Journal of the Endocrine Society

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EISSN: 24721972
Total articles ≅ 9,693

Latest articles in this journal

Jared Kaplan, Steven Tommasini, Gang-Qing Yao, Mei-Ling Zhu, Sayoko Nishimura, Sevanne Ghazarian, Angeliki Louvi,
Published: 6 February 2023
Journal of the Endocrine Society; https://doi.org/10.1210/jendso/bvad022

Abstract:
X-Linked Hypophosphatemia (XLH) is a genetic disease, causing life-long hypophosphatemia due to overproduction of FGF23. XLH is associated with Chiari malformations, cranial synostosis, and syringomyelia. FGF23 signals through FGFR1c and requires a co-receptor, α-Klotho, which is expressed in the renal distal convoluted tubules and the choroid plexus (ChP). In the ChP, α-Klotho participates in regulating cerebral spinal fluid (CSF) production by shuttling the sodium/potassium adenosine triphosphatase (Na+/K+-ATPase) to the luminal membrane. The sodium/potassium/chloride cotransporter 1 (NKCC1) also makes a substantial contribution to CSF production. Since CSF production has not been studied in XLH, we sought to determine if there are changes in the expression of these molecules in the ChP of Hyp mice, the murine model of XLH, as a first step towards testing the hypothesis that altered CSF production contributes to the cranial and spinal malformations seen this disease. Real-time PCR (RT-PCR) demonstrated significant upregulation of Klotho transcripts in the fourth ventricle of Hyp mice compared to controls. Transcript levels for Fgfr1c were unchanged in Hyp mice. Atp1a1 transcripts encoding the alpha-1 subunit of Na+/K+-ATPase were significantly downregulated in in the third and lateral ventricles. Expression levels of the Slc12a2 transcript (which encodes NKCC1) were unchanged in Hyp mice compared to controls. In situ hybridization (ISH) was used to obtain anatomical correlates to the changes observed by RT-PCR. ISH confirmed the presence of all four transcripts in the lateral ventricle ChP of both WT and Hyp mice. This is the first study to document a significant change in the level of expression of the molecular machinery required for CSF production in Hyp mice. Whether similar changes occur in patients with XLH, potentially contributing to the cranial and spinal cord abnormalities frequently seen in XLH, remains to be determined.
, Stephanie Kim, Javier Villanueva-Meyer, Catherine Coupe, Arabella Young, Jee Hye Kang, , Gabriela Schmajuk, Stephanie Rush, , et al.
Published: 6 February 2023
Journal of the Endocrine Society; https://doi.org/10.1210/jendso/bvad012

Abstract:
Introduction: Hypophysitis is a known immune related adverse event (irAE) of immune checkpoint inhibitors (CPIs), commonly associated with CTLA-4 inhibitors and less often with PD-1/PD-L1 inhibitors. Methods: We examined the clinical and biochemical characteristics, magnetic resonance imaging (MRI) of the pituitary and association with HLA type in patients with CPI-induced hypophysitis (CPI-hypophysitis). Results: Forty-nine patients were identified. Mean age was 61.3 years, 61.2% were men, 81.6% were Caucasian, 38.8% had melanoma and 44.5% received PD-1/PD-L1 inhibitor monotherapy while the remainder received CTLA-4 inhibitor monotherapy or CTLA-4/PD-1 inhibitor combination therapy. A comparison of CTLA-4 inhibitor exposure versus PD-1/PD-L1 inhibitor monotherapy revealed faster time to CPI-hypophysitis (median 84 days vs 185 days, p<0.01) and abnormal pituitary appearance on MRI [odds ratio (OR) 7.00, p=0.03]. We observed effect modification by sex in the association between CPI-type and time to CPI-hypophysitis. In particular, anti-CTLA-4 exposed men had a shorter time to onset than women. MRI changes of the pituitary were most common at the time of hypophysitis diagnosis (55.6% enlarged, 37.0% normal, 7.4% empty or partially empty) but persisted in follow up (23.8% enlarged, 57.1% normal, 19.1% empty or partially empty). HLA typing was done on 55 subjects; HLA type DQ0602 was overrepresented in CPI-hypophysitis relative to the Caucasian American population (39.4% vs 21.5%, p=0.01) and CPI population. Conclusion: The association of CPI-hypophysitis with HLA DQ0602 suggests a genetic risk for its development. The clinical phenotype of hypophysitis appears heterogenous with differences in timing of onset, changes in thyroid function tests, imaging changes on MRI and possibly sex related to CPI-type. These factors may play an important role in our mechanistic understanding of CPI-hypophysitis.
David T Asuzu, Shyama Bhatt, Diana Nwokoye, Christina Hayes, Michaela Cortes, Raven McGlotten, Meg Keil, , Lynnette Nieman,
Published: 6 February 2023
Journal of the Endocrine Society; https://doi.org/10.1210/jendso/bvad025

Abstract:
Structured Context: Early prediction of hypothalamic-pituitary-adrenal (HPA) axis function following transsphenoidal surgery (TSS) can improve patient safety and reduce costs. Objective: Systematic measurement of adrenocorticotropin (ACTH) and cortisol at extubation following anesthesia to predict remission from Cushing’s disease (CD), and HPA axis preservation following non-CD surgery. Design: Retrospective analysis of clinical data between August 2015 and May 2022. Setting: Referral center. Patients: Consecutive patients (n = 129) undergoing TSS who had peri-operative ACTH and cortisol measurements. Interventions: ACTH and cortisol measurement at extubation. Further serial 6-hourly measurements in CD patients. Main outcome measures: Prediction of future HPA axis status based on ACTH/cortisol at extubation. Results: ACTH and cortisol increased sharply in all patients at extubation. CD patients (n=101) had lower ACTH values than non-CD patients (110.1 vs 293.1 pg/mL; P <0.01). In non-CD patients, lower plasma ACTH at extubation predicted the need for eventual corticosteroid replacement (105.8 vs. 449.1 pg/mL, P < 0.01). In CD patients, the peak post-extubation cortisol at 6 hours was a robust predictor for non-remission (60.7 vs. 219.2 µg/dL, p = 0.03). However, normalized early post-operative value (NEPV, the post-extubation values minus the peak preoperative CRH or DDAVP test values) of cortisol reliably distinguished non-remission earlier, at the time of extubation (-6.1 versus 5.9, P = 0.01) and later. Conclusions: We found that at extubation following TSS, ACTH can predict the need for eventual steroid replacement in non-Cushing’s patients. In patients with CD, we found a robust prediction of non-remission with NEPV cortisol at extubation and later.
, Hiraku Kameda, Masaaki Yamamoto, Toru Tateno, Yasumasa Iwasaki, , , Hiba Hashmi, Angela Radulescu, Lynn A Burmeister, et al.
Published: 3 February 2023
Journal of the Endocrine Society; https://doi.org/10.1210/jendso/bvad023

Abstract:
Context: The coronavirus disease 2019 (COVID-19) pandemic challenged undertaking gradual educational activities for residency and fellowship trainees. However, recent technological advances have enabled broadening active learning opportunities through international online conferences. Objective: The format of our international online endocrine case conference, launched during the pandemic, is introduced. The objective impact of this program on trainees is described. Methods: Four academic facilities developed a semi-annual international collaborative endocrinology case conference. Experts were invited as commentators to facilitate in-depth discussion. Six conferences were held between 2020 and 2022. After the fourth and sixth conferences, anonymous multiple-choice online surveys were administered to all attendees. Results: Participants included trainees and faculty. In each conference, 3-5 cases of rare endocrine diseases from up to 4 institutions were presented, mainly by trainees. Sixty-two percent of attendees reported 4 facilities as the appropriate size for the collaboration to maintain active learning in case conferences. Eighty-two percent of attendees preferred a semi-annual conference. The survey also revealed the positive impact on trainees’ learning regarding diversity of medical practice, academic career development, and confidence in honing of presentation skills. Conclusion: We present an example of our successful virtual global case conference to enhance learning of rare endocrine cases. For the success of the collaborative case conference, we suggest smaller cross-country institutional collaborations. Preferably, they would be international, semi-annual based, and with recognized experts as commentators. Since our conference has engendered multiple positive impacts on trainees and faculty, continuation of virtual education should be considered even following the pandemic era.
Ning Ding, Emily Zheutlin, Siobán D Harlow, John F Randolph, ,
Published: 3 February 2023
Journal of the Endocrine Society; https://doi.org/10.1210/jendso/bvad024

Abstract:
Phthalates, ubiquitous endocrine-disrupting chemicals, may impact ovarian folliculogenesis and steroidogenesis. We examined the associations of urinary phthalate metabolites with hormones including estradiol, testosterone, follicle-stimulating hormone (FSH), sex hormone-binding globulin (SHBG), and anti-Müllerian hormone (AMH), and timing of natural menopause in midlife women. Data were from 1,189 multi-racial/ethnic women aged 45-56 years without hormone therapy from the Study of Women’s Health Across the Nation (SWAN). Urinary concentrations of 12 phthalate metabolites and hormones were repeatedly measured in 1999-2000 and 2002-2003, resulting in a total of 2,111 observations. Linear mixed-effect models were used to calculate percent differences (%D) and 95% confidence intervals (95% CIs) in serum concentrations of estradiol, testosterone, FSH, SHBG, and AMH. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% CIs of natural menopause. We observed significant associations of phthalate metabolites with lower testosterone concentrations: MCOP with testosterone (%D: -2.08%, 95% CI: -3.66, -0.47), and MnBP with testosterone (%D: -1.99%, 95% CI: -3.82, -0.13), after adjusting for multiple comparisons with false discovery rates<5%. Lower AMH concentrations were also found with higher MECPP (%D: -14.26%, 95% CI: -24.10, -3.14), MEHHP (%D: -15.58%, 95% CI: -24.59, -5.50), and MEOHP (%D: -13.50%, 95% CI: -22.93, -2.90). No associations were observed for other hormones or timing of natural menopause. These results suggest that exposure to phthalates may affect circulating levels of testosterone and diminish the ovarian reserve in midlife women. Given the widespread exposure, reduced exposure to phthalates may be a key step to prevent reproductive effects of phthalates.
Published: 2 February 2023
Journal of the Endocrine Society; https://doi.org/10.1210/jendso/bvad014

Abstract:
Context Adults with cerebral palsy (CP) display a higher prevalence of cardiometabolic disease compared to the general population. Studies examining cardiometabolic disease risk in children with CP are limited. Purpose The purpose of this study was to determine if children with CP exhibit higher cardiometabolic risk than typically developing children, and to examine its relationship with visceral adiposity and physical activity. Methods Thirty ambulatory children with CP and 30 age-, sex-, and race-matched typically developing control children were tested for blood lipids, glucose, and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Visceral fat was assessed using dual-energy X-ray absorptiometry. Physical activity was assessed using accelerometer-based monitors. Results Children with CP had higher total, low-density lipoprotein, and non-high-density lipoprotein (non-HDL-C) cholesterol, glucose, prevalence of dyslipidemia, prevalence of prediabetes, and visceral fat mass index (VFMI), and lower physical activity than controls (all p < 0.05). In the groups combined, non-HDL-C and glucose were positively related to VFMI (r = 0.337 and 0.313, respectively, p < 0.05), and non-HDL-C and HOMA-IR were negatively related to physical activity (r = -0.411 and -0.368, respectively, p < 0.05). HOMA-IR was positively related to VFMI in children with CP (r = 0.698, p < 0.05), but not in controls. Glucose was not related to physical activity in children with CP, but was negatively related in controls (r = -0.454, p < 0.05). Conclusions Children with CP demonstrate early signs of cardiometabolic disease, which are more closely related to increased visceral adiposity than decreased physical activity.
Yee-Ming M Cheung, Ole-Petter R Hamnvik, Afreen Shariff,
Published: 1 February 2023
Journal of the Endocrine Society; https://doi.org/10.1210/jendso/bvad019

Abstract:
Immune checkpoint inhibitors (ICIs) are a rapidly expanding class of targeted therapies effective in the treatment of various cancers. However, whilst efficacious, ICIs have been associated with treatment complications, namely immune-related adverse events (irAEs). IrAEs of the endocrine system are amongst the most commonly reported irAEs, but despite their high incidence, standardized disease definitions and endocrine IrAE-specific International Classification of Disease (ICD) codes remain lacking. This dearth of standardized nomenclature and ICD codes has in many ways, impeded both the clinical care of patients and the progress of endocrine irAE-related research. ICD codes are used internationally and are essential for medical claims reporting in the healthcare setting, and provide a universal language system for recording, reporting, and monitoring diseases. These codes are also a well-accepted form of electronic health record data capture that facilitates the collection, storage and sharing of data. Therefore, the lack of standardized disease definitions and ICD codes has been associated with misclassification and suboptimal management of individuals with endocrine irAEs, and has also been associated with reduced data availability, comparability, and quality. Harmonized and clinically relevant disease definitions along with the subsequent development of endocrine-irAE-specific ICD codes will provide a systematic approach to understand the spectrum and burden of endocrine irAE diseases, and will have a positive impact across clinical, public health and research settings.
Published: 31 January 2023
Journal of the Endocrine Society; https://doi.org/10.1210/jendso/bvad018

Abstract:
Objective: we assessed the diagnostic accuracy of insulin-like growth factor 1 (IGF-1) measurements with one growth hormone stimulation test (GHST) versus performing two GHSTs as the standard test to confirm the diagnosis of growth hormone deficiency (GHD) in children. Methods: we retrospectively analyzed the baseline characteristics, anthropometric measurements, and laboratory data of 703 children with short stature, aged 4–14 years (mean age, 8.46 ± 2.7 years), who had undergone two GHSTs. We compared the diagnostic values of IGF-1 levels by using a cutoff value of ≤ 0 standard deviation score (SDs), along with results of a single clonidine stimulation test (CST). We evaluated the false-positive rate, specificity, likelihood ratio, and area under the curve (AUC) of the two diagnostic methods. GHD was diagnosed if the peak growth hormone level was <7 ng/mL on two GHSTs. Results: Of the children, 577 (79.7%) had a low IGF-1 level (mean, 104.9 ± 61.4 ng/mL), and 147 (20.3%) had a normal IGF-1 level (mean, 145.9 ± 86.9 ng/mL). GHD was diagnosed in 187 patients (25.8%), of whom 146 (25.3%) had a low IGF-1 level. An IGF-1 level reflecting ≤ 0 SDs in combination with results of a single CST had a specificity of 92.6%, a false-positive rate of 5.5%, and an AUC of 0.6088. Using an IFG-1cut-off level of ≤–2 SDs didn’t alter the diagnostic accuracy. Conclusions: Low IGF-1 values of ≤0 SDs or ≤–2 SDs in combination with results of a single CST had poor diagnostic accuracy for GHD.
, Jennifer A Collister, Lei Clifton, David J Hunter, Thomas J Littlejohns
Published: 30 January 2023
Journal of the Endocrine Society; https://doi.org/10.1210/jendso/bvad020

Abstract:
Objective To investigate whether genetic risk of type 2 diabetes modifies associations between body mass index (BMI) and first degree family history of diabetes with 1) prevalent pre-diabetes or undiagnosed diabetes; and 2) incident confirmed type 2 diabetes. Methods We included 431,658 40-69 year olds at baseline of multi-ethnic ancestry from the UK Biobank. We used a multi-ethnic polygenic risk score for type 2 diabetes (PRST2D) developed by Genomics PLC. Pre-diabetes or undiagnosed diabetes was defined as baseline HbA1c ≥ 42 mmol/mol (6.0%) and incident type 2 diabetes was derived from medical records. Results At baseline, 43,472 participants had pre-diabetes or undiagnosed diabetes, and 17,259 developed type 2 diabetes over 15 years follow-up. Dose-response associations were observed for PRST2D with each outcome in each category of BMI or first degree family history of diabetes. Those in the highest quintile of PRST2D with a normal BMI, were at the similar risk as those in the middle quintile who were overweight. Participants who were in the highest quintile of PRST2D and did not have a first degree family history of diabetes were at the similar risk than those with a family history who were in the middle category of PRST2D. Conclusions Genetic risk of type 2 diabetes remains strongly associated with risk of pre-diabetes, undiagnosed diabetes and future type 2 diabetes within categories of non-genetic risk factors. This could have important implications for identifying individuals at risk of type 2 diabetes for prevention and early diagnosis programmes.
, David J Torpy
Published: 30 January 2023
Journal of the Endocrine Society; https://doi.org/10.1210/jendso/bvad017

Abstract:
Context: Adrenal insufficiency-related morbidity persists despite efforts to minimise its impact. Reasons for this are unknown and warrant examination. Objective: To investigate trends in adrenal insufficiency hospitalisations and glucocorticoid replacement therapy use. Methods: Data on hospitalisations for a principal diagnosis of adrenal insufficiency and prescriptions for short-acting glucocorticoids between 2000 to 2019 were extracted from national repositories. Age standardised admission and prescription rates were calculated using census data. Rates were compared over time overall and according to age, sex, and disease subtype. Results: Adrenal insufficiency admissions increased by 62.0%, from 36.78/million to 59.59/million (trend p < 0.0001). Adrenal crisis admissions also increased, by 90.1% (from 10.73/million to 20.40/million, trend, p < 0·00001). These increases were more pronounced in the second decade. Prescriptions for short-acting glucocorticoids also increased (by 67.2%, from 2198.36/million in 2000/1 to 3676.00/million). Females had higher average admission rates and a greater increase in admission rates than males. Increased adrenal insufficiency admissions were found in all age groups among females but only in men aged 70 + yrs. Secondary adrenal insufficiency admission rates increased by 91.7%, while admission rates for primary adrenal insufficiency remained unchanged. Conclusion: The prevalence of adrenal insufficiency and hospitalisations for this disorder (including adrenal crises) have increased since 2000, with a greater increase occurring after 2010. Admission rates for secondary adrenal insufficiency increased but primary adrenal insufficiency admissions remained stable. Possible causes include immunotherapies for malignancy, increased cranial imaging detecting pituitary tumours and their subsequent treatment, and increased use of low dose short acting glucocorticoid replacement therapy.
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