bluuebunny/crossref_metadata_2025 huggingface dataset:
PMON191 Current Management of Acute Adrenal Insufficiency Related Adverse Events in Children with Congenital Adrenal Hyperplasia- Results of an International Survey of Specialist Centres
Authors: Ali Salma Rashid , Bryce JIllian , Krone Nils , Claahsen-van der Grinten Hedi , Ahmed S Faisal
Published: November 2022

Background

There is wide variation in the reported rate of acute adrenal insufficiency (AI) related adverse events (sick day episodes and adrenal crises) between centres and the definition of these events as well as their management may vary from one centre to another. A greater standardisation of the definition and management of these events would facilitate the benchmarking and comparison of care across centres.

Objective

Evaluate the level of consensus on the criteria that should be considered 'essential' for defining and managing acute AI related adverse events in children with Congenital Adrenal Hyperplasia.

Methods

Active users of the International Congenital Adrenal Hyperplasia & International Disorders of Sex Development (I-CAH/I-DSD) Registries (n=66), non-active users of I-CAH/I-DSD (n=35) and the EuRRECa e-Reporting Registry (n=10) were approached to complete an online survey.

Results

56 clinicians from 27 countries responded to the survey; response rates for the three Registry groups were 42 (65%), 11 (31%) and 3 (30%), respectively. Written corticosteroid management plans and one to one patient/parent education were provided by 54 (96%) and 51 (91%) clinicians, respectively; 33 (59%) provided steroid-aware emergency cards. 56 (100%) and 55 (98%) clinicians advised an increase in glucocorticoid dosing (sick day dosing) in the event of fever or severe infection (eg. pneumonia). Less common indications for sick day dosing included vaccination and mild afebrile intercurrent illness, recommended by 17 (30%) and 9 (16%) clinicians, respectively. The most frequently reported sick day dosing regimen was tripling the total daily dose of hydrocortisone and administering 3 times daily, reported by 24 (43%) clinicians. 40 (71%) specified the duration of sick day dosing as ≥48 hours for severe infections. Vomiting and diarrhoea were the most common indications for intramuscular hydrocortisone, reported by 34 (61%) and 25 (45%) clinicians, respectively. Over 50% of respondents indicated that essential clinical criteria for adrenal crisis should include fatigue and nausea or vomiting and over 60% indicated that the criteria should include hypotension, hyponatraemia, hyperkalaemia and clinical improvement following parenteral glucocorticoids. A bolus parenteral injection of hydrocortisone and glucose infusions were the most frequently administered medications, reported by 50 (89%) and 32 (57%) of clinicians, respectively.

Conclusions

Although there is considerable variation in the definition and management of AI related adverse events in children amongst specialist centres, there is also good evidence of consensus on specific aspects that can be used to develop standardised criteria and lead to greater benchmarking of care.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
PMON319 A Pure Androgen Secreting Adrenal - Cortical Tumor in a 13 Year Old Female
Authors: Senguttuvan Rajan , Brown Gilda , Cannon Kendall , Jovel Valeria Munguia
Published: November 2022

Background

Adrenal cortical adenomas are exceedingly rare representing 0.2% of pediatric malignancies and often present with signs of Cushing syndrome, virilization and mixed elevated hormones.[1] We present a rare case of a virilizing androgen only secreting adrenal cortical adenoma with resolution after surgical removal.

Clinical Case

A 13-year-old female was referred to endocrine clinic for 1 year history of deep masculine voice, hirsutism and elevated DHEA-S levels. She also reported facial hair requiring removal every 3 to 4 days, back hair, acne, and dull aching back pain. Pubertal changes began at age 9 with breast development and menarche at age 11 followed by amenorrhea. On physical exam, she had a significantly deep masculine voice, axillary hair, female genitalia with prominent clitoris, Tanner Stage IV pubic hair and Stage III breast development. Blood pressure was within normal limits and weight was historically consistent in the 90th percentile.

Initial labs were significant for elevated 17-Hydroxypregnenolone 353 ng/dL (ref: 44-235), Androstenedione LCMS 903 ng/dL (ref: 50-170), Testosterone 100 ng/dL (ref: 15-35), DHEA 5460 ng/dL (ref: <202) and DHEA-S >1000 ug/dL (ref: 67.8–328.6). LH, FSH, Estradiol, Cortisol LCMS, and Chromogranin A were within normal limits for her sex and age. Further work up ruled out pheochromocytoma, paraganglioma, Cushing's syndrome and congenital adrenal hyperplasia. Magnetic resonance imaging revealed a well-circumscribed 5.5×5.8×6.4 cm cystic and solid left adrenal mass and displacement of the left kidney.

She was referred to endocrine oncology and surgery specialists. Genetic testing showed absence of TP53 involvement. Patient underwent open left adrenalectomy, and remained hospitalized for 3 days in recovery. The surgical pathology identified an adrenal cortical adenoma Stage II (pT2, pN0, cM0) measuring 8.7×6.0×3.3cm with slight increase of ki67 index at 3.7% (average 8044 nuclei counted) and hot spot with 4.6% (1266 nuclei counted). Follow up revealed resumption of regular periods, improvement in acne and male-pattern hair growth, and voice becoming less deep beginning 3 months post-operatively. DHEA-S returned to normal ranges at 220 ug/dL (ref: 67.8–328.6). Patient did well post-operatively except for occasional sharp back pain.

Discussion

Rare amongst adrenal tumors are isolated androgen-secreting sub types. To our knowledge, this is one of the first documented cases of a pure androgen secreting adrenal cortical tumor without symptoms of Cushing's syndrome in the pediatric population.

References

1. Pinto EM, Zambetti GP, Rodriguez-Galindo C. Pediatric adrenocortical tumours. Best Pract Res Clin Endocrinol Metab. 2020;34(3): 101448. doi: 10.1016/j.beem.2020.101448

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
PMON330 The Relationship between Pituitary Volume and Chiari Malformation in Growth Hormone Deficiency and Idiopathic Short Stature
Authors: Manely Sarah , Noto Richard , Sayegh Emily , McGuirk Liam , Patale Tara , Krasnow Matt , Epstein Ben , Tenner Michael , Mehta Shilpa , Schefflein Javin , Mehta Hasit
Published: November 2022

Patients with a small posterior cranial fossa may present with cerebellar tonsillar herniation through the foramen magnum, known as Chiari malformation (CM). The relationship between CM, pituitary volume (PV), and growth hormone deficiency (GHD) has not yet been explored and is the subject of this abstract. This study seeks to compare the differences in PV in short patients with CM with a diagnosis of either GHD or idiopathic short stature (ISS), to normal controls (NCs). The database of a Peds Endo Center between 2013-21 was queried for patients with CM and who had undergone MRI evaluation. Patients were separated into 4 groups: CM and GHD, CM and ISS, GHD without CM, and ISS without CM. These groups’ PV results were compared with NCs who we previously reported. The ages of short patients with CM (n=29) were compared to the ages of NCs (n=170); no significant difference was found (p = 0.12). The MN and MD PV for patients with GHD alone were 230.8 ± 89.64 and 217.62mm3, respectively. The MN and MD PV for patients with GHD and CM (n=23) were 246.55 ± 128.0 and 200.5mm3, respectively. The MN and MD PV for CM and ISS (n=6) were 671.54 ± 350.25 and 619.55mm3, respectively. The MN and MD PV for NCs were 364.0 ± 145.2 and 346.0mm3, respectively. The PV of patients with GHD alone were compared to the PV of patients with both GHD and CM; there was no significant difference found (p=1.0). Next, the PV of patients with GHD alone were compared to the PV of patients with both ISS and CM which showed that patients with GHD alone had significantly smaller PV compared to patients with both ISS and CM (p<0.05). Lastly, we compared the PV of patients with both GHD and CM versus patients with both ISS and CM, which showed that patients with both GHD and CM had significantly smaller PVs compared to patients with both ISS and CM (p<0.05). The PV of short patients with CM (n=29) were compared to the PV of NCs (n=170) and there was no significant difference found (p = 0.58). Our study demonstrates that PV is smaller in patients with GHD regardless of whether they have CM or not. We speculate that CM appears to be a radiological finding with no significant impact on PV, whereas GHD appears to have a significant impact on PV. Therefore we speculate the small PV exhibited in patients with CM and GHD appear to be related to GHD. A larger sample size will be needed to further elaborate on this concept.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
PSAT111 Neudesin Plasmatic Levels and Glucose Metabolism in Obese and Overweight Children: Preliminary Data
Authors: Vergani Edoardo , Bruno Carmine , Gavotti Cesare , Cipolla Clelia , Currò Diego , Mancini Antonio
Published: November 2022

Neudesin, a newly discovered peptide mainly secreted in brain and adipose tissue, is under evaluation for its possible activity as negative regulator of energy expenditure. In pre-adipocyte cultures neudesin promotes adipogenesis, while in mice model neudesin decreases food intake. Childhood overweight and obesity are among the main health issues in modern times, especially in western countries, due to the association to increased cardiovascular and oncological risk in adult age. No data on neudesin in obese and overweight children are currently available. Given that, we aim to perform an observational cross-sectional study testing the hypothesis that neudesin plasmatic levels may be affected in obese and overweight children. We also evaluated any eventual relationship between neudesin and metabolic and anthropometric parameters to gain insight on a possible role in childhood obesity.

34 children were included in the study and divided in two groups according to Cole's criteria. Group A included obese and overweight children, 23 patients, 17 females (Tanner stage 1) and 6 males, aged 4-10 years; Group B included normal-weight children, 11 patients, 7 females (Tanner stage 1) and 4 males, aged 3-10 years. Metabolic (glucose and insulin, total - LDL - HDL-cholesterol, triglycerides, uric acid) and hormonal (fT3, fT4, TSH, IGF-1, leptin) parameters were evaluated. HOMA index, QUICKI index and the area under the curve (AUC) of glucose and insulin after oral glucose load were calculated in obese and overweight children. Neudesin was measured by ELISA system.

Neudesin levels did not significantly differ between the two groups, even though a trend toward higher levels in group A was found (mean±SEM 3±0.32 ng/ml vs 1.98±0.15 ng/ml, p = 0.1). As expected, obese and overweight children showed significantly higher blood glucose, total and LDL cholesterol, triglycerides and leptin levels than those with normal weight. Interestingly, in obese and overweight children plasmatic neudesin levels significantly directly correlated with blood glucose and AUC of glucose. No other new significant correlation was detected in both groups.

Very few data on serum neudesin levels in human are available. To note, neudesin was lower in obese adolescents compared to age-matched normal controls (1), while children affected by type 1 diabetes mellitus showed higher levels than age-matched controls (2). Taken together, these results, although preliminary, may suggest a possible age-related role of neudesin in glucose homeostasis in obese/overweight children.

References

1. Celikkol A. et al, J Clin Res Pediatr Endocrinol, 2021 2. Polkowska A. et al, Biomed Res Int, 2019

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
LBSAT309 Recurrent Nephrolithiasis As A Presenting Feature Of Primary Hyperparathyroidism
Authors: Patel Toral , Arora Gunjan
Published: November 2022

Introduction

Primary hyperparathyroidism entails hyperfunctioning of the parathyroid gland and is characterized by hypercalcemia in the setting of inappropriately normal or elevated PTH. Evidence of nephrolithiasis is an indication for surgical intervention. We present a case of primary hyperparathyroidism presenting as recurrent nephrolithiasis.

Case presentation

A 57 year old female with past medical history significant for hypertension, pre-diabetes and recurrent nephrolithiasis presented to the ED with subjective fever, chills and dysuria. Of note, she had a long standing history of nephrolithiasis with multiple instances of cystoscopic lithotripsy and stent placement with recurrent UTIs over the past decade. She was noted to be in septic shock secondary to urosepsis. She was managed in the ICU with broad spectrum intravenous antibiotics and pressor support. Her workup revealed hypercalcemia with serum calcium 12 mg/dL (8.6 - 10.3), albumin 3.4 g/dL (3.5 - 5.7) in the setting of inappropriately elevated parathormone PTH at 120.4 pg/ml (12 - 88). Endocrinology was consulted. Extensive chart review revealed that she had a long standing history of hypercalcemia and prior urinary calculi analysis were consistent with calcium oxalate and calcium phosphate stones. She endorsed polyuria, polydipsia, constipation and low mood. Medications were reviewed and she had not been on any agents known to cause hypercalcemia. 25 Hydroxyvitamin D was low at 20 ng/ml (30 -100) and appropriately 24 hour urine calcium was low - suppressed at 157 mg (100 - 300). The Sestamibi scan did not show an adenoma. A parathyroid ultrasound showed a possible hypoechoic area bilaterally in the parathyroid region. She underwent parathyroid exploration with excision of right superior parathyroid adenoma. Pathology report showed hypercellular parathyroid tissue consistent with a parathyroid adenoma. Post operatively, calcium and PTH value normalized.

Discussion

Primary hyperparathyroidism is associated with nephrolithiasis and nephrocalcinosis. Nephrolithiasis is an indication for surgical intervention. Our patient had the classic signs of primary hyperparathyroidism for at least a decade; however, it was not diagnosed until she presented with urosepsis and ended up in the ICU. Primary hyperparathyroidism is often thought of as a disease commonly seen in the outpatient setting. However, a high radar of suspicion must be maintained in both inpatient and outpatient settings as this disorder, when left untreated can have dangerous consequences. Similarly, in patients presenting with nephrolithiasis, a thorough history and physical examination in addition to a complete review of systems and medication review must be carried out to effectively rule out primary hyperparathyroidism.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
ODP057 The Unusual Case of Hypercortisolism in a Patient with Juvenile Onset Hypophosphatasia
Authors: Maler Neal , Idriss Almoatazbellah
Published: November 2022

Juvenile onset hypophosphatasia is a rare, genetic disease that is caused by inactivating mutations in the ALPL gene which encodes tissue non-specific alkaline phosphatase (TNSALP). This leads to decreased activity of the TNSALP enzyme in target tissues and accumulation of TNSALP substrates, including inorganic pyrophosphate, an inhibitor of mineralization. This disease is characterized by low levels of alkaline phosphatase in serum and bone, osteomalacia, and periodontal disease. Patients with juvenile onset hypophosphatasia present with premature loss of primary teeth, delayed walking, and a waddling gait. These symptoms may improve spontaneously after puberty and recur later in life. Here we report the case of a 51 year old male who presented initially to endocrinology clinic with a metatarsal stress fracture with subsequent diagnosis of osteoporosis, periodontal infections, and associated myopathy and joint calcifications. The patient also had a prior history of a low alkaline phosphatase level as a child. Genetic testing showed a single variant of undetermined significance found in the ALPA gene. Of note, recent lab work for the patient showed AM cortisol 27.7 mcg/dL (reference range 4. 0-22. 0 mcg/dL) with ACTH 60 pg/mL (reference range 6 - 50 pg/mL). Prior 24 hour urine free cortisol measurements with LC/MS have demonstrated elevated values 159 mcg/24 hr and 256 mcg/24 hr (reference range 4. 0 - 50. 0 mcg/24 hr) . However, most recent testing demonstrated 24 hour urine free cortisol 3.6 mcg/24 hr, and the majority of midnight salivary cortisol tests were within normal. Pituitary MRI demonstrated no abnormalities. The patient has in the past reported findings of a dorsocervical fat pad, abdominal striae, and weight gain. There is no history of diabetes mellitus or hypertension, and the patient at this time reports stable weight without current presence of a fat pad or striae. There are no clinical features of Cushing's syndrome on exam. To our knowledge, this is the second case in the literature detailing hypercortisolism in a patient with hypophosphatasia. The etiology of the hypercortisolism is likely multifactorial, with unknown association with hypophosphatasia. Based on the clinical data it appears that the patient's chronic stress, pain, and anxiety are contributing to the hypercortisolism, and that this is not a true Cushing's or cyclical Cushing's case. Repeated midnight salivary cortisol tests have excluded the possibility of Cushing's as well.

Presentation: No date and time listed
ODP428 The Effects of Asprosin Pubertal Maturation in Female Rats
Authors: OZ Zeynep Dila , Ozdede Mehmet Ridvan , Kocoglu Samet Ramazan , Gok Gulendam , Ozgen Aslisah , Horoz Mert Ali , Yasar Abdullah , Kacar Emine , Serhatlioglu Ihsan , Yilmaz Bayram , Kelestimur Haluk
Published: November 2022

Adipokines play an important role in sexual maturation and reproduction in a variety of ways. The central Asprosin administration of asprosin, a new adipokine secreted by white adipose tissue, has been found to have the potential to stimulatory effects influence on the hypothalamus-pituitary-gonadal axis (HPG)pubertal maturation in male rats. However, there is no study on the effects of asprosin on the HPG axis. Interestingly, peri-ovarian adipose tissues, which surround the ovaries and perform both autocrine and paracrine functions, suggest that asprosin may have a role in ovarian function. Asprosin has been also shown to cross the blood-brain barrier. However, the effects of asprosin, a novel adipokine, are not fully defined on the hypothalamus-pituitary-gonadal axis at the peripheral levels. The aim of the research study aims is to see how asprosin affects pubertal maturation in female rats when it is given parentally. For the experimental studies, totally a total of 24 female Sprague-Dawley rats, 21 days old and 35 ± 2 g weight, were used and randomly divided into two groups as control and asprosin groups (n=12). Asprosin (500 ng/kg) was given intraperitoneally daily in the animals in the asprosin group from postnatal day 21 for about 8 weeks. Similarly, the control group received only saline. For determining the puberty onset, vaginal opening (complete canalization of the vagina, an external index of puberty onset) was monitored daily in rats. Vaginal smears were performed daily from the date of puberty onset to determine the day of the first estrus. The ELISA method is used to analyze hormones in blood samples. Asprosin administration did not affect the onset of puberty or pubertal weight compared to the control group (p>0. 05). The first day of estrus in female rats administered with asprosin was shown to be significantly earlier than control rats (p<0. 05). Asprosin administration significantly increased the levels of FSH, oxytocin, and estradiol in the blood(p<0. 05). It significantly decreased inhibin B level (p<0. 05). There was no significant difference in LH level (p>0. 05). In conclusion, our findings suggest that asprosin may have stimulatory effects on pubertal maturation of the reproductive system in female rats. However, we believe that more research is needed to determine the mechanism by which asprosin affects the pubertal maturation of the reproductive system. This study was supported by TUBITAK (Project# 220S744).

Presentation: No date and time listed
ODP060 Treatment of Aldosterone-producing adenoma by CT-guided radiofrequency ablation in a high surgical risk patient: biochemical and clinical outcomes.
Authors: Lafranchi Andre , Filho Gilmar Tostes , Ravizzini Pedro Ivo , da Cunha Scalco Tirapelli Renata , Bueno Cristina Belotti Formiga , Scalissi Nilza Maria , Junior Jose Viana Lima
Published: November 2022

Background

Primary aldosteronism (PA) is a leading cause of secondary hypertension and harness a much higher cardiovascular risk than essential hypertension. About 30% of PA cases are due the existence of an aldosterone-producing adenoma (APA). Although the current guidelines recommend unilateral laparoscopic adrenalectomy as the standard treatment of APA, some patients might no be suited for the procedure.

Clinical Case

A 66-year man was referred to our institution following a 14-year history of resistant hypertension. His past history included a stage III chronic kidney disease, type 2 diabetes mellitus, dyslipidemia, obstructive sleep apnea (OSA), hypothyroidism, grade I obesity, and rheumatoid arthritis. Initial tests were consistent with PA: elevated serum aldosterone (26 ng/dL), suppressed plasma renin activity (PRA: 0. 07 ng/ml/H) and a high aldosterone/renin ratio (RAR: 65) with concomitant hypokalemia (3,4 mEq/L). Abdominal CT-scan demonstrated a 11×8 mm left adrenal nodule with an absolute washout of 60%. A diagnosis of an APA was confirmed by an adrenal vein sampling. Since the patient had multiple comorbidities and an unequivocal high surgical risk, laparoscopic adrenalectomy was contraindicated, and pharmacologic treatment was started with spironolactone. Despite the use of high doses of spironolactone, blood pressure (BP) control was not achieved. Moreover, severe side effects were experienced, notably sexual dysfunction and painful gynecomastia. In this setting, a decision for a CT-guided radiofrequency ablation was made. The procedure underwent under general anesthesia and had no adverse events. Three days after the ablation, biochemical analysis demonstrated a significant reduction of aldosterone (10 ng/dL) and RAR (10), whereas the PRA was notably higher (1,45 ng/mL/h). He transitioned from 6 different classes of anti-hypertensives drugs to only one and his blood pressure was well controlled in an appointment 30 days after the procedure. On the other hand, his glomerular filtration rate had decayed from 44 mL/min to 31 mL/h due to a rapid blood pressure control. Despite no changes in anthropometric measures and OSA related symptoms were observed, an expressive reduction in microalbuminuria (191 mg/dL to 28,6 mg/dL) was noticed.

Conclusion

The CT-guided radiofrequency ablation is a suitable minimally invasive treatment for PA in high surgical risk patients. For patients with high surgical risk and intolerance to clinical treatment, radiofrequency should be offered as an option for treatment in a specialized center.

Presentation: No date and time listed
ODP600 Is this a case of surreptitious hormonal supplements?
Authors: Rimal Priya , Musurakis Clio , Gilden Janice
Published: November 2022

Background

Hypogonadism in males results when there is either a failure of the testes to produce testosterone, hypothalamic or pituitary dysfunction. Although testosterone supplementation is used for documented hypogonadism, it has become widely abused, with a variety of false claims for promoting energy, virility, and muscular development, as well as enhanced athletic performance. We present a case of surreptitious abuse.

Clinical Case

A 63-year-old male with coronary artery disease, was initially consulted to endocrinology for evaluation of Graves’ disease with ophthalmopathy. He was treated with methimazole 5 mg daily. However, on subsequent visits, he requested measurement of testosterone levels. Laboratory tests showed FSH<0.2 mIU/ml (0.7-10.8); LH<0.2 mIU/ml; free testosterone 3050 pg/ml (35-155); total testosterone 7377 ng/DL (250-1100); prolactin 9.6 ng/ml; Hgb 14.7 g/dL (13. -17); HCT 45.5% (40-51); TSH 1.94 uIU/ml (0.358-3,74); Free T4 0.74 ng/dL (0.76-1.46); Free T3 2.60 pg/ml (2.82-3.98). When confronted with these values, he admitted that due to interest in building muscle mass and energy, for lifting weights, he was taking hormone and protein supplements ordered from an internet program. These therapies were claimed to enhance muscle mass and energy, increase testosterone and lower estrogen. He did not have blood tests for over 6 months, and it was not clear who monitored this plan. He was taking testosterone 400 mg injections of testosterone cypionate and proprionate twice weekly, as well as another form of oral testosterone, which amounted to more than double the total dose required to treat hypogonadism in 1 week. He was counseled about the risks of taking excess testosterone, for which he had no prior knowledge (including CAD, cardiomyopathy, erythrocytosis, coagulation abnormalities, major mood disorder, gynecomastia, increased risk for prostate cancer), and also that it is unclear whether he even had hypogonadism. He agreed to stop taking these supplements. Four months later, he reported slightly less energy, but he was not exercising due to back pain, and no other changes. Laboratory tests: Total testosterone 572 ng/dL, Free Testosterone 74.6, LH 3. 0 mIU/ml; FSH =3.4 mIu/ml (8-10.8).

Discussion and Conclusion

Although hyperthyroidism can cause an increase in total testosterone via an increase in hepatic synthesis of SHBG, the free level is normal. Abnormally high testosterone levels in men are most commonly due to anabolic steroids taken to increase muscle mass and enhance athletic performance. It is also important to evaluate for other causes, such as adrenal or testicular tumors. This case is an example of a patient innocently taking unregulated and hazardous hormonal supplements for false claims, which may result in abnormal hormonal laboratory results, and lead to unnecessary and expensive evaluations. Therefore, it is important to take a good medication history, and to query abnormal lab results at each outpatient visit.

Presentation: No date and time listed
RF10 | PMON216 Aromatase Inhibition Fails to Exaggerate Weight Gain and Induce Bone Loss in Ovariectomized Female Marmosets
Authors: Willging Molly , Kraynak Marissa , Kuehlmann Alex , Kapoor Amita , Flowers Matthew , Colman Ricki , Levine Jon , Abbott David
Published: November 2022

Declining serum estradiol (E2) levels during the menopausal transition are associated with increased central adiposity and heightened risk for metabolic disease. Ovarian estradiol, E2, supports female metabolic function. While ovariectomy (OVX) in rodents enables obesity, OVX in nonhuman primates (NHPs) inconsistently alters weight gain. We therefore hypothesized that in female NHPs, extra-ovarian E2 provides key support for metabolic homeostasis. To test this, we employed aromatase inhibition to eliminate extra-ovarian E2 biosynthesis together with diet-induced obesity (DIO) to enhance weight gain. Thirteen adult female marmoset monkeys were OVX and received: (1) E2-containing capsules and daily oral treatments of vehicle (E2; n=5); empty capsules and daily oral treatments of either vehicle (VEH, 1ml vehicle/kg, n=4), or (3) letrozole (LET, 1 mg/kg in 1ml vehicle/kg, n=4). After 6-7 months, VEH and LET compared to E2 females demonstrated increased % body weight gain (p=0.01) and increased caloric intake VEH (p<0.001) and LET (p<0.001) corrected for fat-free mass. Dual energy x-ray absorptiometry (DXA)-determined body composition at 6 months showed no between female group differences in total fat mass or fat mass in validated body regions of interest. Total body (p=0.014), abdominal region (p=0.002) and upper leg region (p=0.025) DXA-determined fat free mass, however, increased ∼5-10% in all female groups. In addition, lumbar spine and total body DXA-determined bone mineral density (BMD) and bone mineral content (BMC) were comparable across all female groups. Relative circulating E2 levels were E2>>>VEH>LET, while those in hypothalamus ranked E2=VEH>LET, confirming aromatase inhibition of local hypothalamic E2 in LET females. Our findings demonstrate ovarian E2 and extra-ovarian E2 depletion induce comparable increases in DIO weight gain without bone loss in female marmoset monkeys and highlight E2 as a key regulator of female metabolic homeostasis in NHPs.

Presentation: Saturday, June 11, 2022 1:48 p.m. - 1:53 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
ODP438 Canonical and Non-canonical Function of EZH2 in Progesterone Receptor Target Genes in Breast Cancer
Authors: Elizalde Patricia , Belmonte Martina , Cenciarini Mauro , Deamicis Agustina Roldan , Madera Santiago , Mercogliano Florencia , Mauro Florencia , Bruni Sofia , Russo Rosalía Cordo , Schillaci Roxana , Proietti Cecilia
Published: November 2022

Enhancer of Zeste homolog 2 (EZH2) is a histone methyltransferase which catalyzes the trimethylation of lysine 27 of histone H3 (H3K27me3), an epigenetic mark associated with chromatin compaction and transcriptional repression of target genes. This constitutes its canonical mechanism of action. Several studies have shown that EZH2 is able to activate gene transcription by forming transcriptional complexes through mechanisms that do not involve histone methylation. Indeed, EZH2 can also act in a non-canonical function by regulating transcription independently of its enzymatic activity. We have previously described that progestins induce the interaction between Progesterone Receptor (PR) and EZH2 in breast cancer (BC) cells, which results in the downregulation of tumor suppressor GATA3 and in the increase in cell proliferation. Since EZH2 has been implicated in the progression of several types of cancer, including those of the breast, and our own previous results indicate that EZH2 is required for progestin-induced breast cancer growth, we hypothesized that EZH2 could function as a mediator in the pro-tumorigenic effects of progestins, targeting specific tumor suppressor and differentiating genes to allow ER/PR-positive BC growth. In the present work we found that progestin treatment of T47D cells induced EZH2 mRNA and protein expression, which was abolished by the use of the progestin antagonist RU486 and when PR expression was blocked by siRNAs. We also studied the participation of EZH2 in the regulation of PR-regulated genes TNFalpha (TNFα), cyclin D1 and TIMP2. By ELISA assays, we observed that progestin treatment of T47D cells for 24 h induced TNFα secretion. This effect was abolished when EZH2 expression was inhibited in the presence of EZH2 siRNAs and when EZH2 enzymatic activity was blocked by the use of GSK126. Regarding TIMP2, we observed that EZH2 canonical activity participates in TIMP2 downregulation exerted by progestin treatment. We showed that EZH2 non-canonical function is also involved in progestin modulation of TIMP2 given that blockage of EZH2 activity did not completely revert progestin effect. Finally, we demonstrated that progestin upregulation of cyclin D1 did not require EZH2 activity. Our results prove that EZH2 engagement in PR target genes may involve its canonical or non-canonical function and therefore support further studies on other progestin-regulated cancer genes implicated in tumor growth.

Presentation: No date and time listed
ODP651 Abnormal Primary Ciliogenesis in the Developing Mouse Kidney of Glucocorticoid Receptor-Deficient Mice
Authors: Cole Timothy , Lao Jianshen , Ng Judy , Short Kelly
Published: November 2022

Glucocorticoid (GC) hormones have well characterised regulatory roles for the development and maturation of several fetal organs, however, specific developmental roles of GCs in the fetal kidney have not been described (1). We have explored both the expression and localisation of the glucocorticoid receptor (GR) within the developing fetal mouse kidney during organogenesis and the effect on the transcriptome of eliminating GR expression in gene-targeted GR-deficient mice. Staining for the GR by immunohistochemistry at E14.5, E16.5 and E18.5 demonstrated widespread expression of the GR in the renal tubule and the interstitial renal mesenchyme, with strong staining in collecting ducts and increasing expression in mesenchyme up to E18.5. Loss of GR expression in GR-null mice had a profound effect on the renal transcriptome with altered expression (at an FDR of 0.5 and fold change >2. 0) for 454 genes in the GR-null mouse kidney at E18.5, with a greater number of genes showing significantly reduced mRNA levels (305) than increased mRNA levels (99) relative to wild-type controls. Interestingly these deregulated genes included key primary cilia-associated genes, such as centrosomal protein 290 (Cep290), with the largest fold change of -3.6, Cep97, Ccp110, and the primary cilia-associated kinesin Kif3A. In addition, two renal tubule markers, Kidney androgen regulated protein (Kap) (proximal tubule marker) and S100 calcium binding protein G (S100g) (distal tubule marker) were also strongly downregulated with fold changes of -8.61 and -2.5 respectively. Analysis of primary cilia in sections of E18.5 kidney using multicolour confocal microscopy demonstrated that primary cilium length was significantly decreased and abnormally projected from kidney proximal tubule cells in E18.5 GR-null mice (5.23 + 0.12, µm + SEM) compared with wild type controls (6.27+ 0.15, µm + SEM). Finally, in cultured IMCD3 mouse collecting duct cells dexamethasone treatment was shown to increase the length of primary cilia compared to vehicle-treated control cells (vehicle 2.49 + 0. 03, µm + SEM vs dexamethasone 3.17 + 0. 05 µm + SEM), an effect that could be blocked by pre-treatment with the GR antagonist RU486. Taken together these results indicate that GC signalling mediated via the GR contributes either directly or indirectly to the normal formation of primary cilia in the proximal tubule and is therefore required for normal kidney development. This also suggests that abnormalities in GR-regulation of ciliogenesis may underpin or contribute to causes of human ciliopathy conditions. 1. Cole TJ, Short KL, Hooper SB (2019) The Science of Steroids. Sem. Fetal and Neonatal Med. 24: 170-175.

Presentation: No date and time listed
OR07-4 Regulation of Mineralocorticoid Receptor Transactivation By Circadian Protein Timeless
Authors: Young Morag
Published: November 2022

The mineralocorticoid receptor (MR) is a ligand activated transcription factor that plays an important role in cardiovascular physiology and disease. MR transactivation is regulated by ligand-dependent conformational change in the MR and recruitment of coregulator binding partners to form a unique DNA-binding complex at the hormone response element in target gene promoters. Differences in the recruitment of coregulatory proteins can promote tissue-, ligand- or gene-specific transcriptional outputs. The goal of this study was to evaluate a candidate MR coregulator, the circadian gene timeless for ligand and cell-selective regulation of MR transactivation. While timeless is not essential for mammalian clock function and does not bind DNA, timeless RNA and protein levels oscillate over 24hr. Co-expression of timeless dose-dependently down-regulated MR transactivation of an MR-responsive reporter in HEK293 cells, yet enhanced transactivation mediated by other steroid receptors. Timeless also inhibited MR transactivation of synthetic and native gene promoters, and expression of endogenous MR target genes, in H9c2 cardiac myoblasts. Immunofluorescence staining of timeless, and MR showed colocalization to the nucleus in the presence of aldosterone and co-immunoprecipitation which suggested an interaction, although a direct interaction was not confirmed. Taken together, these data suggest timeless is a novel MR coregulatory protein that may contribute to time-of-day-dependent MR transcriptional outputs and suggest new opportunities for the development of MR antagonists with selective actions.

Presentation: Saturday, June 11, 2022 12:15 p.m. - 12:30 p.m.
RF03 | PMON289 KLF4 drives estrogen driven tumor heterogeneity in breast cancer
Authors: Mohammed Hisham , Wen Yahong
Published: November 2022

Whilst hormonal therapies have proved effective in targeting ER positive breast cancer, intrinsic and acquired resistance to therapy has meant that the disease remains deadly. To identify potential drivers of transcriptional and epigenetic heterogeneity in breast cancer, we performed detailed single-cell multi-ome experiments +/- estrogen stimulation. Our results identified that the transcription factor KLF4 is highly associated with heterogeneity in our experimental models. KLF4 is one of four Yamanaka pluripotency factors that can reprogram cells to a stem like state and is also a pioneer factor, that possesses the ability to bind to condensed chromatin. Silencing of KLF4 significantly reduced transcriptional heterogeneity in multiple models. Importantly, we also found that KLF4 acts as a pioneer factor for ER. ER binding, transcriptional activity and chromatin accessibility at ER binding sites were lost upon KLF4 silencing. Using proteomics based interactome profiling, we find multiple other signaling pathway rely on KLF4. Together, our results suggest that KLF4 maintains plasticity in ER+ breast cancer cells and also functions as a pivotal factor for ER to function.

Presentation: Saturday, June 11, 2022 1:36 p.m. - 1:41 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
RF15 | PMON294 Disrupting a Key H-bond Network Drives Glucocorticoid Receptor Gene Suppression Without Off-target Gene Activation for Duchenne Muscular Dystrophy Treatment
Authors: Liu Xu , Hoffman Eric , Ortlund Eric
Published: November 2022

Duchenne muscular dystrophy is a genetic disorder that shows chronic and progressive damage to skeletal and cardiac muscle leading to premature death. Anti-inflammatory corticosteroids targeting the glucocorticoid receptor (GR) are the current standard of care but drive adverse side effects such as deleterious bone loss. Through subtle modification to a steroidal backbone, a recently developed drug, vamorolone, appears to preserve beneficial efficacy but with significantly reduced side effects. We use combined structural, biophysical, and biochemical approaches to show that loss of a receptor-ligand hydrogen bond drives these remarkable therapeutic effects. Moreover, vamorolone uniformly weakens coactivator associations but not corepressor associations, implicating partial agonism as the main driver of its dissociative properties. Additionally, we identify a critical and evolutionarily conserved intramolecular network connecting the ligand to the coregulator binding surface. Interruption of this allosteric network by vamorolone selectively reduces GR-driven transactivation while leaving transrepression intact. Our results establish a mechanistic understanding of how vamorolone reduces side effects, guiding the future design of partial agonists as selective GR modulators with an improved therapeutic index.

Presentation: Sunday, June 12, 2022 1:00 p.m. - 1:05 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
ODP472 Creation of the Anaplastic Care Team (ACT) protocol: Establishing a Benchmark for Timely Access to Care for Anaplastic Thyroid Cancer Patients
Authors: Pulipati Priyanjali , Chitagi Pritha
Published: November 2022

Introduction

Novel Coronavirus 19 (COVID19) has been shown to involve multiple organs. Its reported effects on the endocrine system have been via subacute thyroiditis, functional hypopituitarism, and triggering type 1 diabetes with ketosis. We describe a case of COVID19 infection presenting as adrenal insufficiency.

Case

A 35-year-old female with a history of developmental delay, anxiety, and hypothyroidism presented to the emergency department (ED) from her group home with complaints of abdominal pain and 2-3 episodes of nausea and vomiting per day for one week. She denied any changes in bowel habits, chest pain, shortness of breath. On physical examination, there was mild diffuse abdominal tenderness without any skin hyperpigmentation. In the ED, her vitals showed blood pressure 99/56, heart rate 94, respiratory rate 23, saturating at 100% on room air. Laboratory tests were remarkable for hyponatremia (sodium 123), hypokalemia (potassium 1.9), hypochloremia (chloride 88), hypophosphatemia (phosphorus 2), metabolic acidosis with bicarbonate of 14. Her COVID19 test was positive. She was admitted to the intensive care unit as her blood pressure continued to drop to as low as 76/37. Potassium, phosphorus was replaced, and normal saline infusion was started at 75ml/hr with minimal improvement in blood pressure to 94/53 and sodium to 126 in 24 hours. Urine electrolytes showed sodium <15, making SIADH less likely. On day 3, we suspected adrenal insufficiency due to persistent hypotension. Results showed am cortisol of 1 and ACTH of 10. ACTH stimulation test was unable to be done. She was started on hydrocortisone which improved her blood pressure as well as electrolytes. CT abdomen showed no adrenal abnormality. She was able to be tapered off the steroids in 2 weeks.

Conclusion

COVID19 associated hypocortisolism presents both as primary and transient secondary adrenal insufficiency (via suppression of the hypothalamic-pituitary-adrenal axis, like in our case). Similar reversible hypocortisolism post-SARS infection was observed in 24 of 61 patients (39.3%) during the 2005 outbreak. Autopsy studies on patients with COVID19 showed adrenal necroptosis of the adrenal cortex. Although critical illness-related cortical insufficiency is not a new concept, the cortisol levels in COVID19 critically ill patients have been shown to be lower than non-COVID19 critically ill patients. Prompt addition of stress dose steroids can be lifesaving in critically ill COVID patients, especially when associated with resistant hypotension.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
LBODP095 Radiofrequency Ablation Performed By Endocrinologists Is A Viable Treatment Option For Recurrent Thyroid Cancer In The Outpatient Community Setting In The United States
Authors: Ahmad Shahzad , Aljammal Jules , Orozco Ian James , Nikravan Sean P , Zulfiqar Fizza , Raashid Sheharyar , Hussain Iram
Published: November 2022

Objective

To determine if radiofrequency ablation (RFA) performed by endocrinologists for recurrent thyroid cancer in the neck is a treatment option in the outpatient community setting in the USA.

Methods

A review of 9 patients with 12 recurrent thyroid cancer lesions in the neck who were treated with RFA was conducted (July 2020 to November 2021). Recurrence was defined as biochemical and structural identification of disease. Recurrence was confirmed with ultrasound guided fine needle aspiration (US-FNA) cytology and measurement of thyroglobulin (Tg) washout concentration in cases of papillary thyroid cancer (PTC) and calcitonin washout concentration in medullary thyroid cancer (MTC). Informed consent was obtained. RFA was done in the outpatient setting with standard aseptic techniques, conscious sedation, and local anesthesia. Real time US imaging was used to perform hydro-dissection and a limited "moving shot" technique with a medial to lateral approach. Node volume in mL (length x depth x width×0.525) and tumor markers were recorded before at 6 to 12 weeks and at 6 months (m) after RFA. The volume reduction percentage (VRP) for each nodule was calculated using the following equation: VRP = {[baseline volume in mL - final volume in mL]/baseline volume in mL}×100 A VRP of more than 50% was considered a significant response, and VRP of 100% was considered complete response.

Results

A total of 9 patients with 12 nodes were included in the study. 7 patients had nodal recurrence of PTC in the neck. RFA was recommended for 1 patient as palliative treatment while on treatment with chemotherapy. 1 patient had recurrent MTC. There were no serious complications. 6 m data was unavailable for 2 patients. 9 of 10 (90%) nodes for which data is available had a volume decrease of at least 50% at 6 m. The only patient without at least a partial response to therapy was on chemotherapy. 4 of the 10 (40%) metastatic nodes of papillary thyroid cancer had a complete response. Mean volume reduction for all lesions at 6 mos was 0.339 mL, P = 0. 012. Median change in Tg level at 6 months was 0.4 IU/ml with a downward trend in 4/5 (80%) of patients with recurrent papillary thyroid cancer who were not receiving chemotherapy.

Discussion

Complete response may be expected in about 40% of patients after RFA at 6 m, however, this may potentially be improved with extended follow up time or multiple RFA sessions. Patients who are not surgical candidates, refuse surgery, or require palliative treatment may be potential candidates for this procedure. Therefore, RFA appears to be a viable treatment option in selected patients with recurrent thyroid carcinoma.

Presentation: No date and time listed
LBODP097 Malignant Struma Ovarii: Long Term Successful Treatment. Outcome
Authors: Mandal Kaushik , Liao Huijuan , Ashorobi Damilola , Kumar Salini Chellappan , Rosenthal David S
Published: November 2022

18 year old African American female saw her GYN in 9/2008 for abdominal pain. CT: bilateral adnexal masses (10×8 cm left; 6.3×3.1 cm right). Surgical pathology reported a left benign cystic teratoma and right corpus luteum cyst. Pain recurred in 2010. MRI showed: 9×7.5×4 cm right adnexal mass. Repeat surgery was done. Pathology: benign cystic teratoma with focal thyroid tissue - "Struma Ovarii". Abdominal pain recurred yet again in 2012. Sonography revealed a mixed solid/cystic pelvic mass measuring 10.6×7.9×7.6 cm. Exploratory laparotomy 9/2012 revealed a right adnexal mass and widespread peritoneal nodules. Pathology reported follicular tissue with colloid in the nodules - "Peritoneal Strumatosis" suggesting benignity. Upon further review was reclassified as metastatic well differentiated follicular thyroid cancer of ovarian origin with follicular thyroid tissue identified in peritoneal lymph nodes, spleen, bladder and rectal wall. The patient was then referred to endocrinology at our facility. On exam she was clinically euthyroid without thyromegaly or nodularity. Thyroid hormone levels were normal. Antithyroid antibodies were absent. Serum Thyroglobulin (Tg): elevated (229; normal 2-35 ng/ml) as was CA125 (64; normal <21 U/ml). Immunohistochemistry: positive for Tg and Thyroid transcription factor-1. Molecular markers: no mutations in BRAF, RAS, or TP53. In preparation for radioactive iodine (RAI) therapy, total thyroidectomy was performed 4/13/2013 and reported as normal thyroid tissue. Dosimetry findings: very iodine avid tissue with prolonged retention (33% at 6 days). Maximum tolerated dose: 200 mCi. A 62.8 mCi RAI was administered 7/13/2013. Post RAI whole body scan (WBS): numerous focal areas of increased uptake in abdomen and pelvis consistent with metastatic disease. Treatment with L-thyroxine was given to suppress TSH. Follow up WBS 12/26/2013 showed persistent increased uptake in abdomen and pelvis. Serum Tg was high (198. 0). A second RAI dose of 104.8 mCi was given. Post RAI WBS confirmed multiple areas of metastatic disease in abdomen and pelvis. Subsequent serum Tg levels down trended. WBS 11/12/2014: only two residual abnormal foci in the lower neck and one inferior to the liver without abdominal or pelvic foci. Given the dosimetry issue and the reassuring serum Tg levels, surveillance was continued. WBS 9/25/2015: unchanged. Now age 27, WBS 1/26/2022: only residual faint lower neck uptake, resolution of the focus inferior to the liver and no distant foci. Stimulated Tg was normal at 2.2 ng/ml with stimulated TSH >110. 0 uIU/ml.

Presentation: No date and time listed