bluuebunny/crossref_metadata_2025 huggingface dataset:
SAT654 Regulation Of The Melanocortin-4 Receptor (mc4r) By Attractin Like Protein 1 (alp1)
Authors: Buscaglia Paul , Sebag Julien
Published: October 2023

Disclosure: P. Buscaglia: None. J. Sebag: None.

The Melanocortin-4 Receptor (MC4R) plays a central role in the regulation of energy homeostasis. Mutations in MC4R are responsible for up to 6% of early onset obesity in humans and deletion of MC4R in mice results in severe obesity due to hyperphagia. MC4R is a GPCR expressed in different region of the brains including the paraventricular nucleus of the hypothalamus. Stimulation of MC4R by its agonist αMSH and inhibition by its endogenous inverse agonist AGRP result in inhibition or stimulation of food intake respectively. MC4R is known to interact with two single transmembrane proteins, the Melanocortin Receptor Accessory Protein 2 (MRAP2) and Attractin Like Protein 1 (ALP1). Whereas MRAP2 has been shown to promote MC4R signaling in vitro and in vivo, the pharmacological and physiological relevance of ALP1 for MC4R signaling and actions is not known. To determine if ALP1 alters MC4R signaling, we measured αMSH-stimulated cAMP production in cells transfected with MC4R alone or with either ALP1 or MRAP2. We found that ALP1 increases MC4R signaling to a larger extent than MRAP2. We also showed that ALP1 inhibits β-arrestin recruitment to MC4R, thus likely preventing desensitization of the receptor. To assess the physiological importance of ALP1, we generated an ALP1Flox mouse and bred it to MC4RCRE mice. Deletion of ALP1 in MC4R neurons resulted in increased body weight compared to MC4RCRE control on standard diet. This increase in body weight was further exacerbated when animals were fed a high fat diet. In conclusion our results suggest that ALP1 regulates MC4R signaling and that deletion of ALP1 from MC4R neurons causes weight gain that may be due to decreased MC4R activity.

Presentation: Saturday, June 17, 2023
FRI277 Temporal Coordination Of Female Reproductive Axis Activity By Vasoactive Intestinal Polypeptide (VIP) Expressing Cells In The Suprachiasmatic Nucleus
Authors: Phumsatitpong Chayarndorn , Bever Savannah R , Hu Stacy L , Ambrose Mary C , Kriegsfeld Lance J
Published: October 2023

Disclosure: C. Phumsatitpong: None. S.R. Bever: None. S.L. Hu: None. M.C. Ambrose: None. L.J. Kriegsfeld: None.

Circadian rhythms orchestrated by a master clock in the suprachiasmatic nucleus (SCN) are essential for ovulation in spontaneously-ovulating rodents. SCN signaling integrates with estradiol positive feedback to generate the preovulatory luteinizing hormone (LH) surge. Additionally, subordinate clocks in reproductively-relevant SCN targets temporally gate responsiveness to upstream signaling to coordinate ovulation with the active time of day. We have previously shown that the SCN communicates directly to kisspeptin (Kp) and RFamide-related peptide-3 (RFRP-3) neurons to temporally balance key stimulatory and inhibitory input to GnRH neurons required for LH surge generation. Because VIP-expressing neurons in the SCN have been implicated in the LH surge, we employed a cell-specific chemogenetic approach to determine the functional role of this cell phenotype in female reproductive axis regulation required for surge generation. We hypothesized that temporal gating by subordinate cellular clocks will prevent morning stimulation of VIP-expressing cells from increasing Kp and GnRH, and decreasing RFRP-3, cellular activity. In the afternoon, we expected inhibition of VIP-expressing cells to decrease Kp and GnRH, and increase RFRP-3, cellular activity. Specifically, female VIP-Cre mice were stereotaxically injected with either AAV-hM3Dq or hM4Di to express activating (3Dq) or inhibitory (4Di) DREADDs in VIP-expressing SCN cells. Following recovery, mice were injected clozapine n-oxide (CNO) either in the morning, prior to the LH surge (3Dq experiment), or the afternoon, around the time of the LH surge (4Di experiment). Brains were collected to examine neuronal activation in Kp, GnRH, and RFRP-3 neurons using FOS immunofluorescence as a marker. Morning stimulation of SCN VIP neurons decreased RFRP-3 neuronal activation, whereas Kp and GnRH neurons were unaffected at this time, suggesting a temporal gating mechanism at GnRH and/or Kp cells prevents premature ovulation. In contrast, afternoon inhibition of SCN VIP-expressing neurons led to an increase in neuronal activation in RFRP-3 neurons concomitant with a decrease in GnRH and Kp neurons, suggesting that VIP stimulation is required to remove RFRP-3 inhibition on the GnRH and Kp systems. We confirmed this possibility by localizing afternoon injections of CNO to RFRP-3 cells, which led to comparable decreases in GnRH and Kp cellular activity. These data indicate the importance of SCN VIP neurons in the temporally coordinated disinhibition of RFRP-3 neuronal activity required for stimulation of GnRH and Kp neurons around the time of LH surge. Supported by NIH Grant HD-050470.

Presentation: Friday, June 16, 2023
FRI358 A Rare Cause Of SIADH: Leptomeningeal Deposits Metastatic From T-cell Proliferative Disorder
Authors: Bendaram Snigdha Reddy , Zielinski Rachel , Kantorovich Vitaly
Published: October 2023

Disclosure: S. Bendaram: None. R. Zielinski: None. V. Kantorovich: None.

Introduction: Atypical causes of SIADH, though rare, are important to identify and diagnose in order to optimize timely treatment. Case: Patient is a 51-year-old male with history of obesity and pre-diabetes who presented to the ED with symptoms of generalized weakness and severe fatigue with no antecedent events such as nausea, vomiting, diarrhea, fever or recent illness. He denied lightheadedness or a syncopal episode. History was significant for the use of prednisone for a skin rash in the recent past. Labs were significant for mild hyponatremia with sodium level of 130 mmol/L [136-141] with a low serum osmolality at 273 mOsm/kg and a urine osmolality of 287 mOsm/kg. Further evaluation revealed a low cortisol level of 1.9 ug/dL [6.2 - 19.4]. Repeat cortisol was also low at 1.1 ug/dl. Cosyntropin stimulation test resulted in insufficient response, and iatrogenic adrenal insufficiency was suspected due to prior steroid use. Steroid replacement therapy was initiated with Hydrocortisone. The patient’s ACTH was found to be inappropriately normal at 17pg/ml (6-50). For further evaluation, he underwent MRI Pituitary which revealed leptomeningeal lesions concerning for an infectious, inflammatory, or malignant metastatic process. At this time, he was still hyponatremic with sodium of 130 mmol/L and continued to complain of weakness and not feeling well overall, however denied any neurological symptoms. Repeat labs for hyponatremia showed serum osmolality of 283 mOsm/kg and urine osmolality of 573 mOsm/kg while urine sodium was 100 mmol/L, concerning for mild SIADH. This was managed with fluid restriction initially and then with addition of salt tablets. He underwent lumbar puncture with Cerebrospinal fluid analysis, which did not reveal an infectious etiology. A rheumatological work up for inflammatory cause was negative. Imaging of his chest and abdomen in a search for primary malignancy revealed soft tissue lesions in the abdominal subcutaneous fat. Biopsy of the soft tissue lesions were concerning for a T-cell lymphoproliferative disorder with the absence of typical histological features. Repeat biopsy, flow cytometry and cytogenetic studies were inconclusive, which was suspected to be secondary to the patient receiving steroids prior to the biopsy. Conclusion: This case represents SIADH likely caused by a T-cell lymphoproliferative disorder. Although the biopsies have been inclusive, if the patient has Non-Hodgkin’s T cell lymphoma (NHL), leptomeningeal spread is a known complication of this disorder. The underlying mechanism that we propose behind SIADH in our patient is the leptomeningeal lesion located near the hypothalamus enhancing ADH release.

Presentation: Friday, June 16, 2023
FRI364 A Case Of Carcinoid Syndrome Symptoms Masked By Niacin Use
Authors: Yang Sophia , Eldin Randa Sharag , Qualler Dennis Teves
Published: October 2023

Disclosure: S. Yang: None. R. Sharag Eldin: None. D. Teves Qualler: None.

Case Presentation: A 72 male presented with worsening of facial flushing and diarrhea for 10 years. The patient described episodic feeling of hotness in the face associated with red- purplish discoloration of his facial skin lasting for 2 to 3 minutes. He has had 5 to 6 episodes per day. The patient reported the use of Niacin in the past and it was believed that it was the cause of his flushing episodes despite its persistence for years after stopping it. The patient also suffered from long standing diarrhea which started around the same time of the flushing. Diarrhea has been watery or loose and he has 5 to 6 bowel movements a day.

His symptoms were concerning for Carcinoid syndrome and a 24-hour urine collection for HIAA showed elevated HIAA to 108.7 mg/24 hour (<6 mg/24 hour). A CT scan of the abdomen revealed a 1.8 cm wall thickness in the cecum and a 3.6 cm spiculated mesenteric mass with central calcification with multiple hypervascular masses in the liver concerning for a metastatic neuroendocrine tumor. Core biopsy of one of the liver masses showed a well differentiated neuroendocrine tumor. He was also found to have tricuspid valve regurgitation as well as a Glycohemoglobin of 9%. The patient was treated medically with octreotide rather than surgery due to the significant disease burden. Interestingly, he was initially started on Lanreotide but developed foreign body granulomas at the injection sites. Discussion: Carcinoid-syndrome is a category of well-differentiated neuroendocrine neoplasms. The overproduction of serotonin is most used to assess the presence of carcinoid syndrome via its breakdown product 5- HIAA in the urine. Symptoms from niacin supplementation are variable and may include flushing and constipation. Patient’s flushing presented for years after discontinuing niacin supplementation. However, clinicians continued to attribute it to its use despite typical resolution of symptoms within 3 hours of discontinuing use. Niacin exposure may have been a mimicker of his underlying neuro endocrine neoplasia (NEN) as diarrhea is also an overlapping feature as seen in our patient’s presentation. DM as seen in our patient is not well documented in relation to carcinoid syndrome. One study (n=10) of the patients with functionally active NENs, 70% had borderline to diabetic-level blood glucose. Of the patients with carcinoid syndrome, there was no significant difference in fasting plasma glucose concentration or fasting plasma insulin concentration when compared to age-matched normal volunteers. Conclusion: Clinicians should have low level of suspicion in diagnosing carcinoid syndrome in the presence of typical symptoms of flushing and diarrhea. Due to the past use of niacin, our patient’s diagnosis was delayed despite the persistence of flushing years after stopping it.

Presentation: Friday, June 16, 2023
THU175 Incorrect Age Causing Falsely Short Stature In An Afghan Immigrant Girl
Authors: Ing Jordan , Marinkovic Maja
Published: October 2023

Disclosure: J. Ing: None. M. Marinkovic: None.

Background: Evaluation for short stature routinely includes screening for hormone deficiencies, chromosomal abnormalities, gastroenterological diseases, and inflammatory processes. “Incorrect age” resulting in falsely short stature, is not often considered in the differential diagnosis. Clinical Case: A young girl who recently immigrated to the United States from Afghanistan was referred for endocrine evaluation for short stature. At the time of her initial visit, she was listed in the electronic medical record at 10 years and 0 months old. Her medical history was significant for bowel injuries sustained three years prior in a bombing incident that required surgery and from which she completely recovered. Available growth charts from the preceding 6 months showed height and weight consistently less than the 1st percentile for her age but normal height velocity. On the exam she was prepubertal. Her measured height was 117.8 cm (0.06th percentile, Z = -3.24) and her body mass index (BMI) was 14.7 kg/m2 (12th percentile, Z = -1.18). The patient’s calculated mid-parental height was 155.5 cm (12.5th percentile, Z = -1.15). Laboratory work-up obtained by the pediatrician showed normal IGF-1, IGFBP-3, TSH, free and total thyroxine, tissue transglutaminase IgA, sedimentation rate, urinalysis, complete blood panel, complete metabolic panel, and a normal 20 cell count karyotype (46, XX). Her bone age was 5 years and 6 months and was interpreted as markedly delayed. Upon further history gathering using a Pashto interpreter, her father revealed there was an error in the processing of her immigration documents, resulting in being listed as three years older than her actual age. When corrected to that of a 7 year and 0 month old girl, her height improved to the 23rd percentile (Z = -0.73), and her BMI to the 31st percentile (Z = -0.5). Conclusion: This case demonstrates how children, through the immigration process, may have their age incorrectly documented and thereby are at risk for unnecessary and costly medical evaluation. It is possible that language barriers play a role in such errors. Therefore, it is important to verify the patient's true age, as parents may not think to provide this information voluntarily.

Presentation: Thursday, June 15, 2023
FRI600 Growth Attenuation Treatment In A Child With Cdkl5 Deficiency: The First Case In Our Institution
Authors: Cooper Felicia Ilyssa , Padron Marisse , Gurnurkar Shilpa
Published: October 2023

Disclosure: F.I. Cooper: None. M. Padron: None. S. Gurnurkar: None.

Introduction: Growth attenuation is an innovative therapy that may offer an improved quality of life for children who are non-ambulatory and have profound cognitive disability and allow for their families to provide more comfortable and longer-term care. In this case report, we describe growth attenuation treatment of a developmentally delayed 11-year-old male with estradiol to facilitate the family’s care of the patient. Case Presentation: A 11-year-old male with CDKL5 deficiency (consisting of developmental delay, aggression, and seizure disorder) presented for growth attenuation treatment due to parental concerns of tall projected final height (75 inches) posing future care challenges. His height was at the 97th% with Tanner stage II for testicular development and pubic hair. His bone age was consistent with chronological age predicting adult height of 75 inches. The hospital ethics committee was consulted and after discussion with genetics (the condition is expected to worsen with age), primary care and complex care, the committee concluded that growth attenuation treatment was in the best interest of the patient. Treatment with oral estradiol (2 mg/day titrated 2 mg weekly to a final dose of 10 mg daily) was started after normal baseline anti-coagulant factors. Estradiol was held 8 months after starting therapy due to declining protein C (68%, normal 70-180%) and protein S levels (46%, normal 70-150%). Hematology recommended adding low-dose aspirin (81 mg) while restarting estradiol therapy. Fifteen months after beginning estradiol, the bone age was at approximately 16 years (chronological age 13 years 6 months) and he grew approximately 6 inches to a final height of 68 inches. The estradiol is now being tapered off and the family feels more comfortable providing total care for the patient. Conclusion: We describe the first case of growth attenuation treatment in a 11-year-old child with profound intellectual disability and tall family genetics. Treatment decreased his final height from a projected 75 inches to 68 inches which aligned with the family’s goal and aims to decrease future challenges in care due to his size. This is not a standardized treatment and has faced controversy. For this reason, we recommend that treatment decisions be made on a case-by-case basis, in conjunction with the family and under the advice of an ethics committee. Our case also illustrates the need for a multidisciplinary approach in these patients.

Presentation: Friday, June 16, 2023
FRI394 Anti-inflammatory Protein Neuregulin-1 (NRG1) And ErbB3 Receptor In Human Antral Follicle And Endometrium
Authors: Chowdhury Indrajit , Banerjee Saswati , Rodriguez Alyssa
Published: October 2023

Disclosure: I. Chowdhury: None. S. Banerjee: None. A. Rodriguez: None.

Neuregulin 1 (NRG1) is a member of the EGF-like factor family and has recognized pro-survival and anti-inflammatory roles in neurodevelopmental and cardiac function, neurological and psychiatric disorders, cancer, and development. However, the physiological role of NRG1 in the human ovary and uterus has not been well documented. Therefore, we assessed the expression pattern of NRG1 and its receptor ErbB3 in normal human ovary and uterus tissue samples by immunohistochemistry (IHC). ErbB3 is one of the bona fide receptors for NRG1. NRG1 and ErbB3 were colocalized with steroidogenic acute regulatory protein (StAR) in normal human ovarian tissue samples, whereas NRG1 and ErBB3 were colocalized with CD105 (Endoglin) and epithelial cadherin (E-cadherin) in human uterine tissue samples. Our results showed strong immunoreactive signals of NRG1, ErbB3, and StAR in antral follicles, whereas weak or lack of immunoreactive signals in preantral follicles. The strong immunoreactive signals of NRG1 and ErbB3 were observed in granulosa cells and theca interstitial cells of antral follicles. In the uterus, a differential pattern of NRG1, ErbB3, CD105, and E-cadherin expressions were noticed. Interestingly, strong immunoreactive signals of NRG1, ErbB3, CD105, and E-cadherin in the luminal epithelium, and superficial and deep glands of endometrium were observed, whereas weak immunostaining in myometrium was noticed. These findings suggest that NRG1 and ErbB3 are important intracellular autocrine-paracrine anti-inflammatory factors that may govern antral follicular development and uterine implantation. Nothing to Disclose: SB; AR; IC. Sources of Research Support: This study was supported in part by National Institutes of Health Grants 1SC1 GM130544, G12-RR03034, and P50-HD28934. This investigation was conducted in a facility constructed with support from Research Facilities Improvement Grant #C06 RR18386 from NIH/NCRR.

Presentation: Friday, June 16, 2023
FRI397 An Unusual Case Of Galactorrhea- Think About Breast Implants !
Authors: Rimal Priya , Musurakis Clio , Gilden Janice L
Published: October 2023

Disclosure: P. rimal: None. C. Musurakis: None. J.L. Gilden: None.

Introduction: Elevation of prolactin (PRL) levels can occur due to physiologic or pathologic disorders of lactotroph cells. The most common causes for hypersecretion and resulting galactorrhea (GAL), a milky breast discharge, are pregnancy, breast feeding, hypothyroidism, chronic kidney disease, medications, chest wall trauma, or even stress. Although GAL is a rare complication after breast augmentation or reconstruction surgery, it can be bilateral, ipsilateral or contralateral, and is thought to be self-limiting. GAL can be cosmetically and psychologically distressing. The treatment depends on identifying the underlying cause, severity of symptoms, and can be medical, surgical, and might even necessitate breast implant removal. Clinical case: A 34-year-old Latina female G3P2 AB1 with prediabetes (BMI=22), history of gestational diabetes, and migraine headaches, was referred to the endocrine clinic for elevated PRL levels and 2 years of persistent GAL. Although originally regular, she had 3 months of menometrorrhagia following a COVID booster. She denied recent pregnancy, breast-feeding, breast masses, hirsutism, symptoms of thyroid disorders, chest wall trauma, infection, or symptoms of pituitary dysfunction. She was not taking medications associated with PRL elevation. Upon further evaluation, she reported frequently massaging the bilateral cosmetic breast implants to avoid formation of scar tissue. Lab evaluation showed initial PRL elevation of 35.8 ng/mL (nl=2.8-29.2); with normal LH=10.9 mIU/mL(nl 1.9-12.5) and FSH =4.9 mIU/mL(nl 2.5-10.2); estradiol=200.89 pg/mL(19.5-144.2); progesterone <0.5 ng/mL(nl <0.8);urine pregnancy test negative, HCG normal <2.6 mIU/mL (nl 2.6-4.2) ; ACTH=14 pg/mL (nl 0-47); AM cortisol=13.33 mcg/dL; salivary cortisol=<0.03 and 0.05 mcg/dL(nl 0.004-0.56); free testosterone=3.2 pg/mL(nl 0.1-6.4); SHBG =83.55 nmol/L(nl 17.69-138.26) total testosterone slightly elevated 50 ng/dL (nl 2-45); DHEAS=215 mcg/dL(nl 35-430); normal thyroid tests [(TSH 1.06 uIU/mL(0.550-4.780 ), free T4=1.05 ng/dL(0.76-1.46) Thyroid peroxidase antibody 28 U/mL(0-60)], Pelvic Ultrasound-benign right ovarian cyst and left ovary with subcm. follicles. Normal MRI of pituitary. Mammogram-dense breasts with bilateral implants. A Repeat PRL was 20.4 ng/mL with monomeric PRL normal at 8.6 (3.2-25.2 ng/mL), and later 13.70 ng/mL after stopping massaging of the breasts. The etiology of GAL was attributed to the breast implants with massaging, after excluding all other potential causes. Conclusion: Although other etiologies for galactorrhea should be considered, breast implants with manipulation must always be thought of as a possibility. This case highlights the importance of taking a thorough and complete medical history when evaluating all patients with galactorrhea.

Presentation: Friday, June 16, 2023
FRI399 Prevalence Of Polycystic Ovary Syndrome In Women With Type 1 Diabetes In Pregnancy
Authors: Dolatabadi Samin , Yamamoto Jennifer M , Benham Jamie L
Published: October 2023

Disclosure: S. Dolatabadi: None. J.M. Yamamoto: None. J.L. Benham: None.

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder that is a risk factor for cardiometabolic disease such as impaired glucose tolerance, obesity, and hypertension. The prevalence of PCOS in the general population is estimated at 5-15% depending on the diagnostic criteria that is used. Although PCOS is commonly associated with type 2 diabetes (T2D), its association with type 1 diabetes (T1D) is less commonly investigated. The reported prevalence of PCOS in women with T1D is 24%. Furthermore, previous studies have found that women with either PCOS or T1D are at risk of preeclampsia, premature delivery, and neonatal complications such as congenital malformations and neonatal death. Unfortunately, there is a paucity of information regarding prevalence of PCOS in women with T1D in pregnancy as well as maternal and neonatal outcomes in this population. The objectives for this study were to 1) determine the prevalence of PCOS in pregnancies affected by T1D and 2) determine whether maternal and neonatal outcomes differed between women with T1D in pregnancy with or without a concomitant diagnosis of PCOS. A retrospective cohort study was performed of women affected by T1D in pregnancy that attended specialized Diabetes in Pregnancy clinics in Calgary, Alberta, Canada between 2008-2020. An individual was classified as having PCOS if there was a self-reported diagnosis of PCOS or if a patient met at least 2 of the 3 Rotterdam criteria based upon chart review. Logistic regression was planned to examine associations between maternal and neonatal outcomes. From 401 patients with T1D seen at Diabetes in Pregnancy Clinics, 14 (3.5%) patients had a self-reported diagnosis of PCOS. Given the low prevalence of PCOS in our patient population, the planned comparison of maternal and neonatal outcomes in patients with and without PCOS could not be completed. The prevalence of PCOS in women affected by T1D in pregnancy in this cohort was significantly lower than the reported prevalence of PCOS among women with T1D as well as the general population. Given that PCOS is associated with infertility and only women experiencing pregnancy were included in this study, exclusion of patients experiencing infertility could have affected the calculated prevalence. Overall, these results indicate that there is a lack of screening for PCOS in women affected by T1D during pregnancy. Given that both T1D and PCOS are associated with adverse maternal and neonatal outcomes, more education regarding this topic should be provided to healthcare professionals to ensure appropriate periconceptional and antepartum care of women with PCOS and pre-existing diabetes.

Presentation: Friday, June 16, 2023
OR19-04 Hypoglycosylated FSH Enhances Ovarian Follicle Development and Gamete Quality
Authors: Converse Aubrey , Rajendra Kumar T , Duncan Francesca E
Published: October 2023

Disclosure: A. Converse: None. T. Kumar: None. F.E. Duncan: None.

Gamete quality depends on the proper growth and maturation of the ovarian follicle, which consists of the oocyte and its supporting somatic cells. FSH is essential for follicle growth as female Fshb and Fshr null mice are infertile due to arrested follicle development. Macroheterogeneity in N-glycosylation on the FSHß-subunit confers differential bioactivities with hypoglycosylated FSH21 exhibiting higher FSHR binding affinity and bioactivity compared to fully glycosylated FSH24. In females, there is a shift from the highly bioactive FSH21 to FSH24 with increasing age which occurs coordinately with the age-dependent decline in female fertility. In this study, we used an encapsulated in vitro follicle growth assay to test the hypothesis that FSH glycoforms have differential abilities to promote follicle development and gamete quality. Early-stage (preantral) ovarian follicles were isolated from CD-1 mice, cultured in media containing 10 ng/ml of either FSH21 or FSH24 for up to 12 days, and then ex vivo ovulation was induced. While both glycoforms maintained >75% follicle survival through day 12, follicles treated with FSH21 were significantly larger than FSH24-treated follicles between days 4 and 12 of culture. Over the 12 day culture, FSH21-treated follicles grew from 110.9 ± 9.2 µm to 251.3 ± 24.4 µm, while FSH24-treated follicles grew from 109.3 ± 7.1 µm to 229.7 ± 15.4 µm. This difference in growth correlated with a 13.4 and 4.5-fold increase in estradiol secretion by FSH21-treated follicles compared to FSH24 treatment on days 8 and 12, respectively. After ex vivo maturation, FSH21-treated follicles produced a higher proportion (76.9%) of meiotically competent gametes that reached the metaphase II (MII)-arrested state compared to FSH24-treated follicles (62.5%). Furthermore, normal meiotic spindle configuration was observed in 76% of MII eggs from the FSH21 cohort but only 50% of the FSH24 cohort. These results indicate that FSH21 is more bioactive than FSH24 in promoting follicle development and high-quality oocytes. Mechanistically, this is likely due in part to the differential effects of FSH21 and FSH24 on the formation of transzonal projections (TZPs), which are cytoplasmic filaments essential for granulosa-oocyte communication. By 24 hrs, FSH21-treated follicles had more TZPs than FSH24-treated follicles, as demonstrated by increased actin staining (1.6x) and Myo10 foci (5.1x) in the zona pellucida region. Thus, the early establishment of TZPs and increased somatic-oocyte communication in FSH21-treated follicles ultimately results in a more developmentally competent gamete. In addition, we anticipate that ongoing transcriptomic analysis of 24 hr FSH glycoform-treated follicles will highlight other processes involved in early follicle development that contribute to the observed differential effects on oocyte quality.

Presentation Date: Saturday, June 17, 2023
SAT008 Elucidating The Role Of Small Heterodimer Partner In Injury Associated Hepatic Proliferation
Authors: Shaw Ryan P
Published: October 2023

Disclosure: R.P. Shaw: None.

Small Heterodimer Partner (SHP) is an atypical nuclear receptor that is involved in the regulation of several metabolic pathways but lacks the typically conserved DNA binding domain seen in other nuclear receptors. Several studies have found that SHP expression is drastically lower due to epigenetic silencing in human hepatocellular carcinoma (HCC), the fourth most fatal cancer worldwide, indicating a crucial role for SHP in controlling liver proliferation. SHP can modulate the cell cycle by inhibiting cyclin D1, and remarkably, SHP knockout mice develop tumours at 12 to 15 months of age. The underlying mechanism(s) of this tumorigenesis may be consequential to increases in cyclin D1, yes associated protein (YAP), and decreases in apoptosis when SHP expression is reduced. Furthermore, excessive bile acid (BA) levels in cholestatic liver diseases are cytotoxic and in large quantities, can induce hepatic injury and subsequent hepatic proliferation. We have confirmed that in male mice, loss of hepatic SHP leads to increased systemic BA levels, suggesting these mice may also have increased hepatic injury and proliferation. Moreover, BAs have been identified as upstream regulators of YAP. YAP is a transcriptional coactivator that regulates genes involved in cellular proliferation and differentiation and is also overexpressed in hepatic cancers. In addition to BAs, YAP has also been shown to be activated upon treatment with 0.1% DDC (3,5-Diethoxycarbonyl-1,4-Dihydrocollidine) diet, a chemical-based biliary injury model. We have recently demonstrated that male LSHPKO mice exhibit significantly increased hepatic proliferation, inflammation, and cyclin B1 & B2 mRNA expression in response to the DDC challenge. We have also characterized apoptotic pathways and cell death using TUNEL staining in these mice and characterized how the downregulation of YAP in LSHPKO mice affects hepatic proliferation. These results, in tandem with previous studies of YAP, suggest that hepatic SHP may play a role in mediating hepatic proliferation after injury. It is possible that SHP may act as a repressor for YAP-mediated function.

Presentation: Saturday, June 17, 2023
SAT011 Neonatal Endotoxin Exposure Has Long-term Effects On Glucocorticoid Regulation In Blood And Lymphoid Organs Of Mice
Authors: Mazurenko Anna , Salehzadeh Melody , RY Lim Sarah , Soma Kiran K
Published: October 2023

Disclosure: A. Mazurenko: None. M. Salehzadeh: None. S.R. Lim: None. K.K. Soma: None.

Glucocorticoids (GCs) are steroid hormones that play vital roles in immunity. GCs are produced by the adrenal glands and also by lymphoid organs, such as bone marrow, thymus, and spleen. There is a period of decreased adrenocortical activity in neonatal humans and mice termed the stress hyporesponsive period (SHRP), which protects developing tissues from high circulating GCs and allows for fine-tuning of GC levels in lymphoid organs. In neonatal mice, GC levels increase acutely in response to the bacterial endotoxin, lipopolysaccharide (LPS). Yet, it is not known how early-life LPS exposure affects systemic and local GC levels in adulthood. We assessed whether LPS administration during the SHRP (‘first hit’) affects GC regulation in blood and lymphoid organs in adulthood when challenged again with LPS (‘second hit’). We administered LPS (50 μg/kg i.p.) or saline (vehicle control) to male and female C57BL/6J neonatal mice (PND 4 and 6, within the SHRP). We then split the mice into two groups and administered LPS (50 μg/kg i.p.) or saline to adults (PND90) (2x2 design). We collected whole blood, bone marrow, thymus, and spleen 4 hr after LPS administration at PND90. We used liquid chromatography tandem mass spectrometry (LC-MS/MS) to measure 7 steroids, including 11-deoxycorticosterone (DOC; corticosterone precursor), corticosterone (main active GC in mice), and 11-dehydrocorticosterone (DHC; corticosterone metabolite). Preliminary results show that neonatal LPS treatment altered LPS-stimulated corticosterone levels (but not baseline corticosterone levels) in adult mice. Specifically, neonatal LPS treatment increased blood corticosterone levels in LPS-treated adult males, but not females. In contrast, neonatal LPS treatment increased thymus and spleen corticosterone levels in LPS-treated adult females. There were no effects of neonatal LPS treatment on DOC and DHC levels in adult males. In contrast, neonatal LPS treatment increased thymus DOC and spleen DHC levels in LPS-treated adult females. Altogether, our results suggest that LPS exposure during the SHRP has long-term effects on GC regulation in the blood and lymphoid organs when challenged with a ‘second hit’ in adulthood. This research offers vital insights into understanding the development and regulation of the immune and endocrine systems. Critically, this study demonstrates that lymphoid organs modulate local GC levels independently of circulating GC levels. More generally, these data elucidate the long-lasting programming effects of an immunological stressor, such as neonatal sepsis, early in life.

Presentation: Saturday, June 17, 2023
FRI180 Prevalence Of Vertebral Fractures In Patients With Adrenal Adenomas
Authors: Han Hye Jeong , Lam Han , Rao Sudhaker D , Athimulam Shobana
Published: October 2023

Disclosure: H. Han: None. H. Lam: None. S.D. Rao: None. S. Athimulam: None.

Background: Approximately 5% of adults undergoing cross-sectional imaging are reported to have an adrenal adenoma. Although most adenomas are considered non-functioning (NFAT), up to 48% can present with mild autonomous cortisol secretion (MACS). Published studies have reported an increased prevalence of vertebral fractures (VFx) in MACS. However, findings are limited by sample size, selection bias and lack of diversity in patient population. Objective: To determine the prevalence of vertebral fractures and associated risk factors in patients with adrenal adenomas Design: Retrospective cross-sectional study of patients with adrenal adenomas over a 10-year period (Jan 2012 - Dec 2021). Setting: Academic primary and tertiary care setting Main outcomes measured: 1) MACS was diagnosed based on cortisol level ≥ 1.8cmg/dL after overnight 1mg dexamethasone suppression testing (DST) and NFAT if cortisol < 1.8mcg/dL. Patients who did not undergo 1mg DST were categorized as unknown cortisol status (UCS).2) Bone mineral density (BMD), T- and Z-scores of the lumbar spine (LS). 3)Vertebral morphometry, as assessed by Genant scale, to identify asymptomatic vertebral fractures. Results: Preliminary results included 198 patients with adrenal adenomas [(135 women (67%) with a median age of 67y, 106 Black (54%), 83 White (42%) and 9 other races (4%)]. 74 patients (37%) were diagnosed with NFAT, 42 (21%) with MACS, and 82 (41%) with UCS. Prevalence of vertebral fractures by vertebral morphometry assessment was 6%. (n=12, 5 Black, 7 White). In those with VFx (8 UCS, 2 MACS, 2 NFAT), Black patients had lower BMD (Mean BMD ± SD in Black vs Caucasians: 0.85 ± 018 vs 1.02 ± 0.24 g/cm2, p=0.26). Overall, there was no significant difference in mean LS BMD ± SD (0.97 ± 0.23 vs 1.03 ± 0.20 g/cm2, p=0.41) and mean T-score LS ± SD (-1.11 ± 2.28 vs -0.60 ± 1.71, p=0.49), in patients with and without vertebral fractures, respectively. Conclusions: Patients with adrenal adenoma are at risk of vertebral fractures despite normal or osteopenic BMD. Black patients with adrenal adenomas and vertebral fractures have lower BMD compared to White patients. 41% (n=82, 61% AA, 30% Caucasians, 2% Other) of patients were classified as unknown cortisol status indicating further need to educate health care professionals on evaluation of adrenal adenomas to improve health care outcomes and disparities in management.

Presentation: Friday, June 16, 2023
FRI496 A Rare Case Of Thyroid Hormone Resistance Beta
Authors: Kaur Rai Harpreet , Man Pradhan Rubin , Chaudhuri Ajay
Published: October 2023

Disclosure: H.K. Rai: None. R.M. Pradhan: None. A. Chaudhuri: None.

Background: Genetic mutation in the thyroid hormone receptor leads to the reduced affinity of hormone binding; thus, causing thyroid hormone resistance. It is characterized by a wide range of phenotypic variations and subsequent diagnostic and treatment challenges. Here, we present a case of resistance to the thyroid hormone Beta, with a rare genetic abnormality, that was misdiagnosed as hyperthyroidism. Case: A 46-year-old woman diagnosed with hyperthyroidism s/p RAIA resulting in hypothyroidism on levothyroxine therapy (112mcg daily, weight: 55kg), presented with ten pounds of weight gain, constipation, and cold intolerance for the past six months. TFTs were as follows: TSH: 6.493 mcUnits/ml (normal: 0.400-5.00 mcUnits/ml), and free T4: 1.83 ng/dL (normal: 0.80-1.80 ng/dL). The patient was clinically hypothyroid despite having an elevated FT4 and TSH level. She was also on metoprolol succinate 25 mg daily for sinus tachycardia for the past 1 year. Upon inquiring about further details, the patient informed that at the age of 22, she had significant weight loss, palpitations, and anxiety, but also reported dry skin. The patient was seen by multiple endocrinologists and was provided with contradictory diagnoses. She had RAI scan which was significant for increased uptake and subsequently underwent RAIA. The patient was seen by multiple physicians in the past, levothyroxine dose was adjusted on various occasions but her TFTs never normalized. Post-ablation, she continued to require a higher than the weight-based dose of levothyroxine. Upon review of family history, the patient reported that her father, sister, and daughter had a similar pattern of TFTs with elevated FT4 and TSH values. All of them had palpitations and anxiety that were not severe enough to seek medical care. Family history was also significant for ADHD and hyperlipidemia present in the daughter and father. All affected family members have short stature. The levothyroxine dose was slowly titrated based on the clinical presentation. She was euthyroid with 150 mcg daily of levothyroxine with TSH of 4.869 mcUnits/ml and free T4: 1.85 ng/dl. Given her presentation and suspicion of thyroid hormone resistance, we decided to proceed with genetic testing. The result was positive for the THRB (Resistance to thyroid hormone beta) variant c.904A>G.p.(IIe302Val), which is classified as a variant of uncertain significance, as there is currently insufficient evidence to support its disease-causing role. However, there is a strong association between the gene and the patient's phenotype. Conclusion: The distinctive feature of RTH beta is high levels of free T4 while TSH concentration is normal or elevated, with a combination of hypothyroid and hyperthyroid symptoms. Such patients are often misdiagnosed. We herein describe a novel pathogenic RTH beta gene variant causing thyroid hormone resistance that needs to be further explored.

Presentation: Friday, June 16, 2023
FRI557 Don’t Forget The Incidental Thyroid Nodule In Graves’ Disease. A Case of Marine-Lenhart Syndrome
Authors: Andino-Lebrón Katira Nicole , Martinó-Morales Alejandro , M Janet
Published: October 2023

Disclosure: K.N. Andino-Lebrón: None. A. Martinó-Morales: None. J.M. Colón-Castellano: None.

Marine-Lenhart syndrome (MLS) was initially described by Charkes in 1972 as he observed patients with Graves’ disease (GD) and incidental functioning thyroid nodules. He named the disease Marine-Lenhart syndrome based on a paper published by Marine and Lenhart in 1911. MLS is a variant of GD now described as the coexistence of GD and autonomous functional thyroid nodules (AFTN); thus, patients present with thyrotoxicosis due to GD and AFTN. MLS is very rare, and prevalence is estimated to be around 0.8%-2.7%. Here, we present a case of MLS in a 79-year-old female. A 79-year-old Hispanic woman with history of breast metaplasia s/p chemoprevention with tamoxifen for 5 years, atrial premature contractions on metoprolol, among other medical conditions was referred to Endocrinology clinics by her primary care physician (PCP) because of abnormal thyroid function tests and ultrasound. She reported feeling anxious with associated palpitations, she denied weight loss. Physical examination was remarkable for regular rate and rhythm, no goiter, no palpable nodules, no proptosis, and deep tendon reflexes +1. Laboratory testing revealed a suppressed TSH of 0.224 uIU/mL, normal free T4 at 1.17 ng/dL, normal total T3 at 142.5 ng/dL, and positive thyroid stimulating immunoglobulins at 345%. Thyroid ultrasound showed a normal size gland with multiple complex nodules. In the right lobe there was a mixed cystic and solid nodule, measuring 1.48x1.21x1.71cm, wider than tall, with internal vascularity and punctate calcifications. In the left lobe there was an isoechoic and solid nodule measuring 0.7x0.5x0.7cm, wider than tall, without calcifications. Thyroid uptake scan with SPECT-CT demonstrated a focus of increased tracer uptake on the upper pole of the right thyroid lobe that corresponds to the one found on CT scan and a diminished and nonuniform uptake of the tracer in the reminders of the thyroid gland. The 24-hour radioactive iodine uptake was 17.5%. Diagnosis of MLS was made, and the patient was started on methimazole 5mg daily, which she has been tolerating well. Follow up laboratories show a biochemically euthyroid state. Marine-Lenhart syndrome is a rare entity of Graves’ disease which is currently defined as GD and accompanying functioning nodule(s). To establish the diagnosis, it is important the evaluation with scintigraphy and autoimmune testing. Multiple treatment options are available and patients with GD should be evaluated for the presence of thyroid nodules and their functional status to achieve optimal therapy. Patients with GD have a chance of remission when treated with antithyroid drugs. Due to the pathophysiology of AFTN, patients with MLS (concurrent GD and AFTN) have lower remission rates with antithyroid drugs and may require definitive management therapy with radioactive iodine or surgery.

Presentation: Friday, June 16, 2023
FRI562 Not JUST Severe Hypothyroidism: Recognizing Autoimmune Polyglandular Syndrome
Authors: Jafarian-Kerman Scott R , Razzeto Alejandra , Saini Gagandeep , Siddiqui Mariah , Islam Mohammed , Behman Daisy , Carson Michael
Published: October 2023

Disclosure: S.R. Jafarian-Kerman: None. A. Razzeto: None. G. Saini: None. M. Siddiqui: None. M. Islam: None. D. Behman: None. M. Carson: None.

Background: Recognizing Autoimmune Polyglandular Syndrome (AIPS) in a patient who has chronic hypothyroidism, specifically with a non-classic presentation, is challenging. Clinical Case: A woman in her 50’s with hypothyroidism presented with one week of progressive dizziness and weakness. Medications include levothyroxine 125 μg weekly (per the patient, her PCP started this dose 8 months ago based on lab results). On physical examination: BP 101/74 mmHg; HR 56 bpm; T: 98.1 F (36.7 C); RR: 23/min; O2 Sat: 98%. Skin: vitiligo. Lab results demonstrated TSH: 839.6 μIU/mL (0.5-4.5) from 0.28 one year ago, free T4: 0.15 ng/dL (0.4-4.5), phosphorus: 2.3 mg/dL (2.7-4.5), vitamin D: 17.4 ng/dL (>30). She was started on daily levothyroxine 125 μg and intravenous fluids. On day 3 of admission, Rapid Response was called for blood pressure 54/39 mmHg. Myxedema coma was unlikely as she lacked altered mental status, hypothermia, hypoventilation, hyponatremia, or hypoglycemia; CT head was normal. On the same day, hydrocortisone 100 mcg q8h started due to high suspicion of adrenal insufficiency given low normal cortisol [7.1 ug/dL (6-20)] and hypotension. Due to the history of hypothyroidism, vitiligo, and the new diagnosis of adrenal insufficiency, we suspected AIPS. two days later, primary adrenal insufficiency was established by a positive Cosyntropin stimulation test (1 hour cortisol of 14.8 ug/dL; not reaching >18 μg/dL), elevated ACTH 72 pg/mL (6-50), Aldosterone <1 ng/dL (3-16), and low DHEA of 52 ng/dL (345-2030). Other labs were as follow: normal FSH 85.7 mIU/mL (23-116), elevated PTH 153 pg/mL (16-77) which decreased to 62 pg/mL with vitamin D supplementation, normal Vitamin B12, and negative renin and intrinsic factor antibodies. A diagnosis of AIPS was established and she was discharged on levothyroxine, fludrocortisone, and hydrocortisone. Conclusion: AIPS is typically idiopathic and may affect endocrine organ systems either simultaneously or sequentially. The 3 classic patterns are: Type 1 (most common): younger women, presents with candidiasis, hypoparathyroidism, and Addison’s disease. Type 2: middle-aged women, Addison’s disease, autoimmune thyroid disease and/or Type 1 diabetes. Type 3: Type 1 diabetes, pernicious anemia, vitiligo or alopecia, and normal adrenal cortical function. This patient is unique in that she has characteristics of both type 1 and 3 AIPS, but not diabetes. In this case, the combination of hypotension even in the setting of profoundly undertreated hypothyroidism, prompted the expanded evaluation. While isolated hypothyroidism is common among our internal medicine patients, those with additional symptoms, or in this case unexplained hypotension, should be evaluated for AIPS.

Presentation: Friday, June 16, 2023
FRI567 Insulin Autoimmune Syndrome And Grave’s Disease
Authors: Skariah Annie M , Porter Tama
Published: October 2023

Disclosure: A.M. Skariah: None. T. Porter: None.

Background: Insulin autoimmune syndrome (IAS), also known as Hirata’s disease, is a rare condition characterized by immune mediated post prandial hypoglycemia, due to presence of high titers of insulin autoantibodies (IAA). Most cases reported in Asian population with strong association with HLA-DR4 and specifically with the DRB1*0406. Clinical case: Patient is 36-year-old Asian female with no significant past medical history got evaluated by primary care physician because of fatigue, weight loss and neck swelling. Her symptoms are consistent with hyperthyroidism, got evaluated and found to have elevated thyroid hormone levels and suppressed TSH. At the time of diagnosis, free T3 2922 pg/dl(230-420pg/dl), free T4 > 7.7 ng/dl (0.9-1.7 ng/dl), TSH < 0.01uIU/ml (3-4uIU/ml), total T3 599 ng/dl (80-195 ng/dl), total T4 19.6Ug/dl (5-11 Ug/dl). Patient was started on methimazole, and beta blocker. Other labs including autoimmune panel were positive for TSI (2.8 with normal <1.3) and thyroid receptor antibody >40 (<15.5 IU/l) confirming Graves' disease. 4 weeks after starting treatment with methimazole, patient was experiencing episodes of hypoglycemia, related to food intake. She checked her blood sugar and the lowest blood sugar she noticed was 53 mg/dl. She had no history of diabetes and never used insulin or any other oral diabetic medications. Insulin levels >1000 uIU/ml (2.6-24.9uIU/ml), insulin antibody levels >625 uU/ml (<5 uU/ml), C-peptide as high as 9.5ng/ml (1.1-4.4 ng/ml), Insulin/C-peptide ratio 105, proinsulin elevated 40.3pmol/l (0.0-10 pg/l), and oral hypoglycemic agent screening negative. With the lab results, diagnosis of Hirata’s syndrome was made, Management discussed with the patient. Since patient still having labs consistent with hyperthyroidism, continued methimazole and started on diet interventions including low-carb diet and including complex carbohydrates in the diet. Patient gradually responded to dietary interventions with decrease episodes of hypoglycemia. Never required acarbose or steroids. Follow-up labs shows that patient is responding decrease in the levels of insulin antibodies 116 uU/ml and insulin levels 19.5 uIU/ml. Patients’ hyperthyroidism responded to methimazole, and dose reduced eventually to 5 mg daily with latest labs of free T4 1.21 ng/dl, Free T3 2.7 pg/ml and TSH 2.010 uIU/ml. Conclusion: Association between methimazole and IAS has been already reported before. When a patient is presenting outside Asian countries with similar symptoms, differential of IAS can be missed due to its rarity. But because of globalization; people from all races are seen in every part of the world. It will be beneficial to screen patients for IAS which can decrease cost of work up and treatment, when considering imaging modalities which were included as the part of the work up.

Presentation: Friday, June 16, 2023