Background: Recent recommendations guiding appropriate use of telemedicine for endocrinology care have largely relied on expert opinion due to limited evidence on factors that increase quality of telemedicine care. In this study, we assessed the perspectives of front-line specialists on factors and strategies perceived to increase quality of diabetes care delivered via telemedicine after more than two years of widespread use. Methods: Adult diabetes specialists in two academic health systems who recently used video-based telemedicine to provide diabetes care were invited to participate in an online survey study between March and April 2022. Likert-style questions, followed by related open-ended questions, assessed perspectives on availability of key resources, factors affecting quality, and anticipated benefits from telemedicine for diabetes. Results: Response rate was 52% (56/111). More than half (54%) of participants reported better overall quality of diabetes care with face-to-face care vs. telemedicine. Participants reported clinical data supporting high-quality care, such as home blood glucose readings and vital signs, was often not available with telemedicine. Patient factors, including comorbidities and communication barriers, reduced anticipated benefit from telemedicine, while geographic and mobility barriers increased expected benefit. Providers described multiple healthcare setting resources that could promote high-quality telemedicine diabetes care, including greater support for sharing patient-generated health data and coordinating multidisciplinary care. Conclusions: After two years of sustained use, diabetes specialists identified telemedicine as an important way to enhance access to care. However, specialists identified additional supports needed to increase appropriate use and delivery of high-quality telemedicine care for patients with complex clinical needs.

Context: Hypothalamic obesity is a rare, treatment-resistant form of obesity. In preliminary studies, the hypothalamic hormone oxytocin (OXT) has shown promise as a potential weight loss therapy. Objective: To determine whether 8 weeks of intranasal OXT (vs. 8 weeks of placebo) promotes weight loss in children, adolescents, and young adults with hypothalamic obesity. Design: Randomized, double-blind, placebo-controlled, cross-over pilot trial (NCT02849743). Setting: Outpatient academic medical center. Participants: Aged 10y to 35y, hypothalamic obesity from hypothalamic/pituitary tumors. Intervention: Intranasal OXT (Syntocinon, 40 USP units/mL, 4 IU/spray) vs. excipient-matched placebo, 16-24 IU three times daily at mealtimes. Main outcome measure(s): Weight loss attributable to OXT vs. placebo, safety (adverse events). Results: Of 13 individuals randomized (54% female, 31% pre-pubertal, median age 15.3y, IQR 13.3-20.6), 10 completed the entire study. We observed a non-significant within-subject weight change of -0.6 kg (95% CI: -2.7, 1.5) attributable to OXT vs. placebo. A subset (2/18 screened, 5/13 randomized) had prolonged QTc interval on electrocardiography (ECG) prior to screening and/or in both treatment conditions. Overall, OXT was well-tolerated, and adverse events (epistaxis and nasal irritation, headache, nausea/vomiting, and changes in heart rate, blood pressure, and QTc interval) were similar between OXT and placebo. In exploratory analyses, benefits of OXT for anxiety and impulsivity were observed. Conclusions: In this pilot study in hypothalamic obesity, we did not detect a significant impact of intranasal OXT on body weight. OXT was well-tolerated, so future larger studies could examine different dosing, combination therapies, as well as potential psychosocial benefits.

Background In this proof-of-concept study we evaluated if monogenic diabetes due to mutations of the HNF-1α gene (HNF1A-MODY) has a distinctive continuous glucose monitoring (CGM) glucotype, in comparison to type 1 diabetes (T1D). Methods Using CGM data from 5 HNF1A-MODY and 115 T1D subjects we calculated multiple glucose metrics, including measures of within- and between-day variability (such as coefficient variation for each hour (CV_{b_1h}). Results The MODY and T1D cohorts had minimum CV_{b_1h} of 11.3 ± 4.4 and 18.0 ± 4.9, respectively (p = 0.02), and maximum CV_{b_1h} of 33.9 ± 5.0 and 50.3 ± 10, respectively (p < 0.001). All HNF1A-MODY subjects had minimum %CV_{b_1h} ≤ 17.3% and maximum %CV_{b_1h} ≤ 37.1%. In contrast, only 12 of 115 T1D subjects had both a minimum and maximum %CV_{b_1h} below these thresholds (p < 0.001). Conclusion HNF1A- MODY is characterized by a low-hourly between-day glucose variability. CGM-derived glucose metrics may have potential applicability for screening for atypical diabetes phenotypes in the T1D population.

Context: The effects of androgen therapy on arterial function in transgender men (TM) are not fully understood, particularly concerning long-term androgen treatment. Objective: To evaluate arterial stiffness in TM receiving long-term gender-affirming hormone therapy by carotid-femoral pulse wave velocity (cf-PWV). Design: A cross-sectional case-control study. Setting: Gender Dysphoria Unit of the Division of Endocrinology, HC-FMUSP, Sao Paulo, Brazil. Patients: Thirty-three TM receiving intramuscular testosterone (T) esters as regular treatment for an average time of 14 ± 8 years were compared to 111 healthy cisgender men and women controls matched for age and body mass index (BMI). Aortic stiffness was evaluated by cf-PWV measurements using the Complior® device post-testosterone therapy. Main outcome measures: Aortic stiffness by carotid-femoral pulse wave velocity (cf-PWV) as a cardiovascular risk marker in transgender men and control group. Results: The cf-PWV after long-term testosterone therapy was significantly higher in TM (7.4 ± 0.9 m/s; range: 5.8–8.9 m/s) than in cisgender men (6.6 ± 1.0 m/s; range: 3.8–9.0 m/s, p < 0.01) and cisgender women controls (6.9 ± 0.9 m/s; range: 4.8–9.1 m/s, p = 0.02). The cf-PWV was significantly and positively correlated with age. Analysis using blood pressure as a covariate showed a significant relationship between TM SBP and cf-PWV in relation to cisgender women but not to cisgender men. The age, the SBP and the diagnosis of hypertension were independently associated with cf-PWV in transgender men group. Conclusions: The TM group on long-term treatment with testosterone had higher aging-related aortic stiffening than the control groups. These findings indicate that aortic stiffness might be accelerated in the TM group receiving the gender-affirming hormone treatment, and suggest a potential deleterious effect of testosterone on arterial function. Preventive measures in TM individuals receiving testosterone treatment, who are at higher risk for cardiovascular events, are highly recommended.

Fluctuations of reproductive hormones are associated with various forms of sleep disturbances and specific sleep disorders, e.g. insomnia or sleep-disordered breathing, across different stages of reproductive ageing. During the menstrual cycle, sleep is particularly disrupted during the late luteal phase as demonstrated by both objective and subjective measurements of sleep. Progesterone and its metabolites generally have sleep promoting effects. A steep decline in progesterone, e.g. during the late luteal phase, is associated with sleep disruption. Endogenous estrogen shows no clear correlation with sleep alterations in relation to the menstrual cycle. During pregnancy, sleep disruption is not associated with changes in estrogen or progesterone but rather with changing physiological factors, e.g. nocturnal micturition, gastroesophageal reflux or musculoskeletal discomfort, all substantial factors that most likely mask any effect of hormones. Both endogenous and exogenous estrogen, as well as progesterone, are positively associated with sleep during the menopausal transition. A marked improvement of sleep disturbances is observed with perimenopausal hormone therapy. As this effect is not seen in younger women receiving contraceptive therapy, other causes of sleep disturbances, e.g. ageing and related changes in metabolism of stress hormones, secondary effects of vasomotor symptoms or depression, must be considered. Gonadotropins are less associated with sleep disturbances than ovarian hormones, except for during the menopausal transition where follicle-stimulating hormone (FSH) is related to sleep disruption. Further, hyperandrogenism, as seen in women with polycystic ovary syndrome (PCOS), is associated with sleep disturbances and specific sleep disorders, e.g. obstructive sleep apnea (OSA).

Multiple tumors in the same patient suggest a genetic predisposition. Here, we report a patient who presented with several unusual types of malignant and benign tumors, presumably due to a pathogenic germline PMS1 mutation. Case: A 69-year-old woman presented with a 2-year history of abdominal pain and diarrhea. A computed Tomography (CT) scan of the abdomen revealed a gastrointestinal neuroendocrine tumor (GiNET) with liver metastases and a non-functional benign adrenal adenoma. Bilateral large lung nodules were thought to be also metastases from the GiNET but turned out to be differentiated thyroid cancer metastases, which later progressed to anaplastic thyroid cancer (ATC) and led to the patient's demise. A right sphenoid wing meningioma causing partial hypopituitarism was diagnosed during her evaluation. A mammogram and a breast ultrasound revealed a 0.3 cm left breast nodule. Due to the multiplicity of her tumors, whole exome sequencing was performed. This revealed a previously described PMS1 deletion mutation causing a frameshift and truncation (NM_000534c.1258delC, p.His420Ilefs*22) but no other pathogenic variant in other cancer genes. DNA isolated from the ATC tumor tissue showed loss of heterozygosity of the same mutation, highly suggestive of its pathogenic role in thyroid cancer and presumably other tumors Conclusion: This case reports several tumors including thyroid cancer, GiNET, adrenal adenoma, meningioma and breast nodule, likely due to the PMS1 mutation found in this patient.

Polycystic ovary syndrome (PCOS) is an endocrinopathy characterized by hyperandrogenism, anovulation, and polycystic ovaries, in which hyperandrogenism manifests by excess androgen and other steroid hormone abnormalities. Mitochondrial fusion is essential in steroidogenesis, while the role of mitochondrial fusion in granulosa cells of hyperandrogenic PCOS patients remains unclear. In this study, mRNA expression of mitochondrial fusion genes mitoguardin1, −2 (MIGA 1, −2) was significantly increased in granulosa cells of hyperandrogenic PCOS but not PCOS with normal androgen levels, their mRNA expression positively correlated with testosterone levels. Dihydrotestosterone (DHT) treatment in mice led to high expression of MIGA2 in granulosa cells of ovulating follicles. Testosterone or forskolin/ phorbol 12-myristate 13-acetate treatments increased expression of MIGA2 and the steroidogenic acute regulatory protein (StAR) in KGN cells. MIGA2 interacted with StAR and induced StAR localization on mitochondria. Furthermore, MIGA2 overexpression significantly increased cAMP-activated protein kinase A (PKA) and phosphorylation of AMP-activated protein kinase (pAMPK) at T172 but inhibited StAR protein expression. However, MIGA2 overexpression increased CYP11A1, HSD3B2, and CYP19A1 mRNA expression. As a result, MIGA2 overexpression decreased progesterone but increased estradiol synthesis. Besides the androgen receptor, testosterone or DHT might also regulate MIGA2 and pAMPK (T172) through LH/choriogonadotropin receptor-mediated PKA signaling. Taken together, these findings indicate that testosterone regulates MIGA2 via PKA/AMP-activated protein kinase signaling in ovarian granulosa cells. It is suggested mitochondrial fusion in ovarian granulosa cells is associated with hyperandrogenism and potentially leads to abnormal steroidogenesis in PCOS.

Adipokines secreted from adipose tissue, such as adiponectin and leptin, enhance skeletal muscle metabolism. Animal studies have shown that adipokine knockout leads to a reduction in muscle function. Muscle function is determined by muscle size and quality; therefore, it is speculated that lower adipokine levels affect skeletal muscle size and quality, eventually leading to lower muscle function. This study aimed to investigate the relationship between adipokines and skeletal muscle morphology and function in young individuals. A total of 21 young women participated in this study. Adiponectin and leptin levels were analyzed using fasting blood samples from all participants. B-mode ultrasound images of the thigh and calf were obtained, and the muscle thickness and echo intensity were measured in the vastus lateralis (VL) and medial gastrocnemius (MG). The shear modulus was measured from the VL and MG using shear wave elastography. Knee extension and plantar flexion peak torques were measured as muscle functions. Adiponectin and leptin were not related to echo intensity, shear modulus and muscle thickness in the VL and MG (r_s= ˗0.26−0.37, P>0.05). Furthermore, no relationship was observed between adiponectin, leptin, knee extension, and dorsiflexion peak torque (r_s= ˗0.28−0.41, P>0.05). These negative results suggest that adiponectin and leptin levels in young women are not associated with muscle size and quality, nor are they related to muscle function.

Context: Metabolic syndrome (MetS) is associated with increased risk of severe coronavirus disease-2019 (COVID-19). MetS inflammatory biomarkers share similarities with those of COVID-19, yet this association is poorly explored. Objective: Biomarkers of COVID-19 patients with and without MetS, the combination of diabetes, hypertension, obesity and/or dyslipidemia, were analyzed to identify biological predictors of COVID-19 severity. Design: In this prospective observational study, clinical and proteomics data were analyzed from March 24 to April 30, 2020. Setting: The study took place in a large academic emergency department in Boston, Massachusetts. Patients or other participants: Patients age ≥18 with a clinical concern for COVID-19 upon arrival and acute respiratory distress were included. Intervention(s): Not applicable. Main outcome measures (s): The main outcome was severe COVID-19 as defined using World Health Organization COVID-19 outcomes scores ≤4, which describes patients who died, required invasive mechanical ventilation or required supplemental oxygen. Results: Among 155 COVID-19 patients, 90 (58.1%) met the definition of MetS and 65 (41.9%) were identified as Control. The MetS cohort was more likely to have severe COVID-19 compared to the Control cohort (OR 2.67 [CI 1.09-6.55]). Biomarkers, including CXCL10 (OR 1.94 [CI 1.38-2.73]), CXCL9 (OR 1.79 [CI 1.09-2.93]), HGF (OR 3.30 [CI 1.65-6.58]) and IL6 (OR 2.09 [CI 1.49-2.94]) were associated with severe COVID-19. However, when stratified by MetS, only CXCL10 (OR 2.39 [CI 1.38-4.14]) and IL6 (OR 3.14 [CI 1.53-6.45]) were significantly associated with severe COVID-19. Conclusions: MetS-associated severe COVID-19 is characterized by an immune signature of elevated levels of CXCL10 and IL6. Clinical trials targeting CXCL10 or IL6 antagonism in this population may be warranted.

Context Acromegaly presents a unique pattern of lower adiposity and insulin resistance in active disease but reduction in insulin resistance despite a rise in adiposity after surgery. Depot specific adipose tissue masses and ectopic lipid are important predictors of insulin resistance in other populations, but whether they are in acromegaly is unknown. Long-term persistence of body composition changes after surgery is unknown. Objectives To determine how depot-specific body composition and ectopic lipid relate to insulin resistance in active acromegaly and whether their changes with surgery are sustained long-term. Design Cross-sectional study in patients with active acromegaly and longitudinal study in in newly diagnosed patients studied before and in long-term follow up, 3(1-8) years (median, range), after surgery. Patients 71 with active acromegaly studied cross-sectionally and 28 with newly diagnosed acromegaly studied longitudinally. Main Outcome Measures Visceral (VAT), subcutaneous (SAT) and inter-muscular (IMAT) adipose tissue masses by whole-body magnetic resonance imaging (MRI); intrahepatic lipid (IHL) by proton magnetic resonance spectroscopy (¹H-MRS), insulin resistance measures derived from fasting and OGTT insulin and glucose levels. Results SAT and IGF-1 level, but not VAT or IHL, were independent predictor of insulin resistance in active acromegaly. VAT, SAT and IHL gains were sustained long-term after surgery. VAT mass rise with surgery correlated inversely with rise in QUICKI while SAT rise correlated with fall in HOMA score. Conclusions SAT and disease activity are important predictors of insulin resistance in active acromegaly. Adiposity gains are sustained long-term after surgical treatment and impact on the accompanying improvement in insulin resistance.

Context: Thyroid hormone (TH) abuse for performance enhancement in sport remains controversial and it is not prohibited in sports under the World Anti-Doping Code. However, the prevalence of TH usage in athletes is not known.Objective: We investigated TH use among Australian athletes undergoing antidoping tests for competition in World Anti-Doping Agency (WADA)–compliant sports by measuring TH in serum and surveying mandatory doping control form (DCF) declarations by athletes of all drugs used in the week prior to the antidoping test.Methods: Serum thyroxine (T4), triiodothyronine (T3), and reverse T3 were measured by liquid chromatography–mass spectrometry and serum thyrotropin, free T4, and free T3 by immunoassays in 498 frozen serum samples from antidoping tests together with a separate set of 509 DCFs.Results: Two athletes had biochemical thyrotoxicosis giving a prevalence of 4 per 1000 athletes (upper 95% confidence limit [CL] 16). Similarly, only 2 of 509 DCFs declared usage of T4 and none for T3, also giving a prevalence of 4 (upper 95% CL 16) per 1000 athletes. These estimates were consistent with DCF analyses from international competitions and lower than the estimated T4 prescription rates in the age-matched Australian population.Conclusion: There is minimal evidence for TH abuse among Australian athletes being tested for competing in WADA-compliant sports.

Context Growth hormone (GH) therapy can increase linear growth in patients with growth hormone deficiency (GHD), Turner syndrome (TS), Noonan syndrome (NS), and Prader-Willi syndrome (PWS), although outcomes vary by disease state. Objective To assess growth and identify factors associated with growth response with long-term GH therapy. Design, Setting, and Participants Data from pediatric patients with GHD, TS, NS, and PWS obtained at GH treatment initiation (baseline) and annually for 5 years in the ANSWER Program and NordiNet® IOS were analyzed retrospectively. Height standard deviation score (HSDS) was assessed over time, and multivariate analyses determined variables with significant positive effects on growth outcomes in each patient cohort. Results Data from patients with GHD (n = 12,683), TS (n = 1307), NS (n = 203), and PWS (n = 102) were analyzed. HSDS increased over time during GH treatment in all cohorts. Factors with significant positive effects on ΔHSDS were younger age at GH initiation and lower HSDS at baseline (all cohorts) and higher GH dose (GHD and TS only); sex had no effect in any cohort. The modeling analysis showed that ΔHSDS was greatest in year 1 and attenuated over consecutive years through year 5. Estimated LS mean ΔHSDS values at year 5 by cohort were 1.702 (females) and 1.586 (males) in GHD, 1.033 in TS, 1.153 in NS, and 1.392 in PWS. Conclusions Long-term GH therapy results in large increases in HSDS in patients with GHD, TS, NS, and PWS. Greater gains in HSDS can be obtained with higher GH doses and earlier initiation of treatment.

The Editors of Journal of the Endocrine Society thank all those who reviewed during 2022 for their time and effort.

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.

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.

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 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 perioperative 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 nonremission (60.7 vs 219.2 µg/dL, P = 0.03). However, normalized early postoperative value (NEPV; the post-extubation values minus the peak preoperative CRH or desmopressin test values) of cortisol reliably distinguished nonremission earlier, at the time of extubation (−6.1 vs 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 nonremission with NEPV cortisol at extubation and later.

Context: The 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 semiannual 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. At each conference, 3 to 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 semiannual 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 about rare endocrine cases. For the success of the collaborative case conference, we suggest smaller cross-country institutional collaborations. Preferably, they would be international, semiannually based, and with recognized experts as commentators. Since our conference has engendered multiple positive effects on trainees and faculty, continuation of virtual education should be considered even after the pandemic era.

Phthalates, ubiquitous endocrine-disrupting chemicals, may affect 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 1189 multiracial/multiethnic women aged 45 to 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 to 2000 and 2002 to 2003, resulting in a total of 2111 observations. Linear mixed-effect models were used to calculate percentage differences (%D) and 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 statistically significant associations of phthalate metabolites with lower testosterone concentrations: MCOP with testosterone (%D: −2.08%; 95% CI, −3.66 to −0.47) and MnBP with testosterone (%D: −1.99%; 95% CI, −3.82 to −0.13), after adjusting for multiple comparisons with false discovery rates less than 5%. Lower AMH concentrations were also found with higher MECPP (%D: −14.26%; 95% CI, −24.10 to −3.14), MEHHP (%D: −15.58%; 95% CI, −24.59 to −5.50), and MEOHP (%D: −13.50%; 95% CI, −22.93 to −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.

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.

Immune checkpoint inhibitors (ICIs) are a rapidly expanding class of targeted therapies effective in the treatment of various cancers. However, while efficacious, ICIs have been associated with treatment complications, namely immune-related adverse events (irAEs). IrAEs of the endocrine system are among the most commonly reported irAEs, but despite their high incidence, standardized disease definitions and endocrine IrAE-specific International Classification of Diseases (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 health care setting, and they 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 understanding the spectrum and burden of endocrine irAE diseases, and will have a positive effect across clinical, public health, and research settings.

Objective: we assessed the diagnostic accuracy of insulin-like growth factor (IGF) 1 measurements with 1 growth hormone stimulation test (GHST) vs performing 2 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 2 GHSTs. We compared the diagnostic values of IGF-1 levels by using a cut-off value of ≤0 SD score, 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 2 diagnostic methods. GHD was diagnosed if the peak growth hormone level was <7 ng/mL on 2 GHSTs.Results: Of the 724 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-1 cut-off level of ≤−2 SDs did not alter the diagnostic accuracy.Conclusion: Low IGF-1 values of ≤0 SDs or ≤−2 SDs in combination with results of a single CST had poor diagnostic accuracy for GHD.

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 (PRS_T2D) 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 PRS_T2D with each outcome in each category of BMI or first degree family history of diabetes. Those in the highest quintile of PRS_T2D 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 PRS_T2D 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 PRS_T2D. 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.

Context: Recurrent hypoglycemia can result in significant neurological impairments in children and continuous glucose monitoring (CGM) technology has been shown to reduce recurrent hypoglycemia in conditions such as type 1 diabetes. In the United Kingdom, CGM devices are currently only recommended by the National Institute of Clinical Excellence (NICE) for patients with diabetes and not for other diagnoses.Objective: To examine access to CGM technology for children and young people with recurrent hypoglycemia in the United Kingdom.Methods: In 2021, the British Society of Paediatric Endocrinology and Diabetes (BSPED) conducted a national health professional survey in England, Wales, Scotland, and Northern Ireland looking at CGM access to funding for children and young people with recurrent hypoglycemia, without the diagnosis of diabetes. The UK Children's Hyperinsulinism Charity (UK CHC) also conducted a national patient survey.Results: Responses from BSPED were received from 55 units while the UK CHC received 69 responses from individual families, the largest response to a survey carried out by the charity. The results of the BSPED and UK CHC surveys found that funding streams for CGM were highly variable. Only 29% were able to access CGM for recurrent hypoglycemia and from these, 65% were self-funding CGM. Quality of life benefits were evident from the UK CHC survey on the utility of CGM in reducing worry, improving sleep, lessening the burden of frequently finger-pricking and reducing out-of-hours appointments as a result of hypoglycemia. Patient-reported utilization rates of blood glucose test strips per week were significantly reduced.Conclusion: BSPED and UK CHC national surveys support a call and a consideration for CGM access to be widened to patients who suffer from recurrent hypoglycemia such as those with hyperinsulinism or metabolic conditions. The prevention of recurrent hypoglycemia and improving quality of life for patients and carers remain a cornerstone management for people who suffer from frequent hypoglycemia. CGM education is critical to support its use and understand its limitations. Further research is warranted to determine the safety and efficacy of CGM in detection and reduction of hypoglycemic events, impact of hospital stay, and long-term neurological outcomes in those who suffer from recurrent hypoglceamia.

Context: The SARS-CoV-2 virus is dependent on components of the renin-angiotensin-aldosterone system for infectivity. Primary aldosteronism (PA) is a form of secondary hypertension mediated by autonomous aldosterone production. The intersection of COVID-19 and PA, both which may involve components of the renin-angiotensin-aldosterone system, remains unknown.Methods: We assessed PA as a risk factor for COVID-19 infection and compared management, severity of disease, and outcomes during COVID-19 with a matched population of patients with essential hypertension (EH) by conducting a retrospective observational cohort study.Results: Of the patients with PA, 81 had a negative PCR test for COVID-19, whereas 43 had a documented positive PCR test for COVID-19. Those patients with PA who tested positive for COVID-19 tended to be female (P = .08) and the majority of those with COVID-19 infection identified as non-White race (P = .02) and Hispanic ethnicity (P = .02). In a subanalysis, 24-hour urine aldosterone on initial PA diagnosis tended to be higher those in the PA group who developed COVID-19 compared with those in the PA group who did not develop COVID-19 [median (interquartile range): 36.5 (16.9, 54.3) vs 22.0 (15.8, 26.8) mcg, P = .049] and was an independent predictor of COVID-19 infection controlling for sex, race, and ethnicity. Angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, and mineralocorticoid receptor antagonist use did not differ between those patients with PA who did and did not have COVID-19 infection. Comparing those patients with PA and matched patients with EH (n = 286) who were COVID-19 PCR positive, there was a significantly higher incidence of cardiovascular complications (12 vs 2%, P = .004) in the PA vs EH group.Conclusion: These data begin to inform us as to whether PA should be a newly identified subpopulation at risk for COVID-19-related cardiovascular disease sequelae.

Primary hyperparathyroidism (PHPT) is classically characterized by hypercalcemia with elevated or inappropriately normal parathyroid hormone (PTH) levels. Elevated PTH levels in the presence of normal calcium levels are not infrequently found during the evaluation of metabolic bone disorders or kidney stone disease. This can be caused by secondary hyperparathyroidism (SHPT) or normocalcemic primary hyperparathyroidism (NPHPT). NPHPT is due to autonomous parathyroid function whereas SHPT is caused by a physiologic stimulation to PTH secretion. Many medical conditions and medications can contribute to SHPT, and differentiation between SHPT and NPHPT may be difficult. Cases are presented to illustrate examples. In this paper, we review the distinction between SHPT and NPHPT as well as end organ effects of NPHPT and outcomes of surgery in NPHPT. We suggest that the diagnosis of NPHPT be made only after careful exclusion of causes of SHPT and consideration of medications that can increase PTH secretion. Further, we advise a conservative approach to surgery in NPHPT.

Context: Tirzepatide is a dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) approved by the US Food and Drug Administration in May 2022 for patients with type 2 diabetes mellitus (T2DM). Objective: We aimed to determine the rates of individual adverse events (AEs) related to 3 studied doses of tirzepatide. Methods: We performed a systematic review with meta-analysis including 5 databases (PubMed, Embase, CINAHL, Scopus, and Web of Science) for all clinical trials reporting AEs related to tirzepatide. The safety data from individual studies were extracted and analyzed through meta-regression to assess rates of individual AEs. Study quality assessment was performed using the National Heart, Lung, and Blood Institute Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Results: Ten trials (6836 participants) were included. Gastrointestinal (GI) AEs were the most commonly reported AEs and were dose dependent 39% (95% CI, 35%-43%), 46% (95% CI, 42%-49%), and 49% (95% CI, 38%-60%) for the 5, 10, and 15 mg dose, respectively. Among all GI AEs, nausea and diarrhea were most frequent at any dose of tirzepatide. Drug discontinuation due to AEs was highest with the 15 mg dose of tirzepatide (10%). Incidence of mild hypoglycemia (blood glucose < 70 mg/dL) was highest with tirzepatide 10 mg dose 22.6% (9.2%-39.8%). Rates of fatal AEs, severe hypoglycemia, acute pancreatitis, cholelithiasis, and cholecystitis were extremely low (≤ 1%) across all doses of tirzepatide. Conclusion: Tirzepatide is associated with a dose-dependent increase in incidence of GI AEs and AEs leading to drug discontinuation. Severe hypoglycemia, fatal AEs, acute pancreatitis, cholelithiasis, and cholecystitis are rare with this medication.

Cristiane J Gomes-Lima, Sanjita Chittimoju, Leen Wehbeh, Sunita Dia, Prathyusha Pagadala, Mohammad Al-Jundi, Sakshi Jhawar, Eshetu Tefera, Mihriye Mete, Joanna

Wouter T Zandee, Thera P Links; Letter to the Editor from Zandee and Links: “Metastatic Differentiated Thyroid Cancer Survival Is Unaffected by Mode of Preparat

Context: Hyponatremia often reflects a free water excess. Sodium/glucose cotransporter 2 (SGLT2) inhibitors increase free water excretion through glucose-induced osmotic diuresis. In 2 randomized double-blind, placebo-controlled trials in patients with the syndrome of inappropriate antidiuresis (SIAD), we showed that empagliflozin increased plasma sodium concentration more effectively than placebo.Objective: We hypothesized that long-term therapy with SGLT2 inhibitors might reduce the prevalence of hyponatremia on hospital admission.Methods: In this retrospective analysis, we extracted data from adult patients with type 2 diabetes (T2DM) hospitalized at the University Hospital Basel between 2015 and 2020. Patients with an SGLT2 inhibitor on admission were matched 1:1 according to age, gender, diagnosis of heart failure, and principal diagnosis to patients without an SGLT2 inhibitor on admission. The primary outcome was the prevalence of hyponatremia (plasma sodium concentration corrected for glycemia <135 mmol/L) on admission.Results: We analyzed 821 patients with T2DM treated with and 821 patients with T2DM without an SGLT2 inhibitor on admission. Hyponatremia prevalence on admission was 9.9% in the treated group, and 8.9% in the matched control group (P = .554), in other words, the risk for hyponatremia did not differ (multivariable adjusted odds ratio 1.08, 95% CI 0.72-1.44, P = .666). There was no difference in the median (interquartile range) plasma sodium concentration between the groups (treated 140 mmol/L [138-142], controls 140 mmol/L [138-142]; P = .1017).Conclusion: Based on these retrospective findings, treatment with SGLT2 inhibitors does not prevent hyponatremia. However, prospective randomized data suggest their efficacy at a higher dosage in overt SIAD.

Context: The relationship of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) with bone mineral density (BMD) is not well established. Objective: To examine the associations of VAT and SAT with total body BMD in a large, nationally representative population with a wide range of adiposity. Methods: We analyzed 10,641 subjects aged 20-59 in NHANES 2011-2018 who had undergone total body BMD and had VAT and SAT measured by DXA. Linear regression models were fitted while controlling for age, gender, race or ethnicity, smoking status, height, and lean mass index. Results: In a fully adjusted model, each higher quartile of VAT was associated with an average of 0.22 lower T-score (95% CI -0.26 - -0.17, p < 0.001), while SAT had a weak association with BMD but only in men (-0.10, 95% CI -0.17 - -0.04, p = 0.002). However, the association of SAT to BMD in men was no longer significant after controlling for bioavailable sex hormones. In subgroup analysis, we also found differences in the relationship of VAT to BMD in Black and Asian subjects, but these differences were eliminated after accounting for racial and ethnic differences in VAT norms. Conclusions: Visceral adipose tissue has a negative association with BMD. Further research is needed to better understand the mechanism of action and, more generally, to develop strategies for optimizing bone health in obese subjects.

In the above-named article by Ibáñez L, Díaz M, García-Beltrán C, Malpique R, Garde E, López-Bermejo A, and de Zegher F (J Endo Society 2020; 4(5); doi: 10.1210/jendso/bvaa032), there was an error in the Financial Support section of the manuscript:

Context: Adrenal insufficiency (AI)-related morbidity persists despite efforts to minimize its effect. Reasons for this are unknown and warrant examination.Objective: This work aimed to investigate trends in AI hospitalizations and glucocorticoid (GC) replacement therapy use.Methods: Data on hospitalizations for a principal diagnosis of AI and prescriptions for short-acting GCs between 2000 and 2019 were extracted from national repositories. Age-standardized admission and prescription rates were calculated using census data. Rates were compared over time overall and according to age, sex, and disease subtype.Results: AI admissions increased by 62.0%, from 36.78/million to 59.59/million (trend P < .0001). Adrenal crisis (AC) admissions also increased, by 90.1% (from 10.73/million to 20.40/million; trend, P < .00001). These increases were more pronounced in the second decade. Prescriptions for short-acting GCs also increased (by 67.2%, from 2198.36/million in 2000/2001 to 3676.00/million in 2017/2018). Females had higher average admission rates and a greater increase in admission rates than males. Increased AI admissions were found in all age groups among females but only in men aged 70+ yrs. Secondary AI (SAI) admission rates increased by 91.7%, whereas admission rates for primary AI (PAI) remained unchanged.Conclusion: The prevalence of AI and hospitalizations for this disorder (including ACs) have increased since 2000, with a greater increase occurring after 2010. Admission rates for SAI increased but PAI admissions remained stable. Possible causes include immunotherapies for malignancy, increased cranial imaging detecting pituitary tumors and their subsequent treatment, and increased use of low-dose, short-acting GC-replacement therapy.

In the above-named article Carmina E, Dreno B, Lucky WA, Agak WG, Dokras A, Kim JJ, Lobo RA, Tehrani FR, and Dumesic D (J Endo Society. 2022; 6(3); doi: 10.1210/jendso/bvac003), the article contained a recommendation that the authors wish to correct following reconsideration:

Context: Adrenal venous sampling (AVS) is the gold standard technique for subtype differentiation of primary aldosteronism (PA) and to obtain aldosterone and cortisol measurements; however, their secretion patterns show fluctuations during the day. Objective: We aimed to examine the effects of AVS timing on AVS results. Methods: This multicenter, retrospective, observational study included a total of 753 patients who were diagnosed with PA and underwent AVS in 4 centers in Japan. Among them, 504 and 249 patients underwent AVS in the morning (AM-AVS) and in the afternoon (PM-AVS), respectively. The outcome measures were the impact of AVS timing and hormone fluctuations in a day on AVS results. Results: There were no differences in the success rate of AVS, diagnostic rate of disease type, or frequency of discrepancy in PA subtypes between the AM-AVS and PM-AVS groups. Regarding patients with unilateral PA, aldosterone concentrations in adrenal venous blood did not differ between the 2 groups on the dominant or nondominant side. Conversely, regarding patients with bilateral PA, aldosterone concentrations in adrenal venous blood were significantly higher in the AM-AVS than in the PM-AVS group. Conclusions: The timing of AVS did not seem to have a significant impact on subtype diagnosis. The aldosterone levels in adrenal venous blood were significantly higher in patients with bilateral PA in the AM-AVS group, but there was no such difference between patients with unilateral PA in the AM-AVS and PM-AVS groups. Each subtype may have a different hormone secretion pattern in a day.

Context: Participants with stage 1 or 2 type 1 diabetes (T1D) qualify for prevention trials, but factors involved in screening for such trials are largely unknown. Objective: To identify factors associated with screening for T1D prevention trials. Methods: This study included TrialNet Pathway to Prevention participants who were eligible for a prevention trial: oral insulin (TN-07, TN-20), teplizumab (TN-10), abatacept (TN-18), and oral hydroxychloroquine (TN-22). Univariate and multivariate logistic regression models were used to examine participant, site, and study factors at the time of prevention trial accrual. Results: Screening rates for trials were: 50% for TN-07 (584 screened/1172 eligible), 9% for TN-10 (106/1249), 24% for TN-18 (313/1285), 17% for TN-20 (113/667), and 28% for TN-22 (371/1336). Younger age and male sex were associated with higher screening rates for prevention trials overall and for oral therapies. Participants with an offspring with T1D showed lower rates of screening for all trials and oral drug trials compared with participants with other first-degree relatives as probands. Site factors, including larger monitoring volume and US site vs international site, were associated with higher prevention trial screening rates. Conclusions: Clear differences exist between participants who screen for prevention trials and those who do not screen and between the research sites involved in prevention trial screening. Participant age, sex, and relationship to proband are significantly associated with prevention trial screening in addition to key site factors. Identifying these factors can facilitate strategic recruitment planning to support rapid and successful enrollment into prevention trials.

Despite professional society guidelines recommending that obesity be treated as a chronic disease by emphasizing the use of lifestyle modification in conjunction with pharmacotherapy, antiobesity medications are uncommonly prescribed in most clinical practices. The recent Food and Drug Administration approval of semaglutide 2.4 mg weekly to treat obesity—as well as other forthcoming advancements in diabetes and antiobesity medications—highlights the potential of pharmacotherapy to significantly augment weight loss efforts. In this Expert Endocrine Consult, we review the evolving role of antiobesity pharmacotherapy in clinical practice and suggest a framework for the use of these medications.

Context: The occurrence of multiple endocrinopathies due to immune checkpoint inhibitors (ICIs) is a relatively common adverse event. However, the occurrence of a combination of hypophysitis and type 1 diabetes mellitus (T1DM) is extremely rare, and its clinical features are unclear. Objective: We comparatively analyzed the clinical features of this combination and each individual ICI-induced endocrinopathy. Methods: We reported 3 cases that we encountered and reviewed previously reported cases of patients with combined hypophysitis and T1DM due to ICIs. Results: Anti-programmed cell death-1 (anti-PD-1) antibodies were prescribed to all 3 cases. The duration from ICI initiation to the onset of endocrine disease was 12 to 48 weeks. Several human leukocyte antigen (HLA) haplotypes that have disease susceptibility to hypophysitis were detected in all 3 patients. With the 17 previously reported cases, combined endocrinopathies were more common in men (85%). The onset age was in the 60s for both combined and single endocrinopathies. Anti-PD-1 antibodies were used in most of the cases (90%). The time from ICI initiation to the onset of endocrinopathies was 24 (8-76) weeks for hypophysitis and 32 (8-76) weeks for T1DM in patients with combined endocrinopathies, which was not significantly different from that for each single endocrinopathy. Conclusion: We presented 3 cases of patients with combined endocrinopathies of hypophysitis and T1DM that may have been caused by anti-PD-1 antibodies. There was no difference in the time from ICI initiation to the onset of endocrinopathies between combined and single endocrinopathies. Further case accumulation and pathogenic investigations are required.

Context Muscle expresses and secretes several myokines that bring about benefits in distant organs. Objective We investigated impact of critical illness on muscular expression of irisin, kynurenine-aminotransferases and amylase; association with clinical outcome; and impact of interventions that attenuate muscle wasting/weakness. Design/Setting We studied critically ill patients who participated in two RCTs (EPaNIC/NESCI) and documented time profiles in critically ill mice. Patients/other participants 174 intensive-care-unit (ICU) patients (day 8 ± 1) vs 19 matched controls, 60 mice subjected to surgery/sepsis vs 60 pair-fed healthy mice. Interventions Seven-days neuromuscular electrical stimulation (NMES), withholding parenteral-nutrition in the first ICU-week (late-PN) vs early-PN. Main outcome measures FNDC5 (irisin-precursor), KYAT1, KYAT3 and amylase mRNA-expression in skeletal-muscle. Results Critically ill patients showed a 34-80% lower mRNA-expression of FNDC5, KYAT1 and amylases compared with controls (p < 0.0001). Critically ill mice showed time-dependent reductions in all mRNAs compared with healthy mice (p ≤ 0.04). The lower FNDC5 expression in patients was independently associated with a higher ICU-mortality (p = 0.015) and ICU-acquired weakness (p = 0.012), whereas the lower amylase expression in ICU survivors was independently associated with a longer ICU-stay (p = 0.0060). A lower amylase expression was independently associated with a lower risk of death (p = 0.048) and a lower KYAT1 expression with a lower risk of weakness (p = 0.022). NMES increased FNDC5 expression compared with unstimulated muscle (p = 0.016), and late-PN patients had a higher KYAT1 expression than early-PN patients (p = 0.022). Conclusions Expression of the studied myokines was affected by critical illness and associated with clinical outcomes, with limited effects of interventions that attenuate muscle wasting or weakness.

Nuclear receptors are transcription factors that function in normal physiology and play important roles in diseases such as cancer, inflammation, and diabetes. Noninvasive imaging of nuclear receptors can be achieved using radiolabeled ligands and positron emission tomography (PET). This quantitative imaging approach can be viewed as an in vivo equivalent of the classic radioligand binding assay. A main clinical application of nuclear receptor imaging in oncology is to identify metastatic sites expressing nuclear receptors that are targets for approved drug therapies and are capable of binding ligands to improve treatment decision-making. Research applications of nuclear receptor imaging include novel synthetic ligand and drug development by quantifying target drug engagement with the receptor for optimal therapeutic drug dosing and for fundamental research into nuclear receptor function in cells and animal models. This mini-review provides an overview of PET imaging of nuclear receptors with a focus on radioligands for estrogen receptor, progesterone receptor, and androgen receptor and their use in breast and prostate cancer.

Background Prohormone convertase 1/3 (PC1/3), encoded by protein convertase subtilisin kexin type 1 (PCSK1), converts inactive prohormones into biologically active peptides. Somatic mutations of insulinomas are associated with genetic defects interfering with control of insulin secretion from pancreatic beta-cells. However, somatic mutations in proinsulinomas have not been described. Here, we report a case of a proinsulinoma, with suppressed insulin and C-peptide levels. Patients and Methods A 70-year-old woman presented with a 20-year history of ‘blackouts’. During a 72-hour fast, blood glucose level dropped to 1.9 mmol/L with suppressed plasma insulin and C-peptide levels, but proinsulin levels were raised at 37 pmol/L (<10 pmol/L). Imaging revealed three distinct DOTATATE-avid pancreatic lesions. Laparoscopic spleen-preserving distal pancreatomy was performed. In view of discordant insulin, C-peptide and proinsulin levels, whole exome sequencing analysis was performed on the tumour. In the somatic exome of the tumour, we found mutations in PCSK expression regulators, as well as a novel truncating somatic mutation in ATP6V0D1, a subunit of the ion pump that acidifies the β-cell compartments where the PCSKs act. Conclusion Appropriately suppressed insulin levels in the context of hypoglycaemia do not always indicate the absence of neuroendocrine islet cell tumour and proinsulin levels may be indicated to solidify the diagnosis. In the context of elevated proinsulin levels, low insulin and C-peptide levels might be explained by somatic mutations that likely implicate proinsulin processing within the tumour. Furthermore, we propose several mechanistic candidates including ATP6V0D1. Experimental validation using cellular approaches may in future confirm pathomechanisms involved in this rare condition.

Context: Endocrine neoplasia syndromes are phenotypically complex, and there is a misconception that they are universally rare. Genetic alterations are increasingly recognized; however, true prevalence is unknown. The purpose of a clinical registry is to monitor the quality of health care delivered to a specified group of patients through the collection, analysis, and reporting of relevant health-related information. This leads to improved clinical practice, decision-making, patient satisfaction, and outcome. Objective: This review aims to identify, compare, and contrast active registries worldwide that capture data relevant to hereditary endocrine tumors (HETs). Methods: Clinical registries were identified using a systematic approach from publications (Ovid MEDLINE, EMBASE) peer consultation, clinical trials, and web searches. Inclusion criteria were hereditary endocrine tumors, clinical registries, and English language. Exclusion criteria were institutional audits, absence of clinical data, or inactivity. Details surrounding general characteristics, funding, data fields, collection periods, and entry methods were collated. Results: Fifteen registries specific for HET were shortlisted with 136 affiliated peer-reviewed manuscripts. Conclusion: There are few clinical registries specific to HET. Most of these are European, and the data collected are highly variable. Further research into their effectiveness is warranted. We note the absence of an Australian registry for all HET, which would provide potential health and economic gains. This review presents a unique opportunity to harmonize registry data for HET locally and further afield.

Ectopic Cushing syndrome from a primary carcinoma of the cervix is an exceedingly rare phenomenon. The objective of this review is to describe our clinical case and summarize the clinical characteristics, investigations, and outcomes of all published cases. We describe a previously healthy 39-year-old woman presenting with abnormal uterine bleeding, leading to a diagnosis of stage IIIC1 small cell neuroendocrine carcinoma of the cervix, human papillomavirus-associated. She was treated with neoadjuvant chemotherapy, radical hysterectomy, adjuvant chemotherapy, and pelvic radiation. Unfortunately, she developed progressive disease with multifocal hepatic metastases and lesions in the para-aortic lymph nodes. Eighteen months after her initial diagnosis, she presented with severe Cushing syndrome and acute pancreatitis and died from a splenic artery pseudoaneurysm. A literature review identified 10 published cases of ectopic ACTH secretion in the setting of carcinoma of the cervix. The mean age of presentation was 40. The majority (70%) occurred in the small cell neuroendocrine variant. In 80% of patients, cushingoid features developed concomitantly or shortly after the discovery of metastatic disease; cushingoid features included new-onset hypertension (30% of patients), hyperglycemia (50%), and hypokalemia (50%). All 10 patients died of the disease with a median survival of 2.5 months (range, 1-10 months) from the time of presentation with Cushing syndrome. Carcinoma of the cervix is a rare cause of ectopic Cushing syndrome. Nevertheless, it should be considered as a source of ectopic ACTH secretion in all women, especially those presenting with gynecologic complaints. Despite surgical resection and systemic therapy, prognosis is poor.

Context: Chronic exposure of pancreatic islets to elevated glucose levels causes progressive declines in beta cell Pdx-1 and insulin gene expression, and glucose-induced insulin secretion. This has been shown to be associated with excessive islet reactive oxygen species and consequent damage to beta cell function, a process termed glucose toxicity. In short-term rodent in vivo studies, Nrf2 (Kelch-like ECH-associated protein 1:nuclear factor erythroid-derived-2 related factor complex) has been shown to play a central role in defending beta cells from oxidative damage via activation of antioxidant gene expression. Objective: The current studies were primarily designed to examine the behavior of Nrf2 gene expression during longer term exposure of beta cells to glucose toxicity. Methods and Results: We provide evidence that gene expression of Nrf2 in HIT-T15 cells, an insulin-secreting beta-cell line, undergoes a biphasic response characterized by an initial decrease followed by increased expression during prolonged culturing of these cells in a physiologic (0.8 mM) but not a supraphysiologic (16.0 mM) glucose concentration. This was associated with a slight rise in HO-1 gene expression. Pdx-1 and insulin mRNA levels also decreased but then stabilized in late passages of cells that had been cultured in low glucose concentrations. Conclusion: These complex events support the concept that Nrf2 gene expression plays an important regulatory role in defending beta cells during prolonged exposure to oxidative stress.

Aims We evaluated the effect of the achievement of HbA1c, systolic blood pressure (SBP) and LDL (LDLc) or non-HDL cholesterol (non-HDLc) goals (ABC goals) on the development of chronic kidney disease (iCKD) among patients with diabetes. Methods In a nationwide registry of all individuals with diagnosed diabetes assisted by the health system in Colombia, we analyzed the association between baseline or sustained goal achievement and development of iCKD over a four-year follow-up. Incident CKD was defined as a new occurrence of an estimated glomerular filtration rate <60 mL/min/1.73m², hemodialysis, peritoneal dialysis, or kidney transplant. Results The study included 998 790 adults with diabetes (56% female, mean age 59). There were 125 626 cases of incident CKD. After adjustment for multiple confounders, a baseline SBP < 130 mmHg (OR 0.79 [0.78-0.80]) and a baseline HbA1c < 7.0% (OR 0.86 [0.85-0.87]) were negatively associated with iCKD. Sustained achievement showed stronger negative associations with iCKD than just baseline achievement. Considering each goal separately, sustained non-HDLc <130 mg/dL had the strongest negative association with iCKD (OR 0.67 [0.65-0.69]). Patients who maintained the triple ABC goal over the entire follow-up had 32% (29-34) lower odds of developing CKD, 38% (34-42) if they additionally kept a normal body-mass index (BMI). Sustained ABC control including a normal BMI was more strongly associated with a lower incidence of CKD in patients of black race (OR 0.72 vs 0.89, p for interaction 0.002). Conclusions At a country level, sustained achievement of ABC goals and most especially non-HDLc were associated with substantial reductions in iCKD.

Introduction: In addition to their antihyperglycemic action, sodium-glucose cotransporter-2 (SGLT2) inhibitors are used in patients with type 2 diabetes due to their cardioprotective effects. Meta-analyses of large clinical trials have reported mixed results when examining sex differences in their cardioprotective effects. For example, some studies reported that, compared to women, men had a greater reduction in cardiovascular risk with SGLT2 inhibition. Taking advantage of several recently completed large-scale randomized controlled clinical trials, we tested the hypothesis that women have an attenuated response in primary cardiorenal outcomes to SGLT2 inhibition compared to men. Methods: We performed a systematic search using PubMed and the Cochrane Library to find completed large-scale, prospective, randomized controlled Phase III clinical trials with primary outcomes testing cardiovascular or renal benefit. Studies had to include at least 1000 participants and report data about sex differences in their primary cardiovascular or renal outcomes. Results: The present meta-analysis confirmed that SGLT2 inhibition decreased adverse cardiorenal outcomes in a pooled sex analysis using 13 large-scale clinical trials. SGLT2 inhibition exhibited similar reduction in hazard ratios for both men (0.79, 95% CI, 0.73-0.85) and women (0.78, 95% CI, 0.72-0.84) for adverse cardiorenal outcomes. Conclusion: In contrast to previous findings, our updated meta-analysis suggests that women and men experience similar cardiorenal benefit in response to SGLT2 inhibition. These findings strongly suggest that SGLT2 inhibition therapy should be considered in patients with high risk for cardiovascular disease irrespective of the patient sex.

Objective Blood pressure and plasma catecholamines normally decline during sleep and rapidly increase in early morning. This is blunted in adults with T2D. We hypothesize that increased sympatho-adrenal activity during sleep differentiates youth with T2D from nondiabetic obese youth and lean youth. Methods Fasting spot morning and 24-hour urines were collected in obese adolescents with and without T2D, and normal-weight controls. Fractionated free urine catecholamines (epinephrine, norepinephrine, and dopamine) were measured, and the ratio of fasting spot morning to 24-hour catecholamines was calculated. Results Urinary 24-hour catecholamine levels were comparable across the three groups. Fasting morning epinephrine and the ratio of fasting morning/24-hour epinephrine were higher in youth with T2D (p = 0.004 and p = 0.035, respectively). In males, the ratio of fasting morning/24-hour epinephrine was also higher in youth with T2D (p = 0.005). In females, fasting morning norepinephrine and the ratio of fasting morning/24-hour dopamine were lower in obese youth with and without T2D (p = 0.013 and p = 0.005, respectively) compared to lean youth. Systolic BP was higher in diabetic participants than other groups; males trended higher than females. Conclusions Circadian rhythm in catecholamines is disrupted in youth-onset T2D, with a blunted overnight fall in urinary epinephrine in males. Conversely, fasting morning norepinephrine and dopamine levels were lower in obese females with or without T2D. Higher nocturnal catecholamines in males with T2D might associate with, or predispose to, hypertension and cardiovascular complications. Lower catecholamine excretion in females with obesity might serve an adaptive, protective role.

The glucocorticoid stress hormones affect brain function via high-affinity mineralocorticoid receptors (MRs) and lower affinity glucocorticoid receptors (GRs). MR and GR not only differ in affinity for ligand, but also have distinct, sometimes opposite, actions on neuronal excitability and other cellular and higher order parameters related to cerebral function. GR and MR mRNA levels are often used as a proxy for the responsiveness to glucocorticoids, assuming proportionality between mRNA and protein levels. This may be especially relevant for the MR, which due to its high affinity is already largely occupied at low basal (trough) hormone levels. Here we explored how GR and MR mRNA levels are associated with the expression of a shared target gene, glucocorticoid-induced leucine zipper (GILZ, coded by Tsc22d3) with basal and elevated levels of corticosterone in male mice, using in situ hybridization. Depending on the hippocampal subfield and the corticosterone levels, mRNA levels of MR rather than GR mostly correlated with GILZ mRNA in the hippocampus and hypothalamus at the bulk tissue level. At the individual cell level, these correlations were much weaker. Using publicly available single-cell RNA sequencing data, we again observed that MR and GR mRNA levels were only weakly correlated with target gene expression in glutamatergic and GABAergic neurons. We conclude that MR mRNA levels can be limiting for receptor action, but many other cell-specific and region-specific factors ultimately determine corticosteroid receptor action. Altogether, our results argue for caution whilst interpreting the consequences of changed receptor expression for the response to glucocorticoids.

Given the close anatomical and physiological links between the exocrine and endocrine pancreas, diseases of 1 compartment often affect the other through mechanisms that remain poorly understood. Pancreatitis has been associated with both type 1 and type 2 diabetes, but its association with monogenic diabetes is unknown. Patients heterozygous for pathogenic CFTR variants are cystic fibrosis carriers and have been reported to have an increased risk of acute pancreatitis. We describe a 12-year-old patient with monogenic neonatal diabetes due to a pathogenic heterozygous paternally inherited mutation of the insulin gene (INS), c.94 G > A (p.Gly32Ser), who experienced 3 recurrent episodes of acute pancreatitis over 7 months in conjunction with poor glycemic control, despite extensive efforts to improve glycemic control in the past 4 years. Intriguingly, the maternal side of the family has an extensive history of adult-onset pancreatitis consistent with autosomal dominant inheritance and the proband is heterozygous for a maternally inherited, CFTR variant c.3909C > G (p.Asn1303Lys). Paternally inherited monogenic neonatal diabetes may have promoted earlier age-of-onset of pancreatitis in this pediatric patient compared to maternal relatives with adult-onset acute pancreatitis. Further study is needed to clarify how separate pathophysiologies associated with INS and CFTR mutations influence interactions between the endocrine and exocrine pancreas.

Background Identification of insulin resistance (IR) in South Asians (SA), who are at a higher risk for type 2 diabetes is important. Lack of standardization of insulin assays limits the clinical use of insulin-based surrogate indices. The lipoprotein insulin resistance index (LP-IR), a metabolomic marker, reflects the lipoprotein abnormalities observed in IR. The reliability of the LP-IR index in SA is unknown. Objective We evaluated the predictive accuracy of LP-IR compared to other IR-surrogate indices in SA. Methods In a cross-sectional study (n = 55), we used calibration model analysis to assess the ability of the LP-IR score and other simple surrogate indices [HOMA-IR, QUICKI, Adipose insulin resistance index (Adipo-IR), and Matsuda Index] to predict insulin sensitivity (S_I) derived from the reference frequently sampled intravenous glucose tolerance test. LP-IR index was derived from lipoprotein particle concentrations and sizes measured by nuclear magnetic resonance spectroscopy. Predictive accuracy was determined by root mean squared error (RMSE) of prediction and leave-one-out cross-validation-type RMSE of prediction (CVPE). The optimal cut-off of LP-IR index was determined by the area under the receiver operating characteristic curve (AUC-ROC) and the Youden index. Results The simple surrogate indices showed moderate correlations with S_I (r = 0.53-0.69, p < 0.0001). CVPE and RMSE were not different in any of the surrogate indices when compared to LP-IR. The AUC-ROC was 0.77 (95% CI 0.64–0.89). The optimal cut-off for IR in SA was LP-IR >48 (sensitivity: 75%, specificity: 70%). Conclusions LP-IR index is a simple, accurate, and clinically useful test to assess IR in South Asians.

Context The skeletal effects of vitamin D remain controversial and it is uncertain whether variation in serum 25-hydroxyvitamin D (25OHD) levels over time influences bone mineral density (BMD). Objective We evaluated longitudinal stability of serum 25OHD and associations with changes in BMD in participants aged 46-70 years at baseline. Design/Setting/Participants We studied 3698 Busselton Healthy Ageing study participants (2040 females) with serum 25OHD and dual-energy x-ray absorptiometry (DXA) BMD assessments at baseline and at ∼6 years follow-up. Restricted cubic splines were used to evaluate associations between changes in 25OHD and BMD. Results Mean season-corrected serum 25OHD was 81.3 ± 22.7 and 78.8 ± 23.1 nmol/L at baseline and 6 years, respectively, and showed moderate correlation (intraclass correlation coefficient: 0.724). Significant predictors of change in 25OHD concentration (Δ25OHD) included baseline 25OHD, change in body mass index and vitamin D supplementation at follow-up. Greater decline in serum 25OHD over time was associated with significantly greater reduction in BMD at total hip and femoral neck, but the magnitude of the differences was small (estimated differences 0.004 g/cm² and 0.005-0.007 g/cm², respectively, for lowest quartile of Δ25OHD compared with higher quartiles, adjusted for sex, baseline BMD, 25OHD and demographics). No significant associations between Δ25OHD and lumbar spine BMD were observed. Increase in 25OHD levels was not associated with change in BMD. Conclusions In this predominantly vitamin D-replete middle-aged cohort, serum 25OHD showed moderate longitudinal stability. Declining serum 25OHD over time was associated with greater reduction in BMD at the total hip and femoral neck.