bluuebunny/crossref_metadata_2025 huggingface dataset:
MON-645 Association of Baseline Cardio-Metabolic Parameters on the Treatment Effects of Empagliflozin When Added to Metformin in Patients with T2D
Authors: Inzucchi Silvio E , Davies Melanie , Khunti Kamlesh , Trivedi Prabhav , George Jyothis T , Zwiener Isabella , Johansen Odd Erik , Sattar Naveed
Published: May 2020

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are commonly used as 2nd-line therapy after metformin (MET) in patients with type 2 diabetes (T2D), and are now recommended in those with co-existing cardiovascular (CV) and/or chronic kidney disease (CKD). A better understanding of their clinical efficacy across the spectrum of cardio-metabolic characteristics may help to better individualize therapy. It was previously reported (Häring et al., Diabetes Care 2014) that empagliflozin (EMPA) 10 and 25 mg over 24 weeks vs placebo (PLB), when added to MET, led to clinically meaningful improvements in HbA1c, body weight (BW), and systolic blood pressure (SBP).

We explored the magnitude of these effects across categories of baseline (BL) HbA1c, BW, and SBP, comparing EMPA 10 mg (n=217) and 25 mg (n=213) vs PLB (n=207) in the following subgroups: HbA1c <8.5% and ≥8.5%; BW ≤70, 70-≤80, 80-≤90, and >90 kg; and SBP <120, 120-<140, and ≥140 mmHg. Analyses were performed for all randomized patients receiving ≥1 dose of study drug. Differences between treatment groups were assessed using ANCOVA and interaction tests (by respective BL factor and treatment-assignment). At week 24, EMPA 10 mg and 25 mg significantly (p<0.0001) reduced HbA1c vs PLB; the difference from PLB in adjusted mean [±SE] change was greater in the ≥8.5% vs <8.5% subgroup (EMPA 10 mg: -0.73 [±0.14]% vs -0.51 [±0.08]%, respectively; EMPA 25 mg: -0.97 [0.15]% vs -0.52 [0.08]%, respectively; interaction p: 0.029). EMPA also significantly (p<0.05) decreased BW vs PLB, with a trend for larger reductions in those with the highest BW at BL (EMPA 10/25 mg: -1.31 [±0.42]/-1.70 [±0.44], -1.23 [±0.53]/-0.74 [±0.54], -2.12 [±0.60]/-2.56 [±0.56] and -2.11 [±0.46]/-2.93 [±0.47] for ≤70, 70-≤80, 80-≤90, and >90 kg, respectively; interaction p: 0.075). Finally, EMPA significantly (p<0.05) lowered SBP vs PLB, but, in contrast, without significant differences across SBP categories (EMPA 10/25 mg: SBP <120 mg, -4.17 [±2.07]/-2.71 [±2.15]; SBP 120-<140, -4.35 [±1.48]/-4.98 [±1.49]; SBP ≥140, -4.28 [±2.38]/-6.29 [±2.33] mmHg; interaction p: 0.784). The number of patients reporting ≥1 adverse event (AE) was similar across treatment groups (PLB, 58.7%; EMPA 10 mg, 57.1%; EMPA 25 mg, 49.5%) and the AE profile was consistent with the drug’s established safety profile. Confirmed hypoglycemic AEs were reported in 0.5%, 1.8%, and 1.4% of patients, respectively.

These data suggest that EMPA, when used as 2nd-line therapy after MET, is more effective in decreasing HbA1c and reducing BW in those with higher baseline values of these parameters but not for SBP. In addition to EMPA being a glucose-lowering agent recommended in patients with co-existing CVD and/or CKD, these data may help to tailor therapy as regards to important metabolic efficacy considerations.
SAT-351 A Novel Mutation in the Calcium-Sensing Receptor Gene Presenting in a Kindred as Autosomal Dominant Familial Hypocalciuric Hypercalcemia
Authors: Bushman Jordan , Banka Ajaz
Published: May 2020

Rationale: Familial hypocalciuric hypercalcemia (FHH) is a benign cause of hypercalcemia. The majority of cases result from an inactivating mutation in the calcium-sensing receptor (CaSR). While affected patients are usually asymptomatic and require no treatment, this condition may go unrecognized and inappropriate parathyroidectomy for presumed primary hyperparathyroidism could be performed. Over 130 mutations in the CaSR gene have been reported and novel variants continue to emerge.

Methods: The initial patient was a 49 year-old female who presented with mild hypercalcemia, elevated PTH and undetectable urine calcium. She reported several of her family members had elevated calcium levels. Given high clinical suspicion for FHH genetic analysis was performed.

Results: Sequencing of the CaSR gene revealed a point mutation at c.1744T>A which resulted in p.Cys582Ser in exon 7. This cystine residue is highly conserved and predictive algorithms suggest this variant is likely disruptive leading to heterozygous loss of function in the CaSR. The patient’s 26 year-old daughter was tested and found to have the same mutation.

Conclusion: We report the identification of a novel heterozygous mutation in the CaSR gene manifesting as FHH in a family of Iraqi decent. Additional family members are currently undergoing genetic analysis which will be included at the time of presentation.
MON-034 Impact of Race and Obstructive Sleep Apnea on Glucose and Insulin Regulation in Women with PCOS
Authors: Temple Karla A , Mokhlesi Babak , Carter Jason R , Whitmore Harry , Van Cauter Eve , Ehrmann David A
Published: May 2020

The prevalence of prediabetes and diabetes is substantially higher in PCOS women with obstructive sleep apnea (OSA) compared to PCOS women without OSA1,2,3. Prior studies, however, did not examine the complex interaction between race and OSA on metabolic function in PCOS. We sought to determine if the impact of OSA on glucose and insulin metabolism is affected by race. We studied non-Hispanic white (NHW) (n=53) and African-American (AA) (n=48) women with PCOS. Following an overnight polysomnogram (PSG), PCOS women (NHW without OSA n=40; NHW with OSA n=13; AA without OSA n=36; AA with OSA n=12) had a 2-h 75-g oral glucose tolerance test (OGTT) with blood sampling every 30 minutes for measurement of glucose, insulin, and C-peptide concentrations. OSA severity was measured by the Apnea-Hypopnea Index (AHI). Only women without OSA (AHI < 5) or with moderate-to-severe OSA (AHI > 15) were included in these analyses; women with mild OSA were excluded. Insulin secretion rates (ISR) during the OGTT were derived by deconvolution of C-peptide levels 4. Area under the curve (AUC) response to the glucose challenge was calculated using the trapezoidal method. BMI and age did not differ between races in PCOS women without OSA (BMI [kg/m2]: 36.3±1.2 vs. 37.2±1.1, p=0.58; Age [yr]: 27.7±0.8 vs. 27.2±0.8, p=0.65; for NHW and AA respectively), or in PCOS women with OSA (BMI [kg/m2]: 42.8±1.7 vs. 44.7±2.0, p=0.50; Age [yr]: 31.4±1.6 vs. 28.6±1.6, p=0.18; for NHW and AA respectively). OSA severity was similar in NHW and AA PCOS women without OSA (AHI: 1.5±0.2 vs 2.1±0.2, p=0.076), and PCOS women with OSA (AHI: 32.0±4.9 vs. 28.3±4.4, p=0.26). Higher glucose responses during the OGTT were observed in NHW PCOS women with OSA compared to both NHW (AUC: 18,965±648 vs. 15,797±371, p=0.0004) and AA (AUC: 18,965±648 vs. 15,801±497, p=0.0005) PCOS women without OSA. Glucose responses did not differ significantly between AA PCOS women with OSA and AA PCOS women without OSA (AUC: 17,104±965 vs. 15,801±497, p=0.15). Similarly, ISR was higher in NHW PCOS women with OSA compared to both NHW (AUC: 5,648±488 vs. 3,907±231, p=0.0006) and AA (AUC: 5,648±488 vs. 3,981±235, p=0.0011) PCOS women without OSA. ISR did not differ significantly between AA PCOS women with OSA and AA PCOS women without OSA (AUC: 4,827±461 vs. 3,981±235, p=0.09). CONCLUSIONS: OSA has a greater impact on glucose and ISR during an oral glucose challenge in NHW compared to AA women with PCOS. Future studies would benefit from including race when evaluating metabolic outcomes in women with PCOS. References: 1Fogel et al., J Clin Endocrinol Metab. 2001: 86:1175–1180. 2Kapsimalis et al., Sleep. 2002; 25:499–506. 3Kapsimalis et al., Sleep. 2002; 25:412–419. 4Polonsky et al., J Clin Invest. 1986 Jan; 77(1):98–105.
SAT-504 Delayed Hypersensitivity to Levothyroxine, and Oral Desensitization
Authors: Sandooja Rashi , Morocco Michael Dominic , Smith Martin
Published: May 2020

Introduction- Hypothyroidism is a common endocrine disorder, affecting about 4.6 percent of the U.S. population aged 12 and older. The most common treatment is synthetic thyroxine hormone supplementation-levothyroxine, starting at 1.6 mcg/kg.Hypersensitivity reactions to levothyroxine are rare. Two cases have been published of successful oral desensitization, for suspected IgE mediated reactions. There are no published protocols describing induction of drug tolerance to immunologic, non-IgE mediated reaction to levothyroxine. The objective of this case report is to describe a novel outpatient protocol, for oral desensitization to levothyroxine, in the setting of a delayed immunologic (non-IgE mediated) reaction.

Case report- A 66 year old male with history of hypothyroidism, diagnosed in 2010 presented to outpatient endocrinology. Between 2010 and 2019, the patient was on multiple brands and formulations of levothyroxine. He noticed an itchy, raised rash on abdomen, chest and arms, within a few months after starting each of the above. No mucosal involvement or signs of end organ damage were noted. The rash was deemed a type IV delayed hypersensitivity reaction, based on history and histological findings on biopsy. The patient reported clearance of the rash when he was off any form of thyroid supplementation, and reappearance of the rash when he re-trialed it. The patient had normal thyroid stimulating hormone (TSH) levels while he was on supplementation despite the rash. The patient’s TSH after discontinuing treatment was 104 (uIU/mL) and free thyroxine (T4) was 0.13 ng/dl (0.9–1.7). All components of previous brands of levothyroxine were compared and no common ingredient was thought to be contributing to hypersensitivity reactions. Subsequently, an oral desensitization protocol was initiated at 0.075 mcg daily with weekly increase in doses over seven weeks to reach a target dose of 75 mcg.

Discussion- The patient was tried on different brands of levothyroxine and dessicated thyroid hormone. He consistently developed a type IV hypersensitivity reaction within a few months after starting them. The patient had uncontrolled TSH levels after discontinuing the treatment and was at risk of complications of untreated hypothyroidism. This necessitated the need for desensitization. There have been previous case reports of oral or IV desensitization, in suspected IgE mediated reactions, but we describe the first case of induction of levothyroxine tolerance in an immunologic non-IgE mediated reaction. Subsequently, the patient tolerated a therapeutic dose of levothyroxine, with no appearance of rash or itching, for almost 6 months. This case report describes a novel approach to levothyroxine desensitization over a period of seven weeks in an outpatient setting in response to a delayed type hypersensitivity reaction.
SAT-001 Clinically Meaningful Effects of E2/P4 Oral Capsule in Treating Vasomotor Symptoms
Authors: Constantine Ginger , Graham Shelli , Revicki Dennis A , Kagan Risa , Mirkin Sebastian
Published: May 2020

Hormonal therapies effectively reduce the frequency and severity of vasomotor symptoms (VMS) in menopausal women; however, whether the effect is clinically meaningful to women is typically not determined. Oral estradiol/progesterone (E2/P4; mg/mg) 1/100 and 0.5/100 significantly improved moderate to severe VMS versus placebo at weeks 4 and 12. The objective of these analyses was to determine the clinical importance (meaningfulness) of E2/P4 treatment versus placebo in menopausal women.

REPLENISH, a phase 3, randomized, double-blind, placebo-controlled trial, evaluated the safety and efficacy of E2/P4 oral capsules in symptomatic, postmenopausal women with a uterus. Clinically meaningful reductions in weekly VMS frequency were determined using 3 patient-reported outcomes as anchors (VMS severity score, clinical global impression [CGI], and question 1 from the vasomotor domain of the menopause-specific quality of life questionnaire). The proportion of women who had a clinically important response with 0.5/100 was compared with placebo using the Fisher’s exact test. Spearman correlations were also performed across the 3 anchors.

Clinically meaningful reductions in weekly VMS frequency ranged from 32 to 43 at week 4, and from 32 to 48 at week 12. Significantly more responders were observed with 0.5/100 than with placebo for all 3 anchors at both weeks 4 (all, P<0.05) and 12 (all, P≤0.002). All 3 anchors were correlated, supporting their acceptability as appropriate anchors.

Treatment with E2/P4 0.5/100 provided consistent clinically meaningful improvements in the weekly frequency of moderate to severe VMS in menopausal women, similar to what has been observed with the CGI-anchor for E2/P4 1/100.
SUN-368 Wnt Inhibition Decreases Trabecular Bone in a Mouse Model of Fibrous Dysplasia
Authors: Lung Hsuan , Wentworth Kelly , Moody Tania , Kang Misun , Ho Sunita , Hsiao Edward
Published: May 2020

Background: G protein-coupled receptor (GPCR) signaling mediates a wide spectrum of physiological functions, including bone development and remodeling. Fibrous dysplasia (FD) is a common skeletal dysplasia where normal bone and bone marrow are replaced by fibrous tissue and expansile trabecular bone lesions. The craniofacial bones are often involved, leading to pain and facial deformities. FD is a mosaic disease caused by a somatic mutation in the GNAS gene encoding the G-protein alpha subunit (Gsα) that leads to constitutive activation of the Gs signaling pathway. Unfortunately, FD has no effective medical treatments.

Major challenges have hampered the development of pharmacologic strategies that specifically target GNAS or the Gsα protein. We previously developed the Col1(2.3)/Rs1 mouse model (Rs1) in which the Gs signaling pathway is activated specifically in bone by an engineered GPCR protein. These mice showed increased trabecular bone formation with loss of marrow space and cortical bone, which strongly resembles human FD (1–4). There was also a dramatic increase in the number of immature osteoblasts present in the FD lesions, suggesting that activation of Gs signaling caused an accumulation of these cells. Our prior studies showed increased Wnt signaling, which may be a major driver of this effect. Furthermore, blocking the Gs signaling could reverse the bone phenotype, providing proof-of-concept for finding drugs that could reverse the phenotype. Therefore, we administered the Wnt inhibitor LGK974, currently used in human clinical trials, to the Rs1 mice to test if the FD lesions could be pharmacologically reversed.

Methods: We administered LGK974 in 4-week-old Rs1 and non-Rs1 mice. We used a low dose (5mg/kg) for 8 weeks or high dose (30mg/kg) for 4 weeks. The mice were evaluated by histology and micro computed tomography (micro-CT) for mineral density (mg/cm3), bone volume (mm3), and trabecular thickness (um).

Results: LGK974 decreased β-catenin levels in bone on western blots. In the low-dose group, the histology and micro-CT showed no statistically significant differences between drug and control groups. In the high-dose group, the micro-CT showed significantly decreased trabecular bone thickness (p=0.0364, n=3) in the drug-treated group (22±2µm) compared with controls (17±2µm). Furthermore, histology showed resorption of the abnormal bone; however, the fibrocellular infiltrate in the Rs1 mice was still present.

Conclusions: Wnt inhibition can lead to decreased fibrous dysplastic bone, but separates abnormal bone formation from the fibrocellular infiltrate. These results provide new insight into understanding interactions between the Wnt and Gs signaling pathways in FD pathogenesis and bone formation.

References: 1. Hsiao EC et al. PNAS. 2008. 2. Hsiao EC et al. JBMR. 2010. 3. Schepers, Hsiao EC et al. Blood. 2012. 4. Cain CJ et al. Endocrinology. 2016.
SUN-273 A Rare Case of IgG4-Related Hypophysitis
Authors: Ravindra Sindhura , Fazeli Pouneh
Published: May 2020

Introduction:

Hypophysitis is an acute or chronic inflammation of the pituitary gland and is an important diagnostic consideration in a patient with a sellar lesion. The annual incidence of hypophysitis is estimated to be 1 in 7–9 million and it accounts for approximately 0.4% of pituitary surgery cases. The following highlights a rare case of isolated IgG4-related hypophysitis

Clinical Case:

A 63-year-old Caucasian female presented with sudden onset of diplopia and decreased visual acuity. This was associated with a 3-month history of headaches and 5-lbs weight loss. Past medical history was significant for hypertension and a 1.5cm sellar/suprasellar mass incidentally discovered during the work-up for persistent headaches 1-month prior. Initial anterior pituitary hormone evaluation was normal and the patient was scheduled for endoscopic endonasal resection of a presumed non-functioning pituitary adenoma. Family history was negative for pituitary tumors or hyperparathyroidism. Physical examination was notable for medial deviation of her left eye but neurologic examination was otherwise normal. Laboratory studies were notable for a normal TSH [1.769 uIu/ml (normal: 0.3–5.0)] and low free T4 [0.44 ng/ml (normal: 0.89–1.78)] consistent with central hypothyroidism; an inappropriately normal FSH for a postmenopausal woman [5.6 mIu/ml (normal: 0.3–10.5), and a normal prolactin level [16 ng/ml (0.6–20)]. An 8am cortisol was low at 2mcg/dL (5–21) with an ACTH level of 10 pg/mL (9–46). IGF-1 was normal at 89 ng/mL (41–279). Repeat pituitary MRI imaging demonstrated a homogenously enhancing sellar/suprasellar mass measuring 3.8 cm with displacement of the optic chiasm. Serum IgG4 levels were normal. The patient was started on 50mg IV hydrocortisone every 8 hours for central adrenal insufficiency and levothyroxine 88 mcg daily for central hypothyroidism and underwent an endoscopic endonasal biopsy of the lesion. Surgical pathology was notable for plasma cell-rich lymphohistiocytic hypophysitis and IgG4 plasma cells constituted >40% of the total plasma cell population. The patient subsequently received 1g of rituximab and repeat imaging one week later showed marked improvement in the size and extent of the lesion. The patient was discharged on prednisone and levothyroxine and received a second dose of rituximab at follow-up. The patient reports a decrease in the frequency of her headaches but continues to endorse diplopia.

Conclusion:

IgG4-related hypophysitis typically presents as part of a multifocal systemic process. This case highlights a rare entity of IgG4-related hypophysitis without other features of systemic disease and with normal serum levels of IgG4. Although glucocorticoids are universally regarded as the first line of therapy, an immunosuppressive agent or B-cell depletion therapy such as Rituximab may improve remission and decrease the risk of relapse.
MON-675 Ziprasidone Induced Diabetic Ketoacidosis
Authors: Thanikonda Varshitha , Jalil Fatima , Kantorovich Vitaly
Published: May 2020

Introduction: Atypical antipsychotics are known to cause increased risk of type 2 Diabetes Mellitus (DM2), dyslipidemia, and weight gain (metabolic syndrome). Clozapine, a commonly used anti-psychotic, is known to cause Diabetic Ketoacidosis (DKA), but literature has rarely shown an association of DKA with Ziprasidone.

Case: A 42-year-old African American female presented with two weeks of polyuria, polydipsia, 23-pound weight loss, blurriness of vision, and dry mouth. Before the presentation, she had been drinking several drinks with high sugar content. Her medications included Ziprasidone (Geodon), Trileptal, and Cogentin for her bipolar disorder. She was started on Ziprasidone in 2007, changed to Brand name Geodon in 2014. Except for dry mouth, her exam was unremarkable. Labs were significant for blood glucose of 1114 mg/dL, bicarbonate of 18mmol/L, beta-hydroxybutyrate of 3.33 mmol/L, serum osmolality of 334 mOsm/kg. She was diagnosed with new-onset diabetes mellitus presenting as diabetic ketoacidosis. Her mother was diagnosed with DM2 in her 40s. She ha difficult to control blood sugars despite aggressive hydration and required regular insulin drip for 3 days for her anion gap to close. Managing her BGs was challenging.

Discussion: Clozapine and olanzapine are the common atypical antipsychotics that can cause DKA1, 2. To our knowledge, Ziprasidone is associated with hyperglycemia within days of starting the drug and HHS but not with DKA. For atypical antipsychotic associated DKA, risk factors include the duration of antipsychotic therapy, polypharmacy with multiple antipsychotic agents, non-Caucasians, obesity and pre-diabetes2, 3. Proposed mechanisms include peripheral insulin resistance, alteration of pancreatic beta-cell function by inhibiting 5-HT1A/2A/2C and alpha 2 adrenergic receptors1-3. However, there is no explanation of why few people develop complications while others do not. There is hypothesis regarding leptin gene polymorphisms of receptors that may play a role4. While starting patients on Ziprasidone, close monitoring of blood glucose is necessary before initiation and regular follow up thereafter3.

1. Henderson DC. Atypical antipsychotic-induced diabetes mellitus: How strong is the evidence? CNS Drugs. 2002.

2. Vuk A. Diabetic ketoacidosis associated with antipsychotic drugs: Case reports and a review of literature. Psychiatr Danub. 2017.

3. Schwenkreis P. Atypical antipsychotics and diabetes mellitus. World J Biol Psychiatry. 2004.

4. 1. Reynolds GP. Metabolic side effects of antipsychotic drug treatment - pharmacological mechanisms. Pharmacol Ther. 2010.
SAT-686 Type 1 Diabetes Diagnosed in an 83 Year Old Man After Nivolumab Therapy
Authors: Joseph Marina , Borikar Madhura , Bursey Deborah I
Published: May 2020

BACKGROUND

Immune checkpoint inhibitors are increasingly being used for a variety of cancers and are a promising treatment option. Immune related adverse effects are their major side effects, most common being hypophysitis and hypothyroidism. While diabetes and adrenalitis have only been rarely reported, these too are becoming more common. We present a case of type 1 diabetes associated with Nivolumab therapy diagnosed in an 83-year-old man.

CASE

An 83 year old male with past medical history of emphysema, coronary artery disease, hypertension, non-small cell lung cancer treated with lobectomy, hepatitis C cirrhosis with hepatocellular carcinoma with metastasis to lungs, who completed 10 cycles of Nivolumab presented to oncology clinic with complains of polyuria, polydipsia and a weight loss of 10 pounds over the last one week. Lab work showed a blood glucose of 743 with an anion gap of 18 and bicarb of 18. B-hydroxy butyrate was 3.19. He was admitted to our ICU for diabetic ketoacidosis. He did not have a history of diabetes mellitus. No family history of diabetes was reported. His Hemoglobin A1c was found to be 10.1. He had normal blood sugars before starting Nivolumab therapy. His C-peptide was found to be low at 0.61. Insulin antibody, Islet cell antibody, Zinc transporter antibody and GAD antibodies were negative. He was discharged on basal bolus Insulin regimen. He is being followed in our endocrinology clinic and continues to be insulin dependent.

CONCLUSION

Nivolumab is PD-1 (programmed cell death) inhibitor, which is used as cancer immunotherapy in multiple advanced cancers including hepatocellular carcinoma. Clinically significant endocrinopathies are documented in <5% of patients treated with PD-1 inhibitors. The cause of Diabetes by PD-1 inhibitors is not well defined but believed to be caused by destruction of pancreatic beta cells due to inhibition of autoimmunity by autoreactive T cells. Literature review showed only 42 published cases of PD-1 inhibitor induced type 1 diabetes. Average age at presentation was 62 years and about 69% patients were in DKA at diagnosis. In a recently published study involving 1163 patients who received PD-1 inhibitors, only 21 cases of diabetes were identified, 12 of those were with new onset DM and only 1 case was due to Nivolumab use.

Since this type of endocrinopathy is mainly reported in case reports, we will need more research for further understanding of the pathology so that we can keep a watch out for this adverse effect and prevent life- threatening complications.
SUN-719 The Impact of FOXA3 on Testicular Steroidogenesis
Authors: Kim Hansle , Kumar Sudeep , Lee Keesook
Published: May 2020

The Forkhead box(Fox) transcription factors are evolutionarily conserved in organisms and regulate diverse biological processes during development as well as adult life. Among the Fox family, FoxA subfamily members Foxa1-3 have been termed `pioneer’ transcription factors as they bind both nucleosome-bound and nucleosome-free DNA targets with the same recognition site. Foxa3 is the only member of FoxA subfamily that is expressed in both male and female gonads. In the testis, Foxa3 is expressed in spermatids and interstitial Leydig cells. We focused our study to elucidate the role of FOXA3 in Leydig cells and its impact on testicular steroidogenesis. Expression of FOXA3 dramatically decreased in mouse Leydig cells during testicular development. In addition, the time-dependent expression of FOXA3 showed an opposite pattern to that of steroidogenic genes in cAMP-induced primary Leydig cells. Meanwhile, Nur77 is among the prime regulators of steroidogenesis in the testicular Leydig cells. Overexpression of FOXA3 in MA-10 cells (mouse Leydig tumor cell line) repressed the cAMP-induced Nur77 promoter activity, which further resulted in the reduced activity of Nur77-target steroidogenic gene promoters (StAR, CYP17A1and 3β-HSD). Similar to above results, the expression of Nur77 and its target genes,StAR, 3β-HSD and CYP11A1, were repressed by adenovirus-mediated overexpression of FOXA3 in mouse primary Leydig cells, although the expression of CYP17A1, another steroidogenic gene, was differentially affected. These results suggest that FOXA3 locally regulates the expression of steroidogenic genes through Nur77 during testicular development.
SAT-070 Nutritional Deficiency of Calcium Mimicking P Seudohypoparathyroidism
Authors: Lee Yoonji , Ahn Moon Bae , Lee Na yeong , Lee Seonhwa , choi Yujung , Kim Seulki , Jung Min-Ho , Suh Byung-Kyu
Published: May 2020

BACKGROUND: Childhood hypocalcemia in general is caused by problems associated with calcium absorption and excretion, parathyroid hormone (PTH) secretion, and vitamin D metabolism. Clinical manifestations can vary from asymptomatic hypocalcemia to life-threatening conditions including convulsions, tetany and laryngeal spasm. As many symptoms are nonspecific, laboratory tests are essential for diagnosis. Nevertheless, the causes of hypocalcemia may not be determined by simple interpretation of baseline calcium, phosphorus, alkaline phosphatase (ALP), PTH and calcidiol (25OHD).

Case presentation: We report a case of 11-month-old female with a generalized tonic type seizure with low serum calcium level (5.7 mg/dl), 25OHD (23.2 ng/mL) and calcitriol (1,25OH2D) (12.83 pg/mL). Serum phosphorus (5.9 mg/dL), ALP (209 mg/dL) were above normal range and PTH (484 pg/mL) was markedly elevated. She had a problem with weaning process after age of 5 months and milk powder was her main staple diet. Pseudohypoparathyroidism (PHP) was suspected due to slightly increased serum phosphorus, however Albright’s hereditary osteodystrophy manifestation was absent and no GNAS methylation defect was identified. Serum calcium was normalized by intravenous calcium-gluconate followed by oral calcium carbonate and vitamin D supplement. Two months of oral oral calcium carbonate and vitamin D supplementation alone normalized all laboratory results.

Conclusions: Severe nutritional deficiency of calcium could mimic laboratory findings of PHP, therefore clinical judgement should not be made solely on biochemical markers.

Keywords: Hypocalcemia, pseudohypoparathyroidism, rickets

제1저자: Yoonji Lee, Moonbae Ahn, Na yeong Lee, Seonhwa Lee, Yujung Choi, Seulki Kim, Shinhee Kim, Wonkyoung Cho, Kyoungsoon Cho, Minho Jung, and Byungkyu Suh*

Department of Pediatrics, College of Medicine, Catholic University of Korea
OR10-02 Diagnosis of Severe GH Deficiency in Newborns: New Reference Range for the Preterm and Confirmation of the GH Cut-Off
Authors: Binder Gerhard , Weber Karin , degree no , Rieflin Nora , degree no , Steinruck Louis , degree no , Franz Axel
Published: May 2020

Introduction

Inborn severe GHD is caused by rare disorders of pituitary morphogenesis or function and frequently associated with additional pituitary hormone deficiencies. Affected newborns commonly present with recurrent hypoglycemia; therefore early diagnosis and therapy is warranted. The GH content of the newborn screening card is a reliable indicator of severe neonatal GHD. Here, we studied the GH content in screening cards and the history of 25 newborns with severe GHD. In addition, we determined the reference range of the GH content in screening cards from 282 healthy preterm newborns.

Patients and Methods

Since 2010, a total of 110 screening cards from hospitalized ill newborns were sent to our laboratory for measuring GH content. Using a questionnaire we obtained relevant clinical information from senders in 61 cases. Severe GHD was defined by the presence of recurrent neonatal hypoglycemia with either a significant cerebral MRI morphology or two additional pituitary hormone deficiencies. In addition, the GH content of screening cards from 282 healthy newborns born preterm with a gestational age at birth from 34.0 to 37.9 weeks was prospectively analyzed. The GH concentration of the eluate from the screening card was measured by a highly sensitive ELISA (Mediagnost, Germany); the GH serum concentration was calculated.

Results

In 25 patients, the definition of severe GHD of the newborn was fulfilled; based on recurrent hypoglycemia in combination with ectopia of the neurohypophysis in 17, septum pellucidum agenesis plus opticus hypoplasia in two, severely hypoplastic pituitary gland in two, and combined TSH and ACTH deficiency with no cMRI findings in four newborns. Five newborns with severe GHD were preterm. The median GH concentration of the term newborns with severe GHD (n=20) was 3.9 µg/l (range; 1.1 to 11.8). This was significantly below the previously reported reference data from healthy term newborns (n=269) (median 16.4 µg/l; 95% reference range 7.0 to 39.4) (p<0.001). Using ROC plot analysis a GH serum concentration of 7.0 µg/l was identified as cut-off with the highest accuracy (90.0% sensitivity and 98.7% specificity). The median GH concentration of the 5 preterm newborns with severe GHD was 7.7 µg/l (range; 2.1 to 9.9). The newly determined 95% reference range for healthy newborns born preterm with a gestational age from 34.0 to 37.9 weeks (n=282) spanned from 7.9 to 41.1 µg/l with a median of 20.3 µg/l.

Conclusions

A GH content below 7.0 ng/ml in the newborn screening card identified severe GHD with 90% sensitivity and 98.7% specificity. In preterm newborns, the lower limit of the 95% reference interval was by 0.9 µg/l higher than in term newborns. The newborn screening card is a valuable source for the diagnosis of GH deficiency in newborns and young infants.
OR12-02 When the Glucocorticoid Receptor Meets the Mineralocorticoid Receptor in the Nucleus of Human Cells
Authors: Petrillo Maria G , Jewell Christine M , Oakley Robert H , Cidlowski John A
Published: May 2020

Adrenal corticosteroids, such as glucocorticoids and mineralocorticoids, are indispensable for mediating response to stress, development, limiting inflammation, and maintaining energy and fluid homeostasis. These hormones exert their actions via binding to two closely related nuclear receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). The GR has low affinity for corticosteroids, but is expressed in nearly every cell. In contrast, the MR shows a higher affinity for corticosteroids and its expression is largely confined to those tissues where electrolyte exchange and fluid balance are required. GR and MR act as ligand-activated transcription factors which, following interaction with co-regulators and DNA responsive elements, either promote or repress gene transcription. The affinity for the same ligands, structural homology, and binding to the same DNA regions suggest GR and MR can compensate for each other’s actions. Yet, there are specific glucocorticoid and mineralocorticoid-mediated responses indicating GR-MR functional diversity. To investigate this interplay, we developed U-2 OS (human osteosarcoma) cell lines stably expressing GR, MR, and both GR and MR (GRMR). Immunofluorescence analysis showed that treatment of these cell lines with 1 nM of the synthetic glucocorticoid dexamethasone (Dex) induced nuclear traslocation of GR and MR. Conversely, treatment with 1 nM of aldosterone (Aldo) promoted nuclear translocation of the MR only. Moreover, Proximity Ligation Assay revealed that, in the absence of ligand, GR associated with MR in the cytoplasm and, upon 1 nM Dex exposure, GR-MR dimers were detected in the nucleus of GRMR cells. Surprisingly, nuclear GR-MR dimers were also detected in the presence of Aldo, suggesting that it is necessary to activate at least one receptor to induce nuclear traslocation of the heterocomplex. To decipher the functional contribution of GR-MR dimers in the transcriptional response of GR to Dex and MR to Aldo, we performed RNA-seq in GR, MR, and GRMR cells treated with 1 nM of Dex or Aldo. Transcriptome analysis revealed that Dex-activated GR regulated the transcription of 6180 genes. Co-expression of MR resulted in a blunted Dex-mediated gene response which affected only 1608 genes, suggesting a functional antagonism of MR. Aldo-activated MR regulated the transcription of 1660 genes. However, co-expression of GR expanded the Aldo-mediated gene response to 3150 genes. Strikingly, 74% of these genes were also regulated by Dex via GR, suggesting that GR-MR dimers in the presence of aldosterone are able to mimic the glucocorticod transcriptional response. Our data suggest that the role of distinct GR and MR homo- and hetero-dimers is relevant for regulating gene expression. Dissecting the mechanism and investigating the cross-talk between GR and MR may be useful to understanding these two receptors in heath and disease.
OR10-04 Interpretation of Insulin-like Growth Factor-1 (IGF-1) Levels Following Administration of Somatrogon (a Long-acting Human Growth Hormone - hGH-CTP)
Authors: Fisher Dennis M , Pastrak Aleksandra , Choe John , Wajnrajch Michael Paul , Cara José
Published: May 2020

IGF-1 is often used as a biomarker to evaluate the efficacy and safety of hGH replacement therapy. Typically, the mean IGF-1 SDS level during the dosing interval, rather than the peak value, guides clinical decision-making: sustained mean values > +2 may require hGH dose modifications. With long-acting formulations (administered weekly), the IGF-1 evaluation paradigm needs to take into account when the sample was obtained relative to the last administered dose. Previous studies with OPKO’s once weekly Somatrogon (hGH-CTP), demonstrated that IGF-1 SDS peaked ~ 48 hours post-dose and that values at ~ 96 hours best approximated the mean IGF-1 SDS throughout the dosing interval [1]. Data from the pivotal Phase 3 non-inferiority study comparing treatment with Somatrogon to Genotropin allowed further evaluation of the IGF-1 SDS analysis paradigm.

Enrolled subjects were randomized to receive treatment with either once weekly Somatrogon (0.66 mg/kg; N=109) or once daily Genotropin (0.034 mg/kg; N=115). IGF1 was sampled ~ five times during 52 weeks of treatment with Somatrogon, providing a total of 557 samples obtained after the first dose of Somatrogon. IGF-1 SDS values were calculated using Bidlingmaier’s equations [2].

Analysis of IGF-I SDS data from the Phase 3 study showed that the previously-developed model, with adjustments to two parameters (baseline IGF-1, EC50) and adapted to fit IGF-1 values in the absence of Somatrogon concentration data, fit the IGF-1 data for Somatrogon with minimal bias. This allowed prediction of IGF-1 SDS values at timepoints throughout the dosing interval as well as calculation of the mean value during a dosing interval. Of the samples obtained between 48–72 hours post-dose (representing peak IGF-1 SDS), approximately 17% had an IGF1 SDS > +2. At 96 hours (corresponding to mean IFG-1 SDS), fewer than 2% of modeled values were > +2. Mean IGF-1 SDS over the dosing interval was between -1 and +1 for all subjects.

These findings indicate that IGF-1 SDS values need to be interpreted in the context of when the sample was obtained relative to the last dose of Somatrogon. Our results indicate that samples obtained 96 hours post-dose best represent mean IGF-1 levels and that values obtained between 48–72 hours post-dose represent values closer to peak IGF-1 concentrations. In our Phase 3 study, of the 557 samples collected from 114 patients during the 12-month Somatrogon treatment period, fewer than 2% of the corresponding values at 96 hours postdose (estimated from a pharmacokinetic/pharmacodynamic model) had IGF-1 SDS levels > +2.

1. Fisher DM, et al. Horm Res Paediatr 2017;87:324. 2. Bidlingmaier M, et al. J Clin Endocrinol Metab 2014;99:1712
OR26-01 Epinephrine Is Essential for Normal Renal Glucose Reabsorption via the Glucose Transporter GLUT2
Authors: Elsheikh Arwa Mahmoud , de Souza Cordeiro Leticia M , Devisetty Nagavardhini , Ebert Steven N , Chhabra Kavaljit H
Published: May 2020

Humans and mice with Melanocortin 4 receptor (MC4R) deficiency remain protected from hyperglycemia despite chronic obesity and insulin resistance. We have observed that elevated glycosuria in MC4R deficient mice protects them from hyperglycemia. Moreover, our results indicate that circulating epinephrine may couple MC4R signaling with kidney glucose reabsorption. However, the direct role of epinephrine in regulating kidney glucose reabsorption remains unclear. We hypothesize that epinephrine is essential for maintaining glucose homeostasis via kidney glucose reabsorption. To test this hypothesis, we performed oral glucose tolerance tests (OGTTs) and intraperitoneal insulin tolerance tests (ITTs) in phenylethanolamine-N-methyltransferase (Pnmt) knockout (KO) mice that specifically lack epinephrine but have normal norepinephrine levels. Pnmt KO mice exhibited reduced insulin sensitivity compared to their Wild-Type (WT) littermates (Area under the curve for ITT: 9,700±256 vs. 8,482±417 mg/dL.min, p<0.05). Paradoxically, we observed improved rather than impaired glucose tolerance in Pnmt KO mice compared to their WT controls (Area under the curve for OGTT: 32,546±1,592 vs. 40,058±1,918 mg/dL.min, p<0.05). To ascertain if Pnmt KO mice, like MC4R deficient mice, show elevated glycosuria, we quantified their 24 urine glucose levels after oral glucose (250 mg) challenge. Indeed, Pnmt KO mice demonstrated elevated glycosuria compared to their WT littermates (Urine glucose: Baseline, 24.63±2.2 vs. 11.14±0.82 mg/dl; post glucose challenge: 67.83±5 vs. 16.09±1.13 mg/dl, p<0.001), again validating the phenotype similar to that of MC4R deficient mice. To determine the glucose transporters involved in mediating elevated glycosuria in the Pnmt KO mice, we measured the levels of different renal glucose transporters using western blot. We found that GLUT2 was decreased by ~26% in Pnmt KO mice compared to their WT littermates. Levels of other glucose transporters were not changed, indicating that suppression of renal GLUT2 mediates elevated glycosuria in the epinephrine deficient mice. We validated the direct effect of epinephrine on GLUT2 levels in vitro using mouse primary renal proximal tubule epithelial cells. Indeed, epinephrine selectively increased GLUT2, but did not affect other glucose transporters in the mouse kidney primary cells. Our findings establish the essential role of epinephrine in glucose reabsorption via the renal glucose transporter GLUT2. Therefore, modulating the renal adrenergic system, or, kidney-specific GLUT2 may afford alternative strategies to regulate glycosuria and ultimately mitigate diabetes.
MON-105 A Case Report of Neonatal Hyperinsulinism in an Infant with Turner Syndrome Successfully Treated with Diazoxide
Authors: Patterson Rebecca J , Komsky Danielle , D’Ambrosio Fabiola , Mantis Stelios
Published: May 2020

BACKGROUND: Only four previous cases of hyperinsulinemic hypoglycemia have been reported in association with Turner Syndrome. All of these cases involved young females with a mosaic form of Turner Syndrome involving a ring X chromosome; an abnormality found in just 16% of Turner Syndrome karyotypes. Two of these cases showed responsiveness to diazoxide which stabilized their blood glucose levels and allowed for a longer fasting tolerance.

Clinical Case: A 5 day old female who was born at 36 weeks and 1 day with Turner Syndrome was referred to pediatric endocrinology for persistent episodes of hypoglycemia. Patient was started on D10W with electrolytes at an outside hospital due to hypoglycemia and was transferred to the NICU at day of life 3. D10W was discontinued on day of life 5 due to adequate PO feeding and reassuring blood glucose readings. Blood glucose was monitored every 4 hours and infant continued to have episodes of asymptomatic hypoglycemia typically in the mid-low 40’s, with one episode of low blood sugar to 36 mg/dl. Due to a concern for hyperinsulinism, labs were drawn at a serum blood glucose of 46mg/dl. The infant was found to have a beta-hydroxybutyrate of 0.2 (0.0-0.8mmol/L) and insulin of 1.0 (2.0–19.6uIU/mL). Hyperinsulinism was thus confirmed by the presence of inappropriately low ketones and inappropriately normal insulin in the setting of hypoglycemia. We initiated the patient on 7.5mg diazoxide BID (5.9mg/kg/day total) and was highly responsive to diazoxide. After her third dose (36 hours into treatment), her hypoglycemia had resolved and blood sugar readings had normalized. Patient was discharged home with a glucometer and instructions for the mother to call if blood glucose was less than 60. The patient has been stable on diazoxide with no reported episodes of hypoglycemia. Interestingly, her genetic testing demonstrated a complex chromosomal microarray pattern on chromosome X, a mosaicism with 2 cell lines: 1 with monosomy X and 1 cell line with a normal X chromosome with a ringed X chromosome.

Conclusion:This is a case demonstrating the efficacy of diazoxide in the management of asymptomatic hyperinsulinemic hypoglycemia in a neonate with Turner Syndrome with a ring X chromosome.

References: Cappella M, Graziani V, Pragliola A, et al. Hyperinsulinemic Hypoglycaemia in a Turner Syndrome with Ring (X). Case Rep Pediatr 2015; 2015:561974.
SUN-393 The Impact of Micronutrients on Cellular Metabolism and Healthy Aging
Authors: Astrup Arne , Cena Hellas , Frei Balz , Hwalla Nahla C
Published: May 2020

Micronutrients are involved in nearly all cellular processes, inadequacies or deficiencies may accelerate cellular aging and increase risk for chronic diseases later in life.1 Optimizing micronutrient intake may help reduce the risk for developing certain age-related conditions/diseases, including osteopenia/osteoporosis,2 sarcopenia,3 falls,4 mild cognitive impairment,5 immunosenescence,6 impaired resilience,7 hypertension,8 cataracts,9 and age-related macular degeneration.10 The importance of calcium and vitamin D for maintaining bone health has been established,2 but these micronutrients may also be involved with muscle health and reducing the risk for falls and consequent bone fractures in later life.11 Vitamin D may also be involved in stress management and resilience.12 Vitamins C, D, and E, zinc, selenium, and other micronutrients are necessary for healthy immune system function,13,14 and vitamin E is important for cognition,15 immune competence,16 and eye health.10 Although these micronutrients are individually involved with these processes by acting as antioxidants, hormonal regulators of gene expression, or cofactors in enzymatic reactions, there are also important interactions between micronutrients to consider (eg, calcium/vitamin D in musculoskeletal health). Importantly, a significant proportion of the aging population does not meet the recommended intake of many micronutrients.17 Clinical trials on the benefits of micronutrient supplementation have not been conclusive, but adequate intake should be considered an essential component of comprehensive healthcare for older adults.

References

1. Ames BN. Proc Natl Acad Sci U S A. 2006;103:17589–94

2. Nieves JW. Am J Clin Nutr. 2005;81:1232s-9s

3. Stockton KA, et al. Osteoporos Int. 2011;22:859–71

4. Shahar D, et al. Ann Nutr Metab. 2009;54:59–66

5. Barnes JL, et al. Nutr Rev. 2014;72:707–19

6. Cabrera AJ. Pathobiol Aging Age Relat Dis. 2015;5:25592

7. Rucklidge JJ, Blampied NM. NZ J Psychol. 2011;40:51–7

8. de Paula TP, et al. Sci Rep. 2017;7:40751

9. Weikel KA, et al. Nutr Rev. 2014;72:30–47

10. Evans JR, Lawrenson JG. Cochrane Database Syst Rev. 2017;7:CD000254

11. Robinson SM, et al. Clin Nutr. 2018;37:1121–32

12. Bracha HS, et al. Am J Geriatr Psychiatry. 2004;12:544–5

13. Puertollano MA, et al. Curr Top Med Chem. 2011;11:1752–66

14. Prietl B, et al. Nutrients. 2013;5:2502–21

15. Parker RS. In: Stipanuk MH, Caudill MA, eds. Biochemical, Physiological, and Molecular Aspects of Human Nutrition. 3rd ed. St. Louis, MO: Elsevier Saunders; 2013:670–82

16. Maijo M, et al. Mech Ageing Dev. 2014;136–137:116–28

17. Bugel S, Frei B. Care Weekly. 2019;3:1–12
SUN-277 Pituitary Hyperplasia Due to Severe Primary Hypothyroidism: An Uncommon Manifestation of a Common Disease
Authors: Singh Abhilasha , German Massiell , Sharma Anu
Published: May 2020

Background Pituitary hyperplasia (PH) is a non-neoplastic increase in one or more cell subtype of the adenohypophysis. It is physiologically seen in pregnancy from resultant lactotroph hyperplasia and pathologically in organ dysfunctions that lead to loss of negative feedback on hypothalamus like primary hypothyroidism and primary adrenal insufficiency. Although primary hypothyroidism is common, PH is an under-recognized consequence of long-standing hypothyroidism. Case Description A 26-year-old female with class 3 obesity, type 2 diabetes mellitus, and primary hypothyroidism on replacement presented for evaluation of secondary amenorrhea. Two months prior to presentation, she underwent a brain MRI for new-onset headache which revealed diffusely enhancing homogenous pituitary tissue measuring 2.3 cm with upward lifting of the optic chiasm. Serum prolactin was elevated at 86.2 ng/ml (2.8-26 ng/ml). This was presumed to be secondary to a prolactinoma and cabergoline was started by the referring provider. Subsequent workup revealed elevated thyroid-stimulating hormone (TSH) at 494.11 mU/L (0.30- 4.00 mU/L) and a low free thyroxine (FT4) of 0.2 ng/dl (0.8-1.7 ng/dl). Other pituitary hormones were within normal limits. The visual field examination was normal. It was noted she had a persistently elevated TSH over the past five years. On further questioning, the patient ran out of levothyroxine replacement 6 months ago and had been generally non-adherent to therapy for years due to nausea. Improved medication adherence resulted in the normalization of prolactin and reduction in TSH level. Repeat MRI 2 months later revealed a reduction in her pituitary hyperplasia to 2.1 cm. Discussion In severe primary hypothyroidism, there is loss of negative feedback to the hypothalamus due to low circulating FT4 and triiodothyronine (T3) concentrations. As a result, there is stimulation of thyrotropin-releasing hormone (TRH) which promotes thyrotroph hyperplasia. A strong correlation exists between TSH concentration and the degree of pituitary hyperplasia. The typical MRI finding is a diffusely enhancing homogenous pituitary mass. Despite optic chiasm contact, physiologic pituitary hyperplasia rarely causes visual field defects. High concentrations of TRH stimulates prolactin release with resultant mild hyperprolactinemia. Although PH is reversible with therapy, rare cases with subsequent development of panhypopituitarism while on therapy have been reported in the setting of longstanding hypothyroidism. Very rarely, chronically untreated primary hypothyroidism can stimulate the growth of a thyrotroph adenoma. Long-term biochemical and radiological monitoring is therefore recommended until resolution. This case highlights the physiologic responses manifested in severe primary hypothyroidism and the fact that these changes improve with adequate replacement.