clinical presentation of primary autoimmune adrenal insufficiency in patients with COVID-19 disease. Methods: A retrospective chart review was performed on patients presenting to Massachusetts General Hospital (MGH) with primary AI in the setting of recent COVID-19 illness. Review of the literature was performed to identify additional cases. Clinical, biochemical and radiographic characteristics, and interval between the diagnosis of COVID-19 and primary AI diagnosis were evaluated. Criteria for inclusion were biochemical confirmation of AI, clinical signs and/or symptoms of adrenal insufficiency within 6 months of COVID-19 illness, and evidence of autoimmune etiology of AI. Results: Five novel cases of COVID-19 associated primary autoimmune-mediated adrenal insufficiency from our Center were identified. Review of the literature yielded five additional cases. This series combines our Center’s experience, and the cases reported to date, including a total of 10 patients, 6 men and 4 women. All men (6/6) and 2 women (2/4) were < 30 years old. Patients demonstrated clinical evidence of adrenal insufficiency in a median time frame of 14 days (IQR 8.5-23.3) after SARS-CoV-2 infection. Vomiting, hypotension, and hyponatremia were present in all (N=10). Other common symptoms were nausea (90%), fatigue (70%), hyperpigmentation (70%) and hyperkalemia (50%). Nine (90%) had a positive past medical and/or family history of autoimmune disease. Nine (90%) had positive 21-hydroxylase antibodies. The median serum morning cortisol level was 1.1μg/dL with an IQR of 0.7-3.0 μg/dL. The mean ACTH level was 1235.2 pg/mL with a SD of 580.1 pg/mL. The mean ACTH was 19.3 x ULN with a SD of 10.0. Adrenal imaging did not show hemorrhage or necrosis but showed atrophy in 50%. Conclusions: This series reveals that autoimmune-mediated primary adrenal insufficiency may be diagnosed in the aftermath of COVID-19 illness. Age under 30, family history and/or past medical history of autoimmune disease may be associated. Future prospective studies are needed to determine causality.

Presentation: 6/1/2024
8567 Clinical Use of the Androgen Receptor Sensitivity CAG Repeat Polymorphism to Refine and Improve the Diagnosis of Male Hypogonadism
Authors: Mumdzic Enis , Rao Preethi , Jones Thomas Hugh
Published: October 2024

Disclosure: E. Mumdzic: None. P. Rao: None. T.H. Jones: Advisory Board Member; Self; Besins Healthcare. Grant Recipient; Self; Besins Healthcare, Grunenthal, UK. Speaker; Self; Besins Healthcare.

Male hypogonadism is a syndrome comprising symptoms and biochemical evidence of testosterone (T) deficiency. The prevalence of male hypogonadism differs due to different cut-offs in total T (TT) levels used by different guideline committees. TT is a combination of three T sub-fractions: Free T (FT), albumin-bound T, and SHBG-bound T . The FT and albumin-bound T are biologically active (BioT). The biological effects of androgenisation are not only dependent on circulating testosterone but also on the sensitivity of the androgen receptor (AR). The AR sensitivity correlates negatively with the number of CAG repeats in exon 1 of the AR gene (normal range 9 - 37 repeats). The objective of the study was to compare hypogonadal symptoms with the TT:CAG, BioT:CAG, and FT:CAG ratios compared to TT, BioT and FT alone as biochemical tests for the diagnosis of hypogonadism. All blood samples were taken fasting in the morning before 1100h. Subjects were divided, regardless of testosterone level, into Group 1 (G1) (N = 25), those with symptoms of hypogonadism; and Group 2 (G2) (N = 15), those without symptoms of hypogonadism. The Aging Male Symptom (AMS) score was used for symptom assessment. The Receiver Operating Characteristic (ROC) Curve Analysis was generated where testosterone levels (TT, BioT, FT) and TT:CAG and BioT:CAG, and FT:CAG ratios were used as variables. Results: Mean age (years) in G1 and G2 were 55.8 ± 2.0 (range 33 - 74) and 65.3 ± 2.7 (range 48 - 80), respectively. Mean values in ng/dl are included in square brackets after ranges. Mean TT (nmol/L), BioT (nmol/L) and FT (pmol/L) levels in G1 were 8.54 ± 0.48 (range 4.7 - 13.5)[246.3ng/dl], 2.83 ± 0.13 (range 1.86 - 4.28)[81.62ng/dl], and 189.2 ± 9.8 (range 95 - 300)[5.45ng/dl], respectively. Mean TT, BioT and FT levels in G2 were 15.41 ± 1.69 (range 6.4 - 29.5)[444.45ng/dl], 4.24 ± 0.34 (range 2.19 - 6.55)[122.9ng/dl], and 241.7 ± 18.5 (range 133 - 387)[6.97ng/dl], respectively. Mean AR CAG in G1 and G2 were 21.2 ± 0.7 (range 14 - 27) and 22.4 ± 0.6 (range 16 - 26), respectively. The ROC Curve showed that the area under the curve (AUC) for diagnosing male hypogonadism was the greatest for FT:CAG (.317), followed by FT (.289), BioT/CAG (.208), TT/CAG (.187), BioT (.173), and TT (.164). This exploratory study found that the TT:CAG, BioT:CAG and FT:CAG ratios compared to TT, BioT and FT alone may be better biochemical tests for diagnosis of Male Hypogonadism. The higher the value of the ratios the greater the biological androgen status is. Moreover, it could potentially provide a more accurate test to diagnose men with hypogonadism.

Presentation: 6/1/2024
6661 Critical Limb Ischemia - An Unusual Presentation Of A Pheochromocytoma
Authors: Hassan Sameen
Published: October 2024

Disclosure: S. Hassan: None.

Background: Pheochromocytomas can lead to vasoconstriction and its various clinical manifestations due to excess catecholamine release. Critical limb ischemia as a clinical manifestation of pheochromocytoma has been reported sparsely. Clinical Case: A 43 year old female with a past medical history of type 2 diabetes mellitus, Turner syndrome, and hypertension presented to the emergency department with acute on chronic left leg pain. She underwent workup with a CT angiography of the abdomen with runoff for evaluation of her vessels, which revealed an occlusion of her left superficial femoral artery with chronic stenosis of the right femoral system. Multiple unsuccessful attempts were made at revascularization of her left lower extremity, including femoropopliteal bypass, with eventual left above knee amputation, multiple fasciotomies, and angiogram and stenting of multiple vessels. The patient was on a combined OCP (norethindrone-ethinyl estradiol) for hormone replacement for Turner syndrome for the past 30 years, and did not have a personal or family history of clotting disorders. She underwent a hypercoagulable workup which was negative. Echocardiogram was negative for thrombi and was otherwise unremarkable. Incidentally discovered on her initial CT angiography was a heterogeneously enhancing right adrenal mass, which was further delineated on a dedicated CT of the adrenals, which showed a 3.7 cm right adrenal mass with pre-contrast Hounsfield units measuring 46. Biochemical workup revealed a normal plasma renin activity and aldosterone, plasma metanephrine elevated to 5.20 nmol/L (range 0.00 – 0.49 nmol/L), plasma normetanephrine elevated to 4.95 nmol/L (range 0.00 – 0.89 nmol/L), 24 hour urine metanephrine elevated to 3830 ug/d (range 36-229 ug/d), and 24 hour urine normetanephrine 1733 ug/d (range 95 – 650 ug/d). She reports a diagnosis of hypertension at age 36, with no secondary workup pursued; she had suboptimal control on three separate medications, lisinopril, metoprolol, and hydrochlorothiazide. Her blood pressure and heart rate were noted to be labile during her aforementioned surgery. Alpha blockade with doxazosin was started based on her significantly elevated plasma and urine metanephrines and normetanephrines, with improvement in her blood pressure control. She was not found to have a definitive cause of her critical limb ischemia; she was noted to have atherosclerosis in the vessels of her lower extremities, and her chronic oral contraceptive use may also have played a role. However, OCPs are often reported to cause venous rather than arterial thrombi. Therefore, it can be inferred that the catecholamine excess from her presumed pheochromocytoma caused vasoconstriction which may have played a role in the development of her critical limb ischemia. Conclusion: Catecholamine excess that is resultant from a pheochromocytoma may manifest as critical limb ischemia.

Presentation: 6/1/2024
6453 Cushing Syndrome And Bilateral Adrenal Incidentalomas In A Patient With Mucopolysaccharidosis
Authors: John D , Kinaan M
Published: October 2024

Disclosure: D. John: None. M. Kinaan: None.

TITLE Cushing Syndrome & Bilateral Adrenal Incidentalomas in a patient with Mucopolysaccharidosis

Affiliation of Authors Dieula John M.D., M.B.A.,a,b Mustafa Kinaan M.D.,a,baEndocrinology, Diabetes, and Metabolism Fellowship, UCF HCA Healthcare GME, Orlando, FL. bDepartment of Internal Medicine, UCF College of Medicine, Orlando, FL. This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities.

Introduction: Mucopolysaccharidoses (MPS) is a group of hereditary and incurable storage diseases characterized by a deficiency of enzymes involved in the metabolism of glycosaminoglycans (GAGs) at the lysosomal level. MPS are usually inherited in autosomal recessive or x-linked pattern. MPS affects functioning of the cells, tissues and organs where the GAGs products typically accumulate. This can result in neurologic, developmental, and neoplastic issues. While endocrine disturbances in MPS have been reported, the literature on hypercortisolism and adrenal masses in MPS is limited. We present a case of a patient with MPS diagnosed with Cushing Syndrome (CS) as part of evaluation for adrenal incidentalomas. Case Description: A 50 year old male with a medical history of MPS, DVT, and developmental delay presented to our clinic accompanied by his mother for evaluation of adrenal incidentalomas. CT abdomen incidentally showed a left adrenal non-calcified, non-hemorrhagic mass measuring 3.9 x 3.6 cm with a pre-contrast attenuation of 45 Hounsfield units. Delayed washout was not obtained, and washout calculation couldn’t be performed. These radiologic features were suspicious for malignancy. Repeat CT with adrenal protocol showed left adrenal mass measuring 4.5 x 3.9 cm with central necrosis, unenhanced attenuation of 42 HU, and no drop-in attenuation on delayed phase indicating poor absolute and relative washout. There was also a right adrenal mass measuring up to 2.2 cm 54.5% absolute washout and 39.0% relative washout. Biochemical workup showed no pheochromocytoma, hyperaldosteronism, or adrenal hyperandrogenism. However, his dex suppression test was consistent with ACTH-independent CS. The patient was referred to an endocrine surgeon. We anticipate more information to be available based on the pathology of the excised tumor following his urgent surgery. Conclusion: MPS diseases are extremely rare and their effects on the endocrine system in general, and the adrenal gland specifically, is limited. Our case would serve as the first reported case of CS in MPS patient based on our literature search. In addition, we’ll discuss the pathology findings once the tumor is excised and highlight the connection between the adrenal mass and this lysosomal storage disease.

Presentation: 6/3/2024