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Journal of Clinical Endocrinology & Metabolism
Journal Prestige (SJR): 2.941
Citation Impact (citeScore): 5
Number of Followers: 188  
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ISSN (Print) 0021-972X - ISSN (Online) 1945-7197
Published by Endocrine Society, The Homepage  [3 journals]
  • Clinical and Molecular Analysis in 2 Families With Novel Compound
           Heterozygous SBP2 (SECISBP2) Mutations
    • Authors: Fu J; Korwutthikulrangsri M, Gönç E, et al.
      Abstract: AbstractContextSelenocysteine insertion sequence binding protein 2 (SECISBP2, SBP2) is an essential factor for selenoprotein synthesis. Individuals with SBP2 defects have characteristic thyroid function test (TFT) abnormalities resulting from deficiencies in the selenoenzymes deiodinases. Eight families with recessive SBP2 gene mutations have been reported to date. We report 2 families with inherited defect in thyroid hormone metabolism caused by 4 novel compound heterozygous mutations in the SBP2 gene.Case DescriptionsProbands 1 and 2 presented with growth and developmental delay. Both had characteristic TFT with high T4, low T3, high reverse T3, and normal or slightly elevated TSH. The coding region of the SBP2 gene was sequenced and analysis of in vitro translated wild-type and mutant SBP2 proteins was performed. Sequencing of the SBP2 gene identified novel compound heterozygous mutations resulting in mutant SBP2 proteins E679D and R197* in proband 1, and K682Tfs*2 and Q782* in proband 2. In vitro translation of the missense E679D demonstrated all four isoforms, whereas R197* had only 2 shorter isoforms translated from downstream ATGs, and Q782*, K682Tfs*2 expressed isoforms with truncated C-terminus. Reduction in serum glutathione peroxidase enzymatic activity was also demonstrated in both probands.ConclusionsWe report 2 additional families with mutations in the SBP2 gene, a rare inherited condition manifesting global selenoprotein deficiencies. Report of additional families with SBP2 deficiency and their evaluation over time is needed to determine the full spectrum of clinical manifestations in SBP2 deficiency and increase our understanding of the role played by SBP2 and selenoproteins in health and disease.
      PubDate: Fri, 21 Feb 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgz169
      Issue No: Vol. 105, No. 3 (2020)
  • GIP and GLP-1 Receptor Antagonism During a Meal in Healthy Individuals
    • Authors: Gasbjerg L; Helsted M, Hartmann B, et al.
      Abstract: AbstractContextThe actions of both endogenous incretin hormones during a meal have not previously been characterized.ObjectiveUsing specific receptor antagonists, we investigated the individual and combined contributions of endogenous glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) to postprandial glucose metabolism, energy expenditure, and gallbladder motility.DesignRandomized, double-blinded, placebo-controlled, crossover design.SettingOn four separate days, four liquid mixed meal tests (1894 kJ) over 270 minutes (min).Patients or Other ParticipantsTwelve healthy male volunteers.InterventionsInfusions of the GIP receptor antagonist GIP(3–30)NH2 (800 pmol/kg/min), the GLP-1 receptor antagonist exendin(9–39)NH2 (0–20 min: 1000 pmol/kg/min; 20–270 min: 450 pmol/kg/min), GIP(3–30)NH2+exendin(9–39)NH2, or placebo/saline.Main Outcome MeasureBaseline-subtracted area under the curve (bsAUC) of C-peptide.ResultsInfusion of GIP(3–30)NH2+exendin(9–39)NH2 significantly increased plasma glucose excursions (bsAUC: 261 ± 142 mmol/L × min) during the liquid mixed meals compared with GIP(3–30)NH2 (180 ± 141 mmol/L × min; P = 0.048), exendin(9–39)NH2 (171 ± 114 mmol/L × min; P = 0.046), and placebo (116 ± 154 mmol/L × min; P = 0.015). Correspondingly, C-peptide:glucose ratios during GIP(3–30)NH2+exendin(9–39)NH2 infusion were significantly lower than during GIP(3–30)NH2 (P = 0.0057), exendin(9–39)NH2 (P = 0.0038), and placebo infusion (P = 0.014). GIP(3–30)NH2 resulted in significantly lower AUCs for glucagon than exendin(9–39)NH2 (P = 0.0417). Gallbladder ejection fraction was higher during GIP(3–30)NH2 compared with placebo (P = 0.004). For all interventions, energy expenditure and respiratory quotient were similar.ConclusionsEndogenous GIP and GLP-1 lower postprandial plasma glucose excursions and stimulate insulin secretion but only endogenous GIP affects gallbladder motility. The two incretin hormones potentiate each other’s effects in the control of postprandial glycemia in healthy men.
      PubDate: Thu, 20 Feb 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgz175
      Issue No: Vol. 105, No. 3 (2020)
  • Twice as High Diet-Induced Thermogenesis After Breakfast vs Dinner On
           High-Calorie as Well as Low-Calorie Meals
    • Authors: Richter J; Herzog N, Janka S, et al.
      Abstract: AbstractBackgroundThe question of whether there is daytime time variation in diet-induced thermogenesis (DIT) has not been clearly answered. Moreover, it is unclear whether a potential diurnal variation in DIT is preserved during hypocaloric nutrition.ObjectiveWe hypothesized that DIT varies depending on the time of day and explored whether this physiological regulation is preserved after low-calorie compared with high-calorie intake.DesignUnder blinded conditions, 16 normal-weight men twice underwent a 3-day in-laboratory, randomized, crossover study. Volunteers consumed a predetermined low-calorie breakfast (11% of individual daily kilocalorie requirement) and high-calorie dinner (69%) in one condition and vice versa in the other. DIT was measured by indirect calorimetry, parameters of glucose metabolism were determined, and hunger and appetite for sweets were rated on a scale.ResultsIdentical calorie consumption led to a 2.5-times higher DIT increase in the morning than in the evening after high-calorie and low-calorie meals (P < .001). The food-induced increase of blood glucose and insulin concentrations was diminished after breakfast compared with dinner (P < .001). Low-calorie breakfast increased feelings of hunger (P < .001), specifically appetite for sweets (P = .007), in the course of the day.ConclusionsDIT is clearly higher in the morning than in the evening, irrespective of the consumed calorie amount; that is, this physiological rhythmicity is preserved during hypocaloric nutrition. Extensive breakfasting should therefore be preferred over large dinner meals to prevent obesity and high blood glucose peaks even under conditions of a hypocaloric diet.
      PubDate: Wed, 19 Feb 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgz311
      Issue No: Vol. 105, No. 3 (2020)
  • Pharmacological Management of Osteoporosis in Postmenopausal Women: An
           Endocrine Society Guideline Update
    • Authors: Shoback D; Rosen C, Black D, et al.
      Abstract: AbstractObjectiveThe objective is to provide an update of the 2019 Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Clinical Practice Guideline for the pharmacological management of osteoporosis in postmenopausal women using romosozumab.ConclusionsWe reviewed findings from the meta-analysis and primary clinical trials assessing the efficacy of romosozumab, a monoclonal antibody targeting sclerostin, for the prevention of fractures and concluded that this agent can be considered a treatment option for postmenopausal women at very high risk for osteoporotic fracture. The romosozumab label has a boxed warning, recommending careful consideration by the treating clinician as to cardiovascular risk profile in the individual woman who might receive this agent, since clinical trial data from an active comparator study show an imbalance in serious cardiovascular adverse events between romosozumab and alendronate.
      PubDate: Tue, 18 Feb 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa048
      Issue No: Vol. 105, No. 3 (2020)
  • Response to Letter to the Editor: “Cardiovascular Effects of
           Pioglitazone or Sulfonylureas According to Pretreatment Risk: Moving
           Toward Personalized Care”
    • Authors: Vaccaro O; Nicolucci A, Lucisano G, et al.
      Abstract: Defining subgroups of patients with a different likelihood of benefitting from a specific treatment represents an important clinical need, considering the large heterogeneity of patients with type 2 diabetes and the need for a personalized approach.
      PubDate: Sat, 08 Feb 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgz135
      Issue No: Vol. 105, No. 3 (2020)
  • Letter to the Editor: “Cardiovascular Effects of Pioglitazone or
           Sulfonylureas According to Pretreatment Risk: Moving Toward Personalized
    • Authors: de Carvalho L; Coelho O, Sposito A.
      Abstract: The best treatment option for patients with type 2 diabetes mellitus in whom metformin treatment alone did not provide the glycemic control is certainly an important issue. To answer this question, the TOSCA.IT (1) study randomized 3028 individuals to the use of sulfonylureas or pioglitazone as an additive therapy to metformin 2 to 3g/day. The interim futility analysis indicated discontinuation nearly 9 years after the beginning of the study due to low event rate and high dropout. The hazard ratio for the primary outcome was 0.96 (95% confidence interval: 0.74–1.26, P = 0.79).
      PubDate: Sat, 08 Feb 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgz134
      Issue No: Vol. 105, No. 3 (2020)
  • In Memoriam: C. Wayne Bardin, 1934-2019
    • Authors: Santen R; O’Malley B, Sitruk-Ware R, et al.
      Abstract: C. Wayne Bardin, MD, was a giant in the field of endocrinology who contributed substantially to our knowledge of reproductive physiology, the development of unique methods of contraception, and the clinical care of patients with disorders of reproduction. His legacy includes not only his research contributions but also his leadership and service to the endocrine community. For many years he was the director of the Clinical Endocrinology Update course, which included a curriculum imparted by multiple experts in the field of endocrinology. Later he served on the Endocrine Society Council before becoming President (1993–1994).
      PubDate: Thu, 06 Feb 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgz215
      Issue No: Vol. 105, No. 3 (2020)
  • Perioperative Glucocorticoid Therapy for Patients with Adrenal
           Insufficiency: Dosing Based on Pharmacokinetic Data
    • Authors: Arafah B.
      Abstract: AbstractBackgroundPerioperative glucocorticoid therapy for patients with adrenal insufficiency (AI) is currently based on anecdotal reports, without supporting pharmacokinetic data.MethodsWe determined the half-life, clearance, and volume of distribution of 2 consecutive intravenously (IV)-administered doses of hydrocortisone (15 or 25 mg every 6 hours) to 22 dexamethasone-suppressed healthy individuals and used the data to develop a novel protocol to treat 68 patients with AI who required surgical procedures. Patients received 20 mg of hydrocortisone orally 2 to 4 hours before intubation and were started on 25 mg of IV hydrocortisone every 6 hours for 24 hours and 15 mg every 6 hours during the second day. Nadir cortisol concentrations were repeatedly measured during that period.ResultsIn healthy individuals, cortisol half-life was longer when the higher hydrocortisone dose was administered (2.02 ± 0.15 vs 1.81 ± 0.11 hours; P < 0.01), and in patients with AI, the half-life was longer than in healthy individuals given the same hydrocortisone dose. In both populations, the cortisol half-life increased further with the second hormone injection. Prolongation of cortisol half-life was due to decreased hydrocortisone clearance and an increase in its volume of distribution. Nadir cortisol levels determined throughout the 48 postoperative hours were within the range of values and often exceeded those observed perioperatively in patients without adrenal dysfunction.ConclusionsCortisol pharmacokinetics are altered in the postoperative period and indicate that lower doses of hydrocortisone can be safely administered to patients with AI undergoing major surgery. The findings of this investigation call into question the current practice of administering excessive glucocorticoid supplementation during stress.
      PubDate: Thu, 30 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa042
      Issue No: Vol. 105, No. 3 (2020)
  • NPR2 Variants Are Frequent among Children with Familiar Short Stature and
           Respond Well to Growth Hormone Therapy
    • Authors: Plachy L; Dusatkova P, Maratova K, et al.
      Abstract: AbstractContextThe C-type natriuretic peptide receptor encoded by the NPR2 gene is a paracrine regulator of the growth plate; heterozygous NPR2 variants cause short stature with possible presence of different signs of bone dysplasia. To date, the effect of growth hormone (GH) treatment has been described in a few individuals with NPR2 gene variants with inconsistent results.ObjectivesTo identify NPR2 gene variants among children with familial short stature (FSS) and to describe their phenotype, including GH treatment response.Design, Settings and PatientsOut of 747 patients with short stature treated with GH in a single center, 87 with FSS met the inclusion criteria (pretreatment height ≤ –2 standard deviation in both the patient and the shorter parent, unknown genetic etiology). Next-generation sequencing methods were performed to search for NPR2 gene variants. The results were evaluated using the American College of Medical Genetics and Genomics guidelines. The GH treatment response (growth velocity improvement and height standard deviation score development over the first 5 years of treatment) was evaluated.ResultsIn 5/87 children (5.7%), a (likely) pathogenic variant in the NPR2 gene was identified (p.Ile558Thr [in 2], p.Arg205*, p.Arg557His, p.Ser603Thr). Two children had disproportionate short-limbed short stature, 1 a dysplastic 5th finger phalanx. The growth velocity in the first year of GH treatment accelerated by 3.6 to 4.2 cm/year; the height improved by 1.2 to 1.8 SD over 5 years of treatment.ConclusionsNPR2 gene variants cause FSS in a significant proportion of children. Their GH treatment response is promising. Studies including final height data are necessary to assess the long-term efficacy of this therapy.
      PubDate: Tue, 28 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa037
      Issue No: Vol. 105, No. 3 (2020)
  • Effect of Chronic Pancreatitis on Complications and Mortality in DM
           Patients: A 10-year Nationwide Cohort Study
    • Authors: Lin C; Yeh N, Wang J, et al.
      Abstract: AbstractContextChronic pancreatitis (CP), is a long-term inflammation of the pancreatic parenchyma, and might increase risk of a hyperglycemia crisis or hypoglycemia in patients with diabetes mellitus (DM); however, the relationship has not been previously investigated.ObjectiveTo investigate the risk of diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar state (HHS), hypoglycemia, and long-term outcomes in DM patients with CP.DesignA population-based cohort study.Setting and ParticipantsTapping Taiwan’s National Health Insurance Research Database, we identified 506 DM patients with newly diagnosed CP from 1999 to 2010 and created a control cohort consisting of 5060 age- and sex-matched DM patients without CP from the same time period. We followed those 2 cohorts from the index date to occurrence of outcomes, the date of death or 31 December 2012.Main Outcome MeasuresDKA, HHS, hypoglycemia and mortality.ResultsDM patients with CP, who were predominantly male (88%) and younger (60% < 45 years old), had a 9.5-, 5.0-, and 3.0-fold higher risk for DKA (95% confidence interval [CI]: 6.51–13.91), HHS (95% CI: 2.85–8.62), and hypoglycemia (95% CI: 2.23–4.08), respectively. They also had lower 1-, 5-, and 10-year cumulative survival rates (98.4% vs 99.0%, 87.7% vs 96.6%, and 78.7% vs 93.6%, respectively) (log-rank test: P < .001), and a 2.43-fold higher risk for death (HR: 2.43, 95% CI: 1.82–3.27).ConclusionsIn Taiwan, DM patients with CP have a higher incidence of DKA, HHS, hypoglycemia, and mortality. More attention is needed for preventing hyperglycemia crisis and hypoglycemia prevention in this population.
      PubDate: Fri, 24 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa035
      Issue No: Vol. 105, No. 3 (2020)
  • HLA Class II Allele Analyses Implicate Common Genetic Components in Type 1
           and Non–Insulin-Treated Type 2 Diabetes
    • Authors: Jacobi T; Massier L, Klöting N, et al.
      Abstract: AbstractContextCommon genetic susceptibility may underlie the frequently observed co-occurrence of type 1 and type 2 diabetes in families. Given the role of HLA class II genes in the pathophysiology of type 1 diabetes, the aim of the present study was to test the association of high density imputed human leukocyte antigen (HLA) genotypes with type 2 diabetes.Objectives and DesignThree cohorts (Ntotal = 10 413) from Leipzig, Germany were included in this study: LIFE-Adult (N = 4649), LIFE-Heart (N = 4815) and the Sorbs (N = 949) cohort. Detailed metabolic phenotyping and genome-wide single nucleotide polymorphism (SNP) data were available for all subjects. Using 1000 Genome imputation data, HLA genotypes were imputed on 4-digit level and association tests for type 2 diabetes, and related metabolic traits were conducted.ResultsIn a meta-analysis including all 3 cohorts, the absence of HLA-DRB5 was associated with increased risk of type 2 diabetes (P = 0.001). In contrast, HLA-DQB*06:02 and HLA-DQA*01:02 had a protective effect on type 2 diabetes (P = 0.005 and 0.003, respectively). Both alleles are part of the well-established type 1 diabetes protective haplotype DRB1*15:01~DQA1*01:02~DQB1*06:02, which was also associated with reduced risk of type 2 diabetes (OR 0.84; P = 0.005). On the contrary, the DRB1*07:01~DQA1*02:01~DQB1*03:03 was identified as a risk haplotype in non–insulin-treated diabetes (OR 1.37; P = 0.002).ConclusionsGenetic variation in the HLA class II locus exerts risk and protective effects on non–insulin-treated type 2 diabetes. Our data suggest that the genetic architecture of type 1 diabetes and type 2 diabetes might share common components on the HLA class II locus.
      PubDate: Fri, 24 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa027
      Issue No: Vol. 105, No. 3 (2020)
  • Response to Letter to the Editor: “Body Composition and Markers of
           Cardiometabolic Health in Transgender Youth Compared to Cisgender Youth”
    • Authors: Nokoff N.
      Abstract: Thank you for your letter. We are limited in our ability to draw definitive conclusions about the prevalence of polycystic ovarian syndrome or nonclassic congenital adrenal hyperplasia in the transgender males in this study, which was a convenience sample and cross-sectional. A comprehensive androgen profile was not obtained in every participant before initiation of testosterone, but there was not clinical suspicion for these conditions based on history or physical examination by providers. This is an important area of research, ideally in a larger, prospective cohort, as stated by Dr. Sacerdote. More research is needed into the complex interplay among sex steroids, adrenal androgens, and cardiometabolic health, as well as gender identity.
      PubDate: Fri, 24 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa020
      Issue No: Vol. 105, No. 3 (2020)
  • Relationship of Body Mass Index and Waist Circumference With Risk of
           New-Onset Proteinuria in Hypertensive Patients
    • Authors: Liu M; Zhang Z, Zhou C, et al.
      Abstract: AbstractContextThe association of the combination of body mass index (BMI) and waist circumference (WC) with the risk of proteinuria has previously not been comprehensively investigated and results have been inconclusive.ObjectiveTo examine BMI and WC in relation to new-onset proteinuria in Chinese hypertensive patients.Design and SettingPost hoc analysis of the renal substudy of the China Stroke Primary Prevention Trial (CSPPT).Patients10 805 hypertensive patients without proteinuria at baseline.Main Outcome MeasureThe primary outcome was new-onset proteinuria, defined as a urine dipstick protein reading ≥ 1 + at the exit visit, after a median follow-up duration of 4.4 years.ResultsWhen analyzed separately, increased BMI (≥ 28 kg/m2, quartile 4; odds ratio [OR], 1.36; 95% confidence interval [CI], 1.08–1.72), or increased WC (≥ 91cm for females, quartile 4; OR, 1.35; 95% CI, 1.01–1.80; and ≥ 79 cm for males, quartile 2–4; OR, 1.60; 95% CI, 1.03–2.50) were each significantly associated with higher risk of new-onset proteinuria. When analyzed jointly, participants without increased BMI and increased WC had the lowest risk, while those with both increased BMI and increased WC had the highest risk of proteinuria (OR, 1.61; 95% CI, 1.21–2.13). Notably, participants with only increased WC also had significantly increased risk of proteinuria (OR, 1.39; 95% CI, 1.04–1.85).ConclusionIn Chinese hypertensive patients, increased BMI and increased WC were individually and jointly associated with a higher risk of new-onset proteinuria, underscoring the value of monitoring both BMI and WC in assessing proteinuria risk.
      PubDate: Fri, 24 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa026
      Issue No: Vol. 105, No. 3 (2020)
  • Circadian Misalignment of the 24-hour Profile of Endocannabinoid
           2-Arachidonoylglycerol (2-AG) in Obese Adults
    • Authors: Hanlon E; Leproult R, Stuhr K, et al.
      Abstract: AbstractContextThe endocannabinoid (eCB) system partly controls hedonic eating, a major cause of obesity. While some studies suggested an overactivation of the eCB system in obesity, peripheral levels of eCBs across the 24-hour cycle have not been characterized in obese individuals despite the fact that in lean adults, levels of the eCB 2-arachidonoylglycerol (2-AG) vary across the day.ObjectiveWe sought to examine 24-hour profiles of serum concentrations of 2-AG in healthy obese and nonobese adults, under well-controlled laboratory conditions. We also simultaneously assessed 24-hour profiles of 2-oleoylglycerol (2-OG), leptin, and cortisol in each participant.DesignWith fixed light-dark and sleep-wake cycles, blood sampling was performed over an entire 24-hour period, including identical meals at 0900, 1400, and 1900.ParticipantsTwelve obese (8 women, mean body mass index [BMI]: 39.1 kg/m2) and 15 nonobese (6 women; mean BMI: 23.6 kg/m2) healthy adults were studied.ResultsWe observed a 24-hour variation of 2-AG levels in obese individuals but, relative to nonobese adults, the amplitude was dampened and the timings of the nadir and peak were delayed by 4 to 5 hours. The profile of 2-OG was similarly misaligned. In contrast, when expressed relative to the 24-hour mean level, the 24-hour rhythm of cortisol and leptin were similar in obese and nonobese participants.ConclusionsObesity appears to be associated with a dampening and delay of the 24-hour variation of eCB activity relative to the central circadian signal as well as to the daily leptin rhythm. This misalignment may play a role in the pathophysiology of obesity.
      PubDate: Thu, 23 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa028
      Issue No: Vol. 105, No. 3 (2020)
  • An Activating Variant in CTNNB1 is Associated with a Sclerosing Bone
           Dysplasia and Adrenocortical Neoplasia
    • Authors: Peng H; Jenkins Z, White R, et al.
      Abstract: AbstractContextThe WNT/β-catenin pathway is central to the pathogenesis of various human diseases including those affecting bone development and tumor progression.ObjectiveTo evaluate the role of a gain-of-function variant in CTNNB1 in a child with a sclerosing bone dysplasia and an adrenocortical adenoma.DesignWhole exome sequencing with corroborative biochemical analyses.PatientsWe recruited a child with a sclerosing bone dysplasia and an adrenocortical adenoma together with her unaffected parents.InterventionWhole exome sequencing and performance of immunoblotting and luciferase-based assays to assess the cellular consequences of a de novo variant in CTNNB1.Main Outcome Measure(s)/ResultA de novo variant in CTNNB1 (c.131C>T; p.[Pro44Leu]) was identified in a patient with a sclerosing bone dysplasia and an adrenocortical adenoma. A luciferase-based transcriptional assay of WNT signaling activity verified that the activity of β-catenin was increased in the cells transfected with a CTNNB1p.Pro44Leu construct (P = 4.00 × 10–5). The β-catenin p.Pro44Leu variant was also associated with a decrease in phosphorylation at Ser45 and Ser33/Ser37/Thr41 in comparison to a wild-type (WT) CTNNB1 construct (P = 2.16 × 10–3, P = 9.34 × 10–8 respectively).ConclusionIncreased β‐catenin activity associated with a de novo gain-of-function CTNNB1 variant is associated with osteosclerotic phenotype and adrenocortical neoplasia.
      PubDate: Thu, 23 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa034
      Issue No: Vol. 105, No. 3 (2020)
  • Impact of Transition in Metabolic Health and Obesity on the Incident
           Chronic Kidney Disease: A Nationwide Cohort Study
    • Authors: Cho Y; Lee J, Kim H, et al.
      Abstract: AbstractContextMetabolically healthy obesity (MHO) is a dynamic condition.ObjectiveTo evaluate the risk of chronic kidney disease (CKD) among people with MHO according to its longitudinal change.DesignObservational study.SettingA nationwide population-based cohort.ParticipantsA total of 514 866 people from the Korean National Health Insurance Service-National Sample Cohort.InterventionThe initial presence and changes of obesity (using body mass index [BMI] and waist circumference [WC]) and metabolic health status.Main outcome MeasureIncident CKD from 2011 to 2015.ResultsOf the people classified as MHO at baseline (BMI criteria), 47.6% remained as MHO in 2011 and 2012, whereas 12.1%, 5.5%, and 34.8% were classified as metabolically healthy, non-obese (MHNO), metabolically unhealthy, non-obese, and metabolically unhealthy, obese, respectively. The risk of incident CKD in the baseline MHO group was higher than that in the MHNO group (hazard ratio, 1.23; 95% confidence interval, 1.12-1.36). However, when transition was taken into account, people who converted to MHNO were not at increased risk (hazard ratio, 0.98; 95% confidence interval, 0.72-1.32), whereas the stable MHO group and the groups that evolved to metabolically unhealthy status had a higher risk of incident CKD than the stable MHNO group. When the risk was analyzed using WC criteria, it showed a similar pattern to BMI criteria except for the stable MHO group.ConclusionsMHO was a dynamic condition, and people with MHO constituted a heterogeneous group. Although the MHO phenotype was generally associated with incident CKD, maintenance of metabolic health and weight reduction might alleviate the risk of CKD.
      PubDate: Wed, 22 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa033
      Issue No: Vol. 105, No. 3 (2020)
  • Implications of the Hemoglobin Glycation Index on the Diagnosis of
           Prediabetes and Diabetes
    • Authors: Hsia D; Rasouli N, Pittas A, et al.
      Abstract: AbstractObjectiveFasting plasma glucose (FPG), 2-hour plasma glucose (2hPG) from a 75-g oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) can lead to different results when diagnosing prediabetes and diabetes. The Hemoglobin Glycation Index (HGI) quantifies the interindividual variation in glycation resulting in discrepancies between FPG and HbA1c. We used data from the Vitamin D and Type 2 Diabetes (D2d) study to calculate HGI, to identify HGI-associated variables, and to determine how HGI affects prediabetes and diabetes diagnosis.MeasurementsA linear regression equation [HbA1c (%) = 0.0164 × FPG (mg/dL) + 4.2] was derived using the screening cohort (n = 6829) and applied to calculate predicted HbA1c. This was subtracted from the observed HbA1c to determine HGI in the baseline cohort with 2hPG data (n = 3945). Baseline variables plus prediabetes and diabetes diagnosis by FPG, HbA1c, and 2hPG were compared among low, moderate, and high HGI subgroups.ResultsThe proportion of women and Black/African American individuals increased from low to high HGI subgroups. Mean FPG decreased and mean HbA1c increased from low to high HGI subgroups, consistent with the HGI calculation; however, mean 2hPG was not significantly different among HGI subgroups.ConclusionsHigh HGI was associated with Black race and female sex as reported previously. The observation that 2hPG was not different across HGI subgroups suggests that variation in postprandial glucose is not a significant source of population variation in HGI. Exclusive use of HbA1c for diagnosis will classify more Black individuals and women as having prediabetes compared with using FPG or 2hPG.
      PubDate: Wed, 22 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa029
      Issue No: Vol. 105, No. 3 (2020)
  • Letter to the Editor: “Body Composition and Markers of Cardiometabolic
           Health in Transgender Youth Compared With Cisgender Youth.”
    • Authors: Sacerdote A.
      Abstract: I read with interest the article by Nokoff et al referenced below (1). Several investigators have reported an increased prevalence of androgenic disorders, such as polycystic ovarian syndrome and non-classic adrenal hyperplasia, in genetic female individuals with gender dysphoria (2–5). The presence of hyperandrogenemia in a significant proportion of trans men prior to initiation of gender-affirming hormone treatment raises the possibility that some of the observed differences in body composition and biomarkers of cardiometabolic health compared to cisgender youth in this cross-sectional study may already have been present to an extent prior to the initiation of hormone treatment.
      PubDate: Wed, 22 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa018
      Issue No: Vol. 105, No. 3 (2020)
  • Gamma-Glutamyl Transferase Variability and Risk of Dementia in Diabetes
           Mellitus: A Nationwide Population-Based Study
    • Authors: Hong S; Han K, Park S, et al.
      Abstract: AbstractContextGamma-glutamyl transferase (GGT) has been associated with oxidative stress and inflammatory reactions. Variability in various biomarkers has emerged as a new clinical indicator for diseases including neurodegenerative disorders.ObjectiveWe investigated the association between GGT variability and dementia risk in patients with diabetes mellitus (DM).Design, Participants, and MethodsWe used the Korean National Health Insurance Service datasets of Claims and Health Check-ups from 2004 to 2016. The risk of incident dementia (all-cause dementia, Alzheimer disease, vascular dementia) was analyzed by quartiles of GGT variability in ≥ 40-year-old DM individuals without baseline dementia.ResultsDuring 6.12 years of follow-up, 37, 983 cases of dementia developed. In the fully adjusted model, the group with the highest quartile of GGT variability had a 19% increased risk of all-cause dementia when compared with the lowest quartile group (hazard ratio; 95% confidence interval): 1.19; 1.16-1.22, with a small effect size (Cohen d’s = 0.14). Compared with the group with low baseline GGT level and the lowest quartiles of its variability, the group with high baseline GGT level and the highest quartile of its variability increased 27% of all-cause dementia. A 1 SD increment in the GGT variability was associated with a 3% increased risk of all-cause dementia. Subgroup analysis showed a more prominent association between increased GGT variability and dementia risk in men and < 60-year-old individuals (P for interaction ≤ .001).ConclusionsIn subjects with DM, high variability of GGT increased the risk of dementia independently of other factors, including baseline GGT levels.
      PubDate: Sun, 19 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa019
      Issue No: Vol. 105, No. 3 (2020)
  • Infertility, Gravidity, and Risk Of Diabetes among High-Risk Women in the
           Diabetes Prevention Program Outcomes Study
    • Authors: Kim C; Younes N, Temprosa M, et al.
      Abstract: AbstractObjectiveThe extent to which infertility and pregnancy independently increase risk of diabetes and subclinical atherosclerosis is not known.Research Design And MethodsWe conducted a secondary analysis of Diabetes Prevention Program (DPP) and the DPP Outcomes Study over a 15-year period. We included women who answered questions about gravidity and infertility at baseline (n = 2085). Infertility was defined as > 1 year of unsuccessful attempts to conceive; thus, women could have histories of infertility as well as pregnancy. Risk of diabetes associated with gravidity and infertility was calculated using Cox proportional hazards models adjusting for age, race/ethnicity, treatment arm, body mass index, and pregnancy during the study. Among women who underwent assessment of coronary artery calcification (CAC) (n = 1337), odds of CAC were calculated using logistic regression models with similar covariates.ResultsAmong premenopausal women (n = 1075), women with histories of pregnancy and infertility (n = 147; hazard ratio [HR] 1.80; 95% confidence interval [CI] 1.30, 2.49) and women with histories of pregnancy without infertility (n = 736; HR 1.49; 95% CI 1.15, 1.93) had greater diabetes risk than nulligravid women without infertility (n = 173). Premenopausal nulligravid women with histories of infertility had a non-significant elevation in risk, although the number of these women was small (n = 19; HR 1.63; 95% CI 0.88, 3.03). Associations were not observed among postmenopausal women (n = 1010). No associations were observed between infertility or pregnancy with CAC.ConclusionsPregnancy, particularly combined with a history of infertility, confers increased risk of diabetes but not CAC among glucose-intolerant premenopausal women.
      PubDate: Sun, 19 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa013
      Issue No: Vol. 105, No. 3 (2020)
  • Gestational Diabetes Risk in Migrants. A Nationwide, Register-Based Study
           of all Births in Denmark 2004 to 2015
    • Authors: Kragelund Nielsen K; Andersen G, Damm P, et al.
      Abstract: AbstractBackgroundMuch remains to be understood about socioeconomic position and body mass index (BMI) in the pathways linking ethnicity, migration, and gestational diabetes mellitus (GDM). We investigated differences in GDM prevalence according to maternal country of origin and the role played by socioeconomic position and BMI on this relationship. Finally, we examined how length of residency was associated with GDM.MethodsA register-based cohort study of the 725 482 pregnancies that resulted in a birth in Denmark, 2004 to 2015. Of these, 14.4% were by women who had migrated to Denmark. A GDM diagnosis was registered in 19 386 (2.7%) pregnancies, of which 4464 (23.0%) were in immigrant women. The crude risk of GDM according to maternal country of origin compared to Danish-born women ranged from an odds ratio (OR) of 0.50 (95% CI 0.34-0.71) for women from Sweden to an OR of 5.11 (95% CI 4.28-6.11) for women from Sri Lanka. Adjustment for socioeconomic position slightly attenuated the risks. Adjusting for BMI resulted in increased ORs for women, especially from Asian countries. The separate and joint effects of migration and overweight on GDM risk differed substantially between the countries of origin (P value interaction term < .001). Immigrants with 10 or more years of residency had a 56% increased risk of GDM (OR 1.56, 95% CI 1.44-1.68) compared to immigrants with less than 5 years in Denmark. This risk was somewhat diluted when adjusting for age and BMI.ConclusionsThis study demonstrates substantial variation in the risk of GDM according to country of origin. The risk associations are only slightly affected by socioeconomic position and BMI.
      PubDate: Fri, 17 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa024
      Issue No: Vol. 105, No. 3 (2020)
  • Cognitive Function of Children and Adolescents With Congenital Adrenal
           Hyperplasia: Importance of Early Diagnosis
    • Authors: Messina V; Karlsson L, Hirvikoski T, et al.
      Abstract: AbstractContextPatients with classic congenital adrenal hyperplasia (CAH) are treated postnatally with lifelong glucocorticoid (GC) replacement therapy. Previous results on general cognitive ability in individuals with CAH have been conflicting.ObjectiveTo evaluate long-term cognitive effects of GC replacement therapy and the impact of early diagnosis in children with CAH.Design and SettingObservational study with patients from a single research institute.Patients32 children with CAH (mean age 11.5 years) identified through the Swedish national neonatal screening program for CAH and 52 matched population controls (mean age 10.7 years). Eleven (6 female) children with CAH who were treated prenatally with dexamethasone (DEX), (CAH-DEX) (mean age 11.7 years).InterventionGC replacement therapy, neonatal screening for CAH.MeasuresCognitive abilities assessed with standardized neuropsychological tests (Wechsler scales, Span Board Test, Stroop Interference Test, NEPSY list learning).ResultsChildren with CAH (not prenatally treated) performed equally well as population controls on a series of tests assessing general intellectual ability and executive functions. No significant differences were observed in cognitive performance between patients with different genotypes (null, non-null). Patients with salt-wasting CAH performed poorer than patients with simple virilizing CAH in a test assessing visuo-spatial working memory (P = 0.039), although the performance was within the normal range for the population. Prenatally DEX-treated girls with CAH had lower verbal intellectual ability compared with CAH girls not exposed to prenatal treatment (P = 0.037).ConclusionChildren and adolescents with CAH who were diagnosed early via a neonatal screening program and treated with hydrocortisone had normal psychometric intelligence and executive functions.
      PubDate: Sun, 12 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa016
      Issue No: Vol. 105, No. 3 (2020)
  • The Relationship of Gastrinoma in MEN 1 to Helicobacter pylori infection
    • Authors: Endall R; Thompson M, Parameswaran V, et al.
      Abstract: AbstractContextHelicobacter pylori and Multiple Endocrine Neoplasia Type 1 (MEN 1) are risk factors for hypergastrinemia. Gastrin-secreting neoplasms of the foregut mucosa are both a source of, and potentially stimulated by, hypergastrinemia.ObjectiveTo determine the relationship between H pylori exposure and the prevalence and severity of hypergastrinemia in patients with MEN 1.Design, setting & patientsCross-sectional analysis of patients with a common MEN1 gene mutation managed at a tertiary referral hospital that underwent fasting serum gastrin and H pylori serum IgG measurement.InterventionH pylori IgG and serum gastrin concentration, determined via immunoassay.Main outcome measuresThe prevalence and severity of hypergastrinemia and its relationship to past H pylori exposure.ResultsThirty-four of 95 (36%) patients were H pylori IgG seropositive. H pylori seropositive patients were significantly more likely to exhibit hypergastrinemia compared with seronegative patients (relative risk [RR] 1.72, P = .023). H pylori exposure also predicted severe hypergastrinemia (RR 3.52, P = .026 and RR 9.37, P = .031 for patients with gastrin ≥ ×4 and ≥ ×8 the upper limit of normal [ULN], respectively). Gastrin concentrations ≥ ×10 ULN occurred exclusively in H pylori seropositive patients (0/61 vs 6/34, P = .001). Serum gastrin and alpha subunit were positively associated in H pylori-exposed (β = 0.69, P = .001), but not in H pylori-unexposed patients.ConclusionPast H pylori exposure was associated with increased prevalence and severity of hypergastrinemia in MEN 1 patients. Past H pylori-related hypergastrinemia may contribute to the pathogenesis of ongoing gastrin hypersecretion by susceptible foregut neuroendocrine tissues.
      PubDate: Fri, 10 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa004
      Issue No: Vol. 105, No. 3 (2020)
  • Which Drug Next' Sequential Therapy for Osteoporosis
    • Authors: Lukert B.
      Abstract: AbstractThe proliferation of drugs with unique modes of action for treating osteoporosis has been most welcome. Fear of complications, even though rare, associated with long-term bisphosphonates (BPs) changed prescribing patterns. The BPs are stored in bone for years. Drugs not stored in bone; for example, abaloparatide, teriparatide, denosumab, and romosozumab have expanded our armamentarium for treating osteoporosis but have brought new challenges. Bone accrued during treatment with the last 3 drugs, and perhaps abaloparatide, is lost rapidly after their withdrawal due to rebound increase in bone resorption. Treatment with these drugs must be followed by administration of an antiresorptive agent. The article by Kendler et al. (1) in this issue of JCEM reports alendronate preserves bone accrued during administration of denosumab.
      PubDate: Fri, 10 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa007
      Issue No: Vol. 105, No. 3 (2020)
  • Bariatric Surgery vs Lifestyle Intervention for Diabetes Treatment: 5-Year
           Outcomes From a Randomized Trial
    • Authors: Courcoulas A; Gallagher J, Neiberg R, et al.
      Abstract: AbstractContextQuestions remain about bariatric surgery for type 2 diabetes mellitus (T2DM) treatment.ObjectiveCompare the remission of T2DM following surgical or nonsurgical treatments.Design, setting, and participantsRandomized controlled trial at the University of Pittsburgh, in the United States. Five-year follow-up from February 2015 until June 2016.Interventions61 participants with obesity and T2DM who were initially randomized to either bariatric surgical treatments (Roux-en-Y gastric bypass [RYGB] or laparoscopic adjustable gastric banding [LAGB]) or an intensive lifestyle weight loss intervention (LWLI) program for 1 year. Lower level lifestyle weight loss interventions (LLLIs) were then delivered for 4 years.Main Outcomes and MeasuresDiabetes remission assessed at 5 years.ResultsThe mean age of the patients was 47 ± 6.6 years, 82% were women, and 21% African American. Mean hemoglobin A1c level 7.8% ± 1.9%, body mass index (BMI) 35.7 ± 3.1 kg/m2, and 26 participants (43%) had BMI < 35 kg/m2. Partial or complete T2DM remission was achieved by 30% (n = 6) of RYGB, 19% (n = 4) of LAGB, and no LWLI participants (P = .0208). At 5 years those in the RYGB group had the largest percentage of individuals (56%) not requiring any medications for T2DM compared with those in the LAGB (45%) and LWLI (0%) groups (P = .0065). Mean reductions in percent body weight at 5 years was the greatest after RYGB 25.2% ± 2.1%, followed by LAGB 12.7% ± 2.0% and lifestyle treatment 5.1% ± 2.5% (all pairwise P < .01).ConclusionsSurgical treatments are more effective than lifestyle intervention alone for T2DM treatment.
      PubDate: Thu, 09 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa006
      Issue No: Vol. 105, No. 3 (2020)
  • Polycystic Ovary Syndrome Signs and Metabolic Syndrome in Premenopausal
           Hispanic/Latina Women: the HCHS/SOL Study
    • Authors: Meyer M; Sotres‐Alvarez D, Steiner A, et al.
      Abstract: AbstractContextPolycystic ovary syndrome (PCOS), a condition of androgen excess in women, is associated with cardiometabolic risk factors; however, this association is not fully characterized in a population-based sample of premenopausal women and high-risk groups such as Hispanics/Latinas.ObjectiveWe examined the association of PCOS signs and metabolic syndrome (MetS) in premenopausal Hispanic/Latina women.MethodsThis cross-sectional analysis includes 1427 women age 24 to 44 years from the Hispanic Community Health Study/Study of Latinos. PCOS signs included menstrual cycle greater than 35 days or irregular, self-reported PCOS, and oral contraceptive use to regulate periods or acne, and a composite of 1 or more PCOS signs. We calculated odds ratios (OR) and 95% CI for MetS, accounting for sociodemographic factors and the complex survey design; an additional model included body mass index (BMI).ResultsThe mean age was 34 years and 30% reported any PCOS sign. The odds of MetS were higher in women reporting cycles greater than 35 days or irregular (OR 1.63; CI: 1.07-2.49) vs cycles 24 to 35 days, self-reported PCOS (OR 2.49; CI: 1.38-4.50) vs no PCOS, and any PCOS sign (OR 1.58; CI: 1.10-2.26) vs none. We found no association between OC use to regulate periods or acne and MetS (OR 1.1; CI: 0.6-1.8). When adjusting for BMI, only the association of self-reported PCOS and MetS was attenuated (OR 1.78; CI: 0.92-3.44).ConclusionsIn Hispanic/Latina women, irregular menstrual cycles, self-reported PCOS, and any PCOS sign were associated with MetS and could indicate women at metabolic disease risk.
      PubDate: Thu, 09 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa012
      Issue No: Vol. 105, No. 3 (2020)
  • A Polygenic Risk Score Suggests Shared Genetic Architecture of Voice Break
           With Early Markers of Pubertal Onset in Boys
    • Authors: Lardone M; Busch A, Santos J, et al.
      Abstract: AbstractContextVoice break, as a landmark of advanced male puberty in genome-wide association studies (GWAS), has revealed that pubertal timing is a highly polygenic trait. Although voice break is easily recorded in large cohorts, it holds quite low precision as a marker of puberty. In contrast, gonadarche and pubarche are early and clinically well-defined measures of puberty onset.ObjectiveTo determine whether a polygenic risk score (PRS) of alleles that confer risk for voice break associates with age at gonadarche (AAG) and age at pubarche (AAP) in Chilean boys.Experimental DesignLongitudinal study.Subjects and Methods401 boys from the Growth and Obesity Chilean Cohort Study (n = 1194; 49.2% boys).Main Outcome MeasuresBiannual clinical pubertal staging including orchidometry. AAG and AAP were estimated by censoring methods. Genotyping was performed using the Multi-Ethnic Global Array (Illumina). Using GWAS summary statistics from the UK-Biobank, 29 significant and independent single nucleotide polymorphisms associated with age at voice break were extracted. Individual PRS were computed as the sum of risk alleles weighted by the effect size.ResultsThe PRS was associated with AAG (β=0.01, P = 0.04) and AAP (β=0.185, P = 0.0004). In addition, boys within the 20% highest PRS experienced gonadarche and pubarche 0.55 and 0.67 years later than those in the lowest 20%, respectively (P = 0.013 and P = 0.007).ConclusionsGenetic variants identified in large GWAS on age at VB significantly associate with age at testicular growth and pubic hair development, suggesting that these events share a genetic architecture across ethnically distinct populations.
      PubDate: Thu, 09 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa003
      Issue No: Vol. 105, No. 3 (2020)
  • Circulating Unmethylated Insulin DNA As a Biomarker of Human Beta Cell
           Death: A Multi-laboratory Assay Comparison
    • Authors: Speake C; Ylescupidez A, Neiman D, et al.
      Abstract: AbstractContextThere is an unmet need for biomarkers of pancreatic beta-cell death to improve early diagnosis of type 1 diabetes, enroll subjects into clinical trials, and assess treatment response. To address this need, several groups developed assays measuring insulin deoxyribonucleic acid (DNA) with unmethylated CpG sites in cell-free DNA. Unmethylated insulin DNA should be derived predominantly from beta-cells and indicate ongoing beta-cell death.ObjectiveTo assess the performance of three unmethylated insulin DNA assays.Design and ParticipantsPlasma or serum samples from 13 subjects undergoing total pancreatectomy and islet autotransplantation were coded and provided to investigators to measure unmethylated insulin DNA. Samples included a negative control taken post-pancreatectomy but pretransplant, and a positive control taken immediately following islet infusion. We assessed technical reproducibility, linearity, and persistence of detection of unmethylated insulin DNA for each assay.ResultsAll assays discriminated between the negative sample and samples taken directly from the islet transplant bag; 2 of 3 discriminated negative samples from those taken immediately after islet infusion. When high levels of unmethylated insulin DNA were present, technical reproducibility was generally good for all assays.ConclusionsThe measurement of beta cell cell-free DNA, including insulin, is a promising approach, warranting further testing and development in those with or at-risk for type 1 diabetes, as well as in other settings where understanding the frequency or kinetics of beta cell death could be useful.
      PubDate: Wed, 08 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa008
      Issue No: Vol. 105, No. 3 (2020)
  • Fibroblast Growth Factor-21, Leptin, and Adiponectin Responses to Acute
           Cold-Induced Brown Adipose Tissue Activation
    • Authors: Sun L; Yan J, Goh H, et al.
      Abstract: AbstractBackgroundAdipocyte-derived hormones play a role in insulin sensitivity and energy homeostasis. However, the relationship between circulating fibroblast growth factor 21 (FGF21), adipocytokines and cold-induced supraclavicular brown adipose tissue (sBAT) activation is underexplored.ObjectiveOur study aimed to investigate the relationships between cold-induced sBAT activity and plasma FGF21 and adipocytokines levels in healthy adults.DesignNineteen healthy participants underwent energy expenditure (EE) and supraclavicular infrared thermography (IRT) within a whole-body calorimeter at baseline and at 2 hours post-cold exposure. 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography/magnetic resonance (PET/MR) imaging scans were performed post-cold exposure. PET sBAT mean standardized uptake value (SUV mean), MR supraclavicular fat fraction (sFF), anterior supraclavicular maximum temperature (Tscv max) and EE change (%) after cold exposure were used to quantify sBAT activity.Main Outcome MeasuresPlasma FGF21, leptin, adiponectin, and tumor necrosis factor alpha (TNFα) at baseline and 2 hours post-cold exposure. Body composition at baseline by dual-energy x-ray absorptiometry (DXA).ResultsPlasma FGF21 and adiponectin levels were significantly reduced after cold exposure in BAT-positive subjects but not in BAT-negative subjects. Leptin concentration was significantly reduced in both BAT-positive and BAT-negative participants after cold exposure. Adiponectin concentration at baseline was positively strongly associated with sBAT PET SUV mean (coefficient, 3269; P = 0.01) and IRT Tscv max (coefficient, 6801; P  = 0.03), and inversely correlated with MR sFF (coefficient, −404; P  = 0.02) after cold exposure in BAT-positive subjects but not in BAT-negative subjects.ConclusionHigher adiponectin concentrations at baseline indicate a greater cold-induced sBAT activity, which may be a novel predictor for sBAT activity in healthy BAT-positive adults.HighlightsA higher adiponectin concentration at baseline was associated with higher cold-induced supraclavicular BAT PET SUV mean and IRT Tscv max, and lower MR supraclavicular FF. Adiponectin levels maybe a novel predictor for cold-induced sBAT activity.
      PubDate: Wed, 08 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa005
      Issue No: Vol. 105, No. 3 (2020)
  • Effect of the Age at Menarche and Menopause Status Interaction on Type 2
           Diabetes: The Henan Rural Cohort Study
    • Authors: Zhang L; Li Y, Dong X, et al.
      Abstract: AbstractPurposeThe aims of this study were to evaluate the effect of age at menarche (AM) on type 2 diabetes mellitus (T2DM) and to assess whether the fasting plasma glucose (FPG) and homeostasis model assessment (HOMA) index responses to AM and menopause status interact in Chinese rural adults.MethodsA cross-sectional, population-based study including 23 138 participants was performed. Logistic regression and multivariable linear regression were performed to investigate the relationship between AM and glucose status. Generalized linear model was used to calculate the interaction term of AM and menopause status on FPG and the HOMA index. Interaction plot was used to interpret the significant interaction effect.ResultsWomen in the later menarche age group (≥18 years) had a 17.7% lower risk of T2DM (95% confidence interval [CI]: 0.712-0.951, P = .008), after adjusting for multiple variables. Further adjustment for body mass index (BMI) completely attenuated this association (odds ratio = 0.884, 95% CI: 0.764-1.024, P = .099). A significant interaction effect of AM and menopause status on T2DM (P = .004) was observed. The adverse effects of menopausal status on FPG and HOMA-2 of insulin resistance decreased with increasing menarche age, and the age ranges were limited to <18 and 9 to 19 years, respectively.ConclusionsLater menarche was associated with a lower risk of T2DM, and the association appears to be mediated by BMI. More importantly, the adverse effect of menopause status on T2DM was decreased along with increasing menarche age.
      PubDate: Wed, 08 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgz328
      Issue No: Vol. 105, No. 3 (2020)
  • Response to Letter to the Editor: Evaluating the Low-Dose ACTH Stimulation
           Test in Children: Ideal Times for Cortisol Measurement
    • Authors: Ahmet A; Gill H.
      Abstract: We read with interest the letter provided by Dr Hindmarsh and Dr Honour in response to our recently published article entitled “Evaluating the low-dose ACTH stimulation test in children: Ideal times for cortisol measurement.” In our study, we evaluated the added benefit of 15- and 60-minute cortisol samples to the standard 30-minute sample in low-dose adrenocorticotropin (ACTH) stimulation testing and concluded that the addition of the 15- and 60-minute samples reduces the rate of false-positive tests. The commentary asks the Endocrine Society to initiate steps to a harmonized protocol for the low-dose ACTH stimulation tests that would standardize both delivery of Cosyntropin so as to minimize absorption of the ACTH to container surfaces as well as blood sampling time (proposing 5-minute intervals from 15 to 40 minutes). We agree that the lack of standardization of cortisol assays, poor correlation of cortisol thresholds with clinical outcomes, and, as suggested in their letter, inadequate standardization of the ACTH stimulation testing protocol all complicate the evaluation of the hypothalamic–pituitary–thyroid axis. We would like to highlight that, as outlined in our “Methods” section, our low-dose ACTH stimulation protocol was designed to prevent losses of Cosyntropin due to absorption of the ACTH to container surfaces. Although we believe that the research that is highlighted in the commentary is interesting and is worth attention and further study, until there is clear evidence both supporting a significant benefit of frequent sampling and defining a “normal” cortisol response with repeated sampling, it is difficult to advocate for standardization of frequent sampling protocols, particularly in children. In the interim, we believe that our findings that demonstrate the value of 2 additional sampling times at 15 and 60 minutes in addition to the standard 30-minute test will help to prevent misdiagnosis of adrenal insufficiency using the low-dose ACTH stimulation test.
      PubDate: Wed, 08 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa010
      Issue No: Vol. 105, No. 3 (2020)
  • Letter to the Editor: “Evaluating the Low-Dose ACTH Stimulation Test in
           Children: Ideal Times for Cortisol Measurement”
    • Authors: Hindmarsh P; Honour J.
      Abstract: adrencorticotrophinstimulation testcortisolsteroid hormoneschronology
      PubDate: Wed, 08 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa009
      Issue No: Vol. 105, No. 3 (2020)
  • Frequency and Incidence of Carney Complex Manifestations: A Prospective
           Multicenter Study With a Three-Year Follow-Up
    • Authors: Espiard S; Vantyghem M, Assié G, et al.
      Abstract: AbstractIntroductionCarney Complex (CNC) is a rare multiple endocrine and nonendocrine neoplasia syndrome. Manifestations and genotype-phenotype correlations have been described by retrospective studies, but no prospective study evaluating the occurrence of the different manifestations has been available so far.MethodsThis multicenter national prospective study included patients with CNC, primary pigmented nodular adrenal disease (PPNAD), or a pathogenic PRKAR1A mutation; after a full initial workup, participants were followed for 3 years with annual standardized evaluation.ResultsThe cohort included 70 patients (50 female/20 male, mean age 35.4 ± 16.7 years, 81% carrying PRKAR1A mutation). The initial investigations allowed identification of several manifestations. At the end of the 3-year follow-up, the newly diagnosed manifestations of the disease were subclinical acromegaly in 6 patients, bilateral testicular calcifications in 1 patient, and cardiac myxomas in 2 patients. Recurrences of cardiac myxomas were diagnosed in 4 patients during the 3-year follow-up study period. Asymptomatic abnormalities of the corticotroph and somatotroph axis that did not meet criteria of PPNAD and acromegaly were observed in 11.4% and 30% of the patients, respectively. Patients carrying the PRKAR1A c.709-7del6 mutation had a mild phenotype.ConclusionThis study underlines the importance of a systematic follow-up of the CNC manifestations, especially a biannual screening for cardiac myxoma. By contrast, regular screening for the other manifestations after a first extensive workup could be spread out, leading to a lighter and more acceptable follow-up schedule for patients. These are important results for recommendations for long-term management of CNC patients.
      PubDate: Wed, 08 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa002
      Issue No: Vol. 105, No. 3 (2020)
  • Kinome Profiling Reveals Abnormal Activity of Kinases in Skeletal Muscle
           From Adults With Obesity and Insulin Resistance
    • Authors: Qi Y; Zhang X, Seyoum B, et al.
      Abstract: AbstractContextObesity-related insulin resistance (OIR) is one of the main contributors to type 2 diabetes and other metabolic diseases. Protein kinases are implicated in insulin signaling and glucose metabolism. Molecular mechanisms underlying OIR involving global kinase activities remain incompletely understood.ObjectiveTo investigate abnormal kinase activity associated with OIR in human skeletal muscle.DesignUtilization of stable isotopic labeling-based quantitative proteomics combined with affinity-based active enzyme probes to profile in vivo kinase activity in skeletal muscle from lean control (Lean) and OIR participants.ParticipantsA total of 16 nondiabetic adults, 8 Lean and 8 with OIR, underwent hyperinsulinemic-euglycemic clamp with muscle biopsy.ResultsWe identified the first active kinome, comprising 54 active protein kinases, in human skeletal muscle. The activities of 23 kinases were different in OIR muscle compared with Lean muscle (11 hyper- and 12 hypo-active), while their protein abundance was the same between the 2 groups. The activities of multiple kinases involved in adenosine monophosphate–activated protein kinase (AMPK) and p38 signaling were lower in OIR compared with Lean. On the contrary, multiple kinases in the c-Jun N-terminal kinase (JNK) signaling pathway exhibited higher activity in OIR vs Lean. The kinase-substrate–prediction based on experimental data further confirmed a potential downregulation of insulin signaling (eg, inhibited phosphorylation of insulin receptor substrate-1 and AKT1/2).ConclusionsThese findings provide a global view of the kinome activity in OIR and Lean muscle, pinpoint novel specific impairment in kinase activities in signaling pathways important for skeletal muscle insulin resistance, and may provide potential drug targets (ie, abnormal kinase activities) to prevent and/or reverse skeletal muscle insulin resistance in humans.
      PubDate: Thu, 26 Dec 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz115
      Issue No: Vol. 105, No. 3 (2019)
  • A Beginning in the Investigation of the Metabolic Consequences of
           Transgender Hormone Treatment on Young People
    • Authors: Pang J; Safer J.
      Abstract: transgenderyouth transgendercardiac risk factors
      PubDate: Thu, 05 Dec 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz249
      Issue No: Vol. 105, No. 3 (2019)
  • Dynamic Interactions Between LH and Testosterone in Healthy
           Community-Dwelling Men: Impact of Age and Body Composition
    • Authors: Roelfsema F; Liu P, Takahashi P, et al.
      Abstract: AbstractBackgroundAging is associated with diminished testosterone (Te) secretion, which may be attributed to Leydig cell dysfunction, decreased pituitary stimulation, and altered Te feedback.ObjectiveTo study all regulatory nodes—gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and Leydig cell—in the same cohort of healthy men.Study DesignThis was a placebo-controlled, blinded, prospectively randomized cross-over study in 40 men, age range 19 to 73 years, and body mass index (BMI) range 20 to 34.3 kg/m2. A submaximal dose of the GnRH antagonist ganirelix was used to assess outflow of GnRH, by calculating the difference between LH output during the control arm and ganirelix arm. Ketoconazole (a steroidogenic inhibitor) was used to estimate feedback, by the difference in LH output during the ketoconazole and control arm. High-dose ganirelix and repeated LH infusions were used to measure testicular responsivity. Blood sampling was performed at 10-minute intervals.ResultsThere were age-related, but not body composition–related decreases in estimated GnRH secretion, the feedback strength of Te on LH, and Leydig cell responsivity to LH, accompanied by changes in approximate entropy. Bioavailable Te levels were negatively related to both age and computed tomography (CT)–estimated abdominal visceral mass (AVF), without interaction between these variables. The LH response to a submaximal dose of GnRH was independent of age and AVF.ConclusionAdvancing age is associated with (1) attenuated bioavailable Te secretion caused by diminished GnRH outflow and not by decreased GnRH responsivity of the gonadotrope, (2) diminished testicular responsivity to infused LH pulses, and (3) partial compensation by diminished Te feedback on central gonadotropic regulation.
      PubDate: Mon, 02 Dec 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz246
      Issue No: Vol. 105, No. 3 (2019)
  • The Causal Relationship of Circulating Triglyceride and Glycated
           Hemoglobin: A Mendelian Randomization Study
    • Authors: Hsiung C; Chang Y, Lin C, et al.
      Abstract: AbstractContextThe association between circulating triglyceride (TG) and glycated hemoglobin A1c (HbA1c), a biomarker for type 2 diabetes, has been widely addressed, but the causal direction of the relationship is still ambiguous.ObjectiveTo confirm the causal relationship between TG and HbA1c by using bidirectional and 2-step Mendelian randomization (MR) approaches.MethodsWe carried out a bidirectional MR approach using the summarized results from the public database to examine any potential causal effects between serum TG and HbA1c in 16 000 individuals of the Taiwan Biobank cohort. We used the MR estimate and the MR inverse variance–weighted method to reveal that relationship between TG and HbA1c. To further determine whether the DNA methylation at specific sequences mediate the causal pathway between TG and HbA1c, using the 2-step MR approach.ResultsWe identified that a single-unit increase in TG measured via log transformation of mg/dL data was associated with a significant increase of 10 units of HbA1c (95% CI = 1.05−18.95, P = 0.029). In contrast, the genetic determinants of HbA1c do not contribute to the amount of circulating TG (beta = 1.75, 95% CI = –11.50 to 14.90). Sensitivity analyses, included the weighted-median approach and MR-Egger regression, were performed to confirm no pleiotropic effect among these instrumental variables. Furthermore, we identified the genetic variant, rs1823200, is associated with both methylation of the CpG site adjacent to CADPS gene and HbA1c level.ConclusionOur study suggests that higher circulating TG can have an affect on genomic methylation status, ultimately causing elevated level of circulating HbA1c.
      PubDate: Sat, 30 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz243
      Issue No: Vol. 105, No. 3 (2019)
  • Serum Metabolome of Coffee Consumption and its Association With Bone
           Mineral Density: The Hong Kong Osteoporosis Study
    • Authors: Chau Y; Au P, Li G, et al.
      Abstract: AbstractBackgroundInconsistent associations between coffee consumption and bone mineral density (BMD) have been observed in epidemiological studies. Moreover, the relationship of bioactive components in coffee with BMD has not been studied. The aim of the current study is to identify coffee-associated metabolites and evaluate their association with BMD.MethodsTwo independent cohorts totaling 564 healthy community-dwelling adults from the Hong Kong Osteoporosis Study (HKOS) who visited in 2001–2010 (N = 329) and 2015–2016 (N = 235) were included. Coffee consumption was self-reported in an food frequency questionnaire. Untargeted metabolomic profiling on fasting serum samples was performed using liquid chromatography–mass spectrometry platforms. BMD at lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry. Multivariable linear regression and robust regression were used for the association analyses.Results12 serum metabolites were positively correlated with coffee consumption after Bonferroni correction for multiple testing (P < 4.87 × 10–5), with quinate, 3-hydroxypyridine sulfate, and trigonelline (N’-methylnicotinate) showing the strongest association. Among these metabolites, 11 known metabolites were previously identified to be associated with coffee intake and 6 of them were related to caffeine metabolism. Habitual coffee intake was positively and significantly associated with BMD at the lumbar spine and femoral neck. The metabolite 5-acetylamino-6-formylamino-3-methyluracil (AFMU) (β = 0.012, SE = 0.005; P = 0.013) was significantly associated with BMD at the lumbar spine, whereas 3-hydroxyhippurate (β = 0.007, SE = 0.003, P = 0.027) and trigonelline (β = 0.007, SE = 0.004; P = 0.043) were significantly associated with BMD at the femoral neck.Conclusions12 metabolites were significantly associated with coffee intake, including 6 caffeine metabolites. Three of them (AFMU, 3-hydroxyhippurate, and trigonelline) were further associated with BMD. These metabolites could be potential biomarkers of coffee consumption and affect bone health.
      PubDate: Thu, 21 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz210
      Issue No: Vol. 105, No. 3 (2019)
  • Efficacy of Temozolomide Therapy in Patients With Aggressive Pituitary
           Adenomas and Carcinomas—A German Survey
    • Authors: Elbelt U; , Schlaffer S, et al.
      Abstract: AbstractContextDespite growing evidence that temozolomide (TMZ) therapy is effective for the treatment of aggressive pituitary tumors (APTs) or carcinomas (PCs), individual therapy decisions remain challenging.ObjectiveWe therefore aimed to report on clinical characteristics leading to initiation of TMZ therapy and to add evidence on TMZ long-term effectiveness.Design and subjectsRetrospective survey on TMZ treatment in patients with APTs or PCs. TMZ therapy was initiated in 47 patients (22 females) with APTs (n = 34) or PCs (n = 13). Mean age at diagnosis was 45 ± 15 years. The immunohistochemical subtypes were corticotroph (n = 20), lactotroph (n = 18), and nonfunctioning (n = 9) tumors. TMZ therapy started 8 years after initial diagnosis using a standard regimen (median 6 cycles) for the majority of patients.ResultsLong-term radiological response to TMZ after a median follow-up of 32 months with 4 patients still on TMZ therapy was tumor regression for 9 (20%), stable disease for 8 (17%), and tumor progression for 29 patients (63%) (outcome data available for 46 patients). Progression occurred 16 months after initiation of TMZ. Median estimated progression-free survival was 23 months. Disease stabilization and median progression-free survival did not differ between patients with APTs or PCs. Predictors of tumor response were not identified. Overall, TMZ was well tolerated.ConclusionWe performed a nationwide survey on TMZ therapy in patients with APTs and PCs. While early response rates to TMZ are promising, long-term outcome is less favorable. Prolonged TMZ administration should be considered. We were not able to confirm previously reported predictors of tumor response to TMZ.
      PubDate: Wed, 20 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz211
      Issue No: Vol. 105, No. 3 (2019)
  • Prevalence and Mortality of Individuals With X-Linked Hypophosphatemia: A
           United Kingdom Real-World Data Analysis
    • Authors: Hawley S; Shaw N, Delmestri A, et al.
      Abstract: AbstractBackgroundX-linked hypophosphatemia (XLH) is a rare multisystemic disease with a prominent musculoskeletal phenotype. We aim here to improve understanding of the prevalence of XLH across the life course and of overall survival among people with XLH.MethodsThis was a population-based cohort study using a large primary care database in the United Kingdom (UK) from 1995 to 2016. XLH cases were matched by age, gender, and practice to up to 4 controls. Trends in prevalence over the study period were estimated (stratified by age) and survival among cases was compared with that of controls.FindingsFrom 522 potential cases, 122 (23.4%) were scored as at least possible XLH, while 62 (11.9%) were classified as highly likely or likely (conservative definition). In main analyses, prevalence (95% CI) increased from 3.1 (1.5–6.7) per million in 1995–1999 to 14.0 (10.8–18.1) per million in 2012–2016. Corresponding estimates using the conservative definition were 3.0 (1.4–6.5) to 8.1 (5.8–11.4). Nine (7.4%) of the possible cases died during follow-up, at median age of 64 years. Fourteen (2.9%) of the controls died at median age of 72.5 years. Mortality was significantly increased in those with possible XLH compared with controls (hazard ratio [HR] 2.93; 95% CI, 1.24–6.91). Likewise, among those with likely or highly likely XLH (HR 6.65; 1.44–30.72).ConclusionsWe provide conservative estimates of the prevalence of XLH in children and adults within the UK. There was an unexpected increase in mortality in later life, which may have implications for other fibroblast growth factor 23–related disorders.
      PubDate: Fri, 15 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz203
      Issue No: Vol. 105, No. 3 (2019)
  • Obstructive Sleep Apnea in Acromegaly and the Effect of Treatment: A
           Systematic Review and Meta-Analysis
    • Authors: Parolin M; Dassie F, Alessio L, et al.
      Abstract: AbstractBackgroundObstructive sleep apnea (OSA) is a common disorder characterized by upper airway collapse requiring nocturnal ventilatory assistance. Multiple studies have investigated the relationship between acromegaly and OSA, reporting discordant results.AimTo conduct a meta-analysis on the risk for OSA in acromegaly, and in particular to assess the role of disease activity and the effect of treatments.Methods and Study SelectionA search through literature databases retrieved 21 articles for a total of 24 studies (n = 734). Selected outcomes were OSA prevalence and apnea-hypopnea index (AHI) in studies comparing acromegalic patients with active (ACT) vs inactive (INACT) disease and pretreatment and posttreatment measures. Factors used for moderator and meta-regression analysis included the percentage of patients with severe OSA, patient sex, age, body mass index, levels of insulin-like growth factor 1, disease duration and follow-up, and therapy.ResultsOSA prevalence was similar in patients with acromegaly who had ACT and INACT disease (ES = −0.16; 95% CI, −0.47 to 0.15; number of studies [k] = 10; P = 0.32). In addition, AHI was similar in ACT and INACT acromegaly patients (ES = −0.03; 95% CI, −0.49 to 0.43; k = 6; P = 0.89). When AHI was compared before and after treatment in patients with acromegaly (median follow-up of 6 months), a significant improvement was observed after treatment (ES = −0.36; 95% CI, −0.49 to −0.23; k = 10; P < 0.0001). In moderator analysis, the percentage of patients with severe OSA in the populations significantly influenced the difference in OSA prevalence (P = 0.038) and AHI (P = 0.04) in ACT vs INACT patients.ConclusionPrevalence of OSA and AHI is similar in ACT and INACT patients in cross-sectional studies. However, when AHI was measured longitudinally before and after treatment, a significant improvement was observed after treatment.
      PubDate: Wed, 13 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz116
      Issue No: Vol. 105, No. 3 (2019)
  • Changes Over Time in Uric Acid in Relation to Changes in Insulin
           Sensitivity, Beta-Cell Function, and Glycemia
    • Authors: Volpe A; Ye C, Hanley A, et al.
      Abstract: AbstractContextSerum uric acid has been linked to risk of type 2 diabetes (T2DM), but debate persists as to whether it plays a causal role. Indeed, it is unclear if changes in uric acid relate to the pathophysiologic determinants of T2DM (insulin resistance, beta-cell dysfunction), as would be expected if causal.ObjectiveTo evaluate the impact of changes in uric acid over 2 years on changes in insulin sensitivity, beta-cell function, and glycemia in women with and without recent gestational diabetes (GDM), a model of the early natural history of T2DM.Design/Setting/ParticipantsAt both 1 and 3 years postpartum, 299 women (96 with recent GDM) underwent uric acid measurement and oral glucose tolerance tests that enabled assessment of insulin sensitivity/resistance (Matsuda index, homeostasis model assessment of insulin resistance [HOMA-IR]), beta-cell function (insulin secretion-sensitivity index-2 [ISSI-2], insulinogenic index/HOMA-IR [IGI/HOMA-IR]), and glucose tolerance.ResultsWomen with recent GDM had higher serum uric acid than their peers at both 1 year (281 ± 69 vs 262 ± 58 µmol/L, P = 0.01) and 3 years postpartum (271 ± 59 vs 256 ± 55 µmol/L, P = 0.03), coupled with lower insulin sensitivity, poorer beta-cell function, and greater glycemia (all P < 0.05). However, on fully adjusted analyses, neither uric acid at 1 year nor its change from 1 to 3 years was independently associated with any of the following metabolic outcomes at 3 years postpartum: Matsuda index, HOMA-IR, ISSI-2, IGI/HOMA-IR, fasting glucose, 2-hour glucose, or glucose intolerance.ConclusionSerum uric acid does not track with changes over time in insulin sensitivity, beta-cell function, or glycemia in women with recent GDM, providing evidence against causality in its association with diabetes.
      PubDate: Wed, 13 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz199
      Issue No: Vol. 105, No. 3 (2019)
  • Sex-specific Estrogen Levels and Reference Intervals from Infancy to Late
           Adulthood Determined by LC-MS/MS
    • Authors: Frederiksen H; Johannsen T, Andersen S, et al.
      Abstract: AbstractContextThe lack of sensitive and robust analytical methods has hindered the reliable quantification of estrogen metabolites in subjects with low concentrations.ObjectiveTo establish sex-specific reference ranges for estrone (E1) and estradiol (E2) throughout life and to evaluate sex-differences using the state-of-the-art liquid chromatography tandem mass spectrometry (LC-MS/MS) method for quantification of E1, E2, and estriol (E3).DesignLC-MS/MS method development and construction of estrogen reference ranges.SettingsPopulation-based cross-sectional cohorts from the greater Copenhagen and Aarhus areas.ParticipantsHealthy participants aged 3 months to 61 years (n = 1838).ResultsAn isotope diluted LC-MS/MS method was developed and validated for measurements of serum E1, E2, and E3. Limits of detections (LODs) were 3 pmol/L (E1), 4 pmol/L (E2), and 12 pmol/L (E3), respectively. This sensitive method made it possible to differentiate between male and female concentration levels of E1 and E2 in children. In girls, E2 levels ranged from <LOD to 100 pmol/L during mini-puberty, whereas it was ≤20 pmol/L during childhood. E1 and E2 increased with age and pubertal breast stage and varied during the menstrual cycle; E1 was lower than E2 in girls and premenopausal women, and higher than E2 in postmenopausal women. In boys, E1 and E2 increased with age and pubertal stage, whereas little changes with age were observed in men. High E3 concentrations were confirmed in pregnant women.ConclusionReference ranges of simultaneous quantification of E1 and E2 by this novel specific and highly sensitive LC-MS/MS method provide an invaluable tool in clinical practice and in future research studies.
      PubDate: Wed, 13 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz196
      Issue No: Vol. 105, No. 3 (2019)
  • Kinetics and Interrelations of the Renin Aldosterone Response to Acute
           Psychosocial Stress: A Neglected Stress System
    • Authors: Gideon A; Sauter C, Fieres J, et al.
      Abstract: AbstractContextThe renin-angiotensin-aldosterone system (RAAS) plays an important role in cardiovascular homeostasis and its dysfunction relates to negative health consequences. Acute psychosocial stress seems to activate the RAAS in humans, but stress kinetics and interrelations of RAAS parameters compared with a nonstress control group remain inconclusive.ObjectiveWe systematically investigated in a randomized placebo-controlled design stress kinetics and interrelations of the reactivity of RAAS parameters measured in plasma and saliva to standardized acute psychosocial stress induction.Methods58 healthy young men were assigned to either a stress or a placebo control group. The stress group underwent the Trier Social Stress Test (TSST), while the control group underwent the placebo TSST. We repeatedly assessed plasma renin, and plasma and salivary aldosterone before and up to 3 hours after stress/placebo. We simultaneously assessed salivary cortisol to validate successful stress induction and to test for interrelations.ResultsAcute psychosocial stress induced significant increases in all endocrine measures compared with placebo-stress (all P ≤ .041). Highest renin levels were observed 1 minute after stress, and highest aldosterone and cortisol levels 10 and 20 minutes after stress, with salivary aldosterone starting earlier at 1 minute after stress. Renin completed recovery at 10 minutes, cortisol at 60 minutes, salivary aldosterone at 90 minutes, and plasma aldosterone at 180 minutes after stress. Stress increase scores of all endocrine measures related to each other, as did renin and cortisol areas under the curve with respect to increase (AUCi) and salivary and plasma aldosterone AUCi (all P ≤ .047).ConclusionsOur findings suggest that in humans acute psychosocial stress induces a differential and interrelated RAAS parameter activation pattern. Potential implications for stress-related cardiovascular risk remain to be elucidated.
      PubDate: Sun, 10 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz190
      Issue No: Vol. 105, No. 3 (2019)
  • Patients With Primary Aldosteronism Respond to Unilateral Adrenalectomy
           With Long-Term Reduction in Salt Intake
    • Authors: Adolf C; Heinrich D, Holler F, et al.
      Abstract: AbstractContextHigh dietary salt intake is known to aggravate arterial hypertension. This effect could be of particular relevance in the setting of primary aldosteronism (PA), which is associated with cardiovascular damage independent of blood pressure levels. The aim of this study was to determine the impact of therapy on salt intake in PA patients.Patients and MethodsA total of 148 consecutive PA patients (66 with unilateral and 82 with bilateral PA) from the database of the German Conn’s Registry were included. Salt intake was quantified by 24-hour urinary sodium excretion before and after initiation of PA treatment.Study designObservational longitudinal cohort study.SettingTertiary care hospital.ResultsAt baseline, unilateral PA patients had a significantly higher urinary sodium excretion than patients with bilateral disease (205 vs 178 mmol/d, P = 0.047). Higher urinary sodium excretion correlated with an increased cardiovascular risk profile including proteinuria, impaired lipid, and glucose metabolism and was associated with higher daily doses of antihypertensive drugs to achieve blood pressure control. In unilateral disease, urinary sodium excretion dropped spontaneously to 176 mmol/d (P = 0.012) 1 year after unilateral adrenalectomy and remained low at 3 years of follow-up (174 mmol/d). In contrast, treatment with mineralocorticoid receptor antagonists (MRA) in bilateral PA patients was not associated with a significant change in urinary sodium excretion at follow-up (179 mmol/d vs 183 mmol/d).ConclusionPA patients consuming a high-salt diet, estimated based on urinary sodium excretion, respond to adrenalectomy with a significant reduction of salt intake, in contrast to MRA treatment.
      PubDate: Fri, 08 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz051
      Issue No: Vol. 105, No. 3 (2019)
  • Biochemical Control in Acromegaly With Multimodality Therapies: Outcomes
           From a Pituitary Center and Changes Over Time
    • Authors: Ghajar A; Jones P, Guarda F, et al.
      Abstract: AbstractPurposeTo determine the prevalence of insulin-like growth factor-1 (IGF-1) normalization with long-term multimodality therapy in a pituitary center and to assess changes over time.MethodsPatients with acromegaly (N = 409), with ≥1 year of data after surgery and at least 2 subsequent clinic visits were included in long-term analysis (N = 266). Biochemical data, clinical characteristics, and therapeutic interventions were reviewed retrospectively. ResultsAt diagnosis, mean [standard deviation] age was 43.4 [14.3] years, body mass index was 28.5 (24.9–32.1) kg/m2 (median, interquartile range), serum IGF-1 index (IGF-1 level/upper limit of normal) was 2.3 [1.7–3.1], and 80.5% had macroadenomas. Patients with transsphenoidal surgery after 2006 were older [46.6 ± 14.3 vs 40.0 ± 13.4 years; P < 0.001]. Age and tumor size correlated inversely. Overall (N = 266), 93.2% achieved a normal IGF-1 level during 9.9 [5.0–15.0] years with multimodality therapy. The interval to first normal IGF-1 level following failed surgical remission was shorter after 2006: 14.0 (95% confidence interval, 10.0–20.0) versus 27.5 (22.0–36.0) months (P = 0.002). Radiation therapy and second surgery were rarer after 2006: 28 (22%) versus 62 (47.0%); P < 0.001 and 12 (9.4%) versus 28 (21.2%); P = 0.010, respectively. Age at diagnosis increased over time periods, possibly reflecting increased detection of acromegaly in older patients with milder disease. Male gender, older age, smaller tumor and lower IGF-1 index at diagnosis predicted long-term sustained IGF-1 control after surgery without adjuvant therapies.ConclusionThe vast majority of patients with acromegaly can be biochemically controlled with multimodality therapy in the current era. Radiotherapy and repeat pituitary surgery became less frequently utilized over time. Long-term postoperative IGF-1 control without use of adjuvant therapies has improved.
      PubDate: Fri, 08 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz187
      Issue No: Vol. 105, No. 3 (2019)
  • Dissecting the Role of Thyrotropin in the DNA Damage Response in Human
           Thyrocytes after 131I, γ Radiation and H2O2
    • Authors: Kyrilli A; Gacquer D, Detours V, et al.
      Abstract: AbstractBackgroundThe early molecular events in human thyrocytes after 131I exposure have not yet been unravelled. Therefore, we investigated the role of TSH in the 131I-induced DNA damage response and gene expression in primary cultured human thyrocytes.MethodsFollowing exposure of thyrocytes, in the presence or absence of TSH, to 131I (β radiation), γ radiation (3 Gy), and hydrogen peroxide (H2O2), we assessed DNA damage, proliferation, and cell-cycle status. We conducted RNA sequencing to profile gene expression after each type of exposure and evaluated the influence of TSH on each transcriptomic response.ResultsOverall, the thyrocyte responses following exposure to β or γ radiation and to H2O2 were similar. However, TSH increased 131I-induced DNA damage, an effect partially diminished after iodide uptake inhibition. Specifically, TSH increased the number of DNA double-strand breaks in nonexposed thyrocytes and thus predisposed them to greater damage following 131I exposure. This effect most likely occurred via Gα q cascade and a rise in intracellular reactive oxygen species (ROS) levels. β and γ radiation prolonged thyroid cell-cycle arrest to a similar extent without sign of apoptosis. The gene expression profiles of thyrocytes exposed to β/γ radiation or H2O2 were overlapping. Modulations in genes involved in inflammatory response, apoptosis, and proliferation were observed. TSH increased the number and intensity of modulation of differentially expressed genes after 131I exposure.ConclusionsTSH specifically increased 131I-induced DNA damage probably via a rise in ROS levels and produced a more prominent transcriptomic response after exposure to 131I.
      PubDate: Fri, 08 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz185
      Issue No: Vol. 105, No. 3 (2019)
  • Long-Term Outcomes of Treatments for Central Precocious Puberty or Early
           and Fast Puberty in Chinese Girls
    • Authors: Fu J; Zhang J, Chen R, et al.
      Abstract: AbstractContextGonadotropin-releasing hormone analogues (GnRHa) and recombinant human growth hormone (rhGH) have been widely used to treat idiopathic central precocious puberty (CPP) or early and fast puberty (EFP). However, large-scale studies to evaluate the treatment effects on final adult height (FAH) are still lacking.ObjectiveTo assess the effects of long-term treatment for CPP/EFP on FAH and its main influencing factors.Design and SettingRetrospective, multicenter observational study from 1998 to 2017.ParticipantsFour hundred forty-eight Chinese girls with CPP/EFP received GnRHa and rhGH treatment (n = 118), GnRHa alone (n = 276), or no treatment (n = 54).Main Outcome MeasuresFAH, target height (Tht), and predictive adult height (PAH).ResultsThe height gain (FAH–PAH) was significantly different among the GnRHa and rhGH treatment, GnRHa alone, and no treatment groups (P < 0.05; 9.51 ± 0.53, 8.07 ± 0.37, and 6.44 ± 0.91 cm, respectively). The genetic height gain (FAH–Tht) was 4.0 ± 0.5 cm for the GnRHa + rhGH group and 2.0 ± 0.27 cm for the GnRHa group, while the control group reached their Tht. In addition, 5 critical parameters derived from PAH, bone age, and Tht, showed excellent performance in predicting which patients could gain ≥5 cm (FAH–PAH), and this was further validated using an independent study.ConclusionsThe overall beneficial effect of GnRHa + rhGH or GnRHa on FAH was significant. The control group also reached their genetic target height. Clinicians are recommended to consider both the potential gains in height and the cost of medication.
      PubDate: Fri, 08 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz027
      Issue No: Vol. 105, No. 3 (2019)
  • Impact of Estradiol Variability and Progesterone on Mood in Perimenopausal
           Women With Depressive Symptoms
    • Authors: Joffe H; de Wit A, Coborn J, et al.
      Abstract: AbstractContextWomen are at increased risk for depressive symptoms during the menopause transition. Changes in estradiol secretion and presence of vasomotor symptoms (VMS) contribute to perimenopausal depressive symptoms, but links with progesterone have not been investigated.ObjectiveTo determine whether estradiol variability, ovulatory levels of progesterone, and VMS burden are independently associated with perimenopausal depressive symptomatology.Design and InterventionDepressive symptoms, serum levels of estradiol and progesterone, and VMS frequency were assessed weekly in an 8-week observational study. Association of mood with estradiol variability, ovulatory levels of progesterone, and VMS frequency were estimated using generalized estimating equation models.SettingAcademic medical center.PatientsFifty unmedicated perimenopausal women with mild-to-moderate depressive symptoms (mean Montgomery-Åsberg Depression Rating Scale [MADRS] score 15.5 ± 5.3).Main Outcome MeasureDepressive symptoms (MADRS score).ResultsDuring the study, 90.0% of participants had varying estradiol levels, 51.1% had ovulatory progesterone levels, and 90% had VMS. Greater estradiol variability and absence of progesterone levels consistent with ovulation, but not VMS frequency, are associated with higher levels of depressive symptoms (β = 0.11 [95% confidence interval (95% CI), 0.04 to 0.18; P = 0.001]; β = −2.62 [95% CI, −4.52 to −0.71; P = 0.007], respectively), after accounting for higher body mass index, lifetime history of depression, and stressful life events.ConclusionsIncreasing dysregulation of ovarian hormones, but not VMS, associates with more depressive symptom burden during perimenopause. These results suggest that perimenopausal mood instability is driven by the underlying hormonal dysregulation of the menopause transition involving changes in both estradiol and progesterone.
      PubDate: Wed, 06 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz181
      Issue No: Vol. 105, No. 3 (2019)
  • Targeted Analysis of Three Hormonal Systems Identifies Molecules
           Associated with the Presence and Severity of NAFLD
    • Authors: Polyzos S; Perakakis N, Boutari C, et al.
      Abstract: AbstractAimsTo investigate circulating levels and liver gene expression of 3 hormonal pathways associated with obesity, insulin resistance, and inflammation to identify leads towards potential diagnostic markers and therapeutic targets in patients with nonalcoholic fatty liver disease (NAFLD).MethodsWe compared circulating levels of (1) proglucagon-derived hormones (glucagon-like peptide [GLP]-1, GLP-2, glicentin, oxyntomodulin, glucagon, major proglucagon fragment [MPGF]), (2) follistatins-activins (follistatin-like [FSTL]3, activin B), (3) IGF axis (insulin-like growth factor [IGF]-1, total and intact IGF binding protein [IGFBP]-3 and IGFBP-4, and pregnancy-associated plasma protein [PAPP]-A) in 2 studies: (1) 18 individuals with early stage NAFLD versus 14 controls (study 1; early NAFLD study) and in (2) 31 individuals with biopsy proven NAFLD (15 with simple steatosis [SS] and 16 with nonalcoholic steatohepatitis [NASH]), vs 50 controls (24 lean and 26 obese) (study 2). Liver gene expression was assessed in 22 subjects (12 controls, 5 NASH, 5 NASH-related cirrhosis).ResultsPatients in early stages of NAFLD demonstrate higher fasting MPGF and lower incremental increase of glicentin during oral glucose tolerance test than controls. In more advanced stages, FSTL3 levels are higher in NASH than simple steatosis and, within NAFLD patients, in those with more severe lobular and portal inflammation. The IGF-1/intact IGFBP-3 ratio is lower in patients with liver fibrosis. Genes encoding follistatin, activin A, activin B, and the IGF-1 receptor are higher in NASH.ConclusionMPGF and glicentin may be involved in early stages of NAFLD, whereas FSTL3 and IGF-1/intact IGFBP3 in the progression to NASH and liver fibrosis respectively, suggesting potential as diagnostic markers or therapeutic targets.
      PubDate: Wed, 06 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz172
      Issue No: Vol. 105, No. 3 (2019)
  • Estimated Association Between Cytokines and the Progression to Diabetes:
           10-year Follow-Up From a Community-Based Cohort
    • Authors: Cho N; Ku E, Jung K, et al.
      Abstract: AbstractContextThe long-term association between multiple cytokines and progression to diabetes is still uncertain.ObjectiveTo identify which cytokines could predict progression to prediabetes and type 2 diabetes over 10 years.MethodsThe study included 912 participants aged 40 to 69 years at baseline from the Ansung cohort, part of the Korea Genome Epidemiology Study. At baseline, a 75-g oral glucose tolerance test and 8 cytokines were measured: plasminogen activator inhibitor 1 (PAI-1), resistin, interleukin 6, leptin, monocyte chemoattractant protein 1, tumor necrosis factor alpha, retinol binding protein 4 (RBP4), and adiponectin. People with normal glucose tolerance (NGT, n = 241) and prediabetes (n = 330) were followed-up biennially for 10 years. Multinomial logistic regression analysis was used to evaluate the predictability of cytokines on the new-onset prediabetes and type 2 diabetes.ResultsAt 10 years, 38 (15.8%) and 82 (34.0%) of those with NGT had converted to prediabetes and type 2 diabetes, respectively. Of those with prediabetes, 228 (69.1%) had converted to type 2 diabetes. In people with NGT or prediabetes at baseline, the highest tertile of RBP4 was associated with a 5.48-fold and 2.43-fold higher risk of progression to type 2 diabetes, respectively. The odds for converting from NGT to prediabetes in the highest tertile of PAI-1 and the lowest tertile of adiponectin were 3.23 and 3.37, respectively. In people with prediabetes at baseline, those in the highest tertile of resistin were 2.94 time more likely to develop type 2 diabetes (all P < 0.05).ConclusionsIn this 10-year prospective study, NGT with higher serum RBP4 and PAI-1, and with lower adiponectin were associated with new-onset prediabetes and type 2 diabetes.
      PubDate: Wed, 06 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz171
      Issue No: Vol. 105, No. 3 (2019)
  • Glycemic Measures and Risk of Mortality in Older Chinese: The Guangzhou
           Biobank Cohort Study
    • Authors: Jiang C; Xu L, Lam T, et al.
      Abstract: AbstractContextChina has the largest number of people with type 2 diabetes mellitus (T2DM) in the world. Data from previous studies have suggested that up to one-fifth of individuals with diabetes would be missed without an oral glucose tolerance test (OGTT). To date, there is little information on the mortality risk of these individuals.ObjectiveWe estimated the association of different indicators of hyperglycemia with mortality in the general Chinese population.DesignProspective cohort study.SettingChina.ParticipantsA total of 17 939 participants aged 50+ years.ExposuresPreviously diagnosed diabetes and newly detected diabetes defined by fasting glucose (≥7.0 mmol/L), 2-hour postload glucose (≥11.1 mmol/L), or hemoglobin A1c (HbA1c, ≥6.5%).Main Outcomes MeasuresDeaths from all-cause, cardiovascular disease, and cancer were identified by record linkage with death registration.ResultsDuring 7.8 (SD, 1.5) years’ follow-up, 1439 deaths were recorded. Of 3706 participants with T2DM, 2126 (57%) had known T2DM, 118 (3%) were identified by isolated elevated fasting glucose, 1022 (28%) had isolated elevated postload glucose, and 440 (12%) had both elevated fasting and postload glucose. Compared with normoglycemia, the hazard ratio (95% confidence interval) of all-cause mortality was 1.71 (1.46-2.00), 0.96 (0.47-1.93), 1.43 (1.15-1.78), and 1.82 (1.35-2.45) for the 4 groups, respectively. T2DM defined by elevated HbA1c was not significantly associated with all-cause mortality (hazard ratio, 1.17; 95% confidence interval, 0.81-1.69).ConclusionIndividuals with isolated higher 2-h postload glucose had a higher risk of mortality by 43% than those with normoglycemia. Underuse of OGTT leads to substantial underdetection of individuals with a higher mortality risk and lost opportunities for early intervention.
      PubDate: Sun, 03 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz173
      Issue No: Vol. 105, No. 3 (2019)
  • Transcriptome Analysis of lncRNAs in Pheochromocytomas and Paragangliomas
    • Authors: Job S; Georges A, Burnichon N, et al.
      Abstract: AbstractContextPheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors explained by germline or somatic mutations in about 70% of cases. Patients with SDHB mutations are at high risk of developing metastatic disease, yet no reliable tumor biomarkers are available to predict tumor aggressiveness.ObjectiveWe aimed at identifying long noncoding RNAs (lncRNAs) specific for PPGL molecular groups and metastatic progression.Design and MethodsTo analyze the expression of lncRNAs, we used a mining approach of transcriptome data from a well-characterized series of 187 tumor tissues. Clustering consensus analysis was performed to determine a lncRNA-based classification, and informative transcripts were validated in an independent series of 51 PPGLs. The expression of metastasis-related lncRNAs was confirmed by RT-qPCR. Receiver operating characteristic (ROC) curve analysis was used to estimate the predictive accuracy of potential markers.Main Outcome MeasureUnivariate/multivariate and metastasis-free survival (MFS) analyses were carried out for the assessment of risk factors and clinical outcomes.ResultsFour lncRNA-based subtypes strongly correlated with mRNA expression clusters (chi-square P-values from 1.38 × 10–32 to 1.07 × 10–67). We identified one putative lncRNA (GenBank: BC063866) that accurately discriminates metastatic from benign tumors in patients with SDHx mutations (area under the curve 0.95; P = 4.59 × 10–05). Moreover, this transcript appeared as an independent risk factor associated with poor clinical outcome of SDHx carriers (log-rank test P = 2.29 × 10–05).ConclusionOur findings extend the spectrum of transcriptional dysregulations in PPGL to lncRNAs and provide a novel biomarker that could be useful to identify potentially metastatic tumors in patients carrying SDHx mutations.
      PubDate: Sat, 02 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz168
      Issue No: Vol. 105, No. 3 (2019)
  • The Impact of Thyroid Function and TPOAb in the First Trimester on
           Pregnancy Outcomes: A Retrospective Study in Peking
    • Authors: Zhang Y; Sun W, Zhu S, et al.
      Abstract: AbstractContextThe impact of mild TSH elevation (2.5–4.08 mIU/L) on pregnancy outcomes is unclear. The treatment strategy for mild TSH elevation is dependent on thyroid peroxidase antibody (TPOAb) status according to the guidelines.ObjectiveTo assess the effects of mild thyroid dysfunction combined with TPOAb status in the first trimester on pregnancy outcomes and the impact of levothyroxine (L-T4) treatment on pregnancy outcomes.DesignThe study retrospectively evaluated 3562 pregnant women. A total of 3296 untreated women were divided into 4 subgroups: group A: 4.08 < TSH <10 mIU/L, TPOAb+/-; group B: 2.5 < TSH ≤ 4.08 mIU/L, TPOAb+; group C: 2.5 < TSH ≤ 4.08 mIU/L, TPOAb–; and group D: 0.23 ≤ TSH ≤ 2.5 mIU/L, TPOAb+/-. The other 266 women with L-T4 treatment were divided into TSH 4.08 to 10 mIU/L and 2.5 to 4.08 mIU/L subgroups.SettingThe study was conducted at Peking University First Hospital in China.PatientsA total of 3562 pregnant women were evaluated.Main Outcome MeasuresThe incidence of pregnancy outcomes in the untreated subgroups (groups A-D) and treated subgroups were measured.ResultsMiscarriage and maternal composite outcome risks were 3.53 (1.85–6.75) and 2.19 (1.26–3.81) times greater in group A; 1.58 (1.17–2.13) and 1.27 (1.04–1.54) times greater in group C than in group D. L-T4 improved the miscarriage risk in the TSH 4.08 to 10 and 2.5 to 4.08 mIU/L groups but doubled the risk of gestational diabetes mellitus in the TSH 2.5 to 4.08 mIU/L treated group compared with the untreated group.ConclusionsTSH 2.5 to 4.08 mIU/L combined with TPOAb– during early pregnancy was associated with miscarriages and maternal composite outcomes. The advantages and disadvantages of L-T4 administration in TSH 2.5 to 4.08 mIU/L pregnant women remain uncertain.
      PubDate: Sat, 02 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz167
      Issue No: Vol. 105, No. 3 (2019)
  • Bone Mineral Density across the Lifespan in Patients with Type 1 Diabetes
    • Authors: Halper-Stromberg E; Gallo T, Champakanath A, et al.
      Abstract: AbstractContextFracture risk in people with type 1 diabetes (T1D) is higher than their peers without diabetes.ObjectiveTo compare bone mineral density (BMD) across the lifespan in individuals with T1D and age- and sex-matched healthy controls.DesignCross-sectional.SettingSubjects (5–71 years) with T1D and matched controls from ongoing research studies at Barbara Davis Center for Diabetes.Patients or other participantsParticipants with lumbar spine BMD by dual X-ray absorptiometry (DXA) were divided into 2 groups: children ≤20 years and adults >20 years.InterventionNone.Main outcome measuresComparison of BMD by diabetes status across age groups and sex using a linear least squares model adjusted for age and body mass index (body mass index (BMI) for adults; and BMI z-score in children).ResultsLumbar spine BMD from 194 patients with T1D and 156 controls were analyzed. There was no difference in age- and BMI-adjusted lumbar spine BMD between patients with T1D and controls: among male children (least squares mean ± standard error of the mean [LSM ± SEM]; 0.80 ± 0.01 vs 0.80 ± 0.02 g/cm2, P = .98) or adults (1.01 ± 0.03 vs 1.01 ± 0.03 g/cm2, P = .95), and female children (0.78 ± 0.02 vs 0.81 ± 0.02 g/cm2, P = .23) or adults (0.98 ± 0.02 vs 1.01 ± 0.02 g/cm2, P = .19). Lumbar spine (0.98 ± 0.02 vs 1.04 ± 0.02 g/cm2, P = .05), femoral neck (0.71 ± 0.02 vs 0.79 ± 0.02 g/cm2, P = .003), and total hip (0.84 ± 0.02 vs 0.91 ± 0.02, P = .005) BMD was lower among postmenopausal women with T1D than postmenopausal women without diabetes.ConclusionAcross age groups, lumbar spine BMD was similar in patients with T1D compared with age- and sex-matched participants without diabetes, except postmenopausal females with T1D had lower lumbar spine, femoral neck, and total hip BMD.
      PubDate: Sat, 02 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz153
      Issue No: Vol. 105, No. 3 (2019)
  • Diagnosis of Primary Aldosteronism by Seated Saline Suppression
           Test—Variability Between Immunoassay and HPLC-MS/MS
    • Authors: Thuzar M; Young K, Ahmed A, et al.
      Abstract: AbstractBackgroundIn primary aldosteronism (PA), excessive, autonomous secretion of aldosterone is not suppressed by salt loading or fludrocortisone. For seated saline suppression testing (SSST), the recommended diagnostic cutoff 4-hour plasma aldosterone concentration (PAC) measured by high-performance liquid chromatography–mass spectrometry (HPLC-MS/MS is 162 pmol/L. Most diagnostic laboratories, however, use immunoassays to measure PAC. The cutoff for SSST using immunoassay is not known. We hypothesized that the cutoff is different between the assays.MethodsWe analyzed 80 of the 87 SSST tests that were performed during our recent study defining the HPLC-MS/MS cutoff. PA was confirmed in 65 by positive fludrocortisone suppression testing (FST) and/or lateralization on adrenal venous sampling and excluded in 15 by negative FST. PAC was measured by a chemiluminescence immunoassay (PACIA) in the SSST samples using the DiaSorin Liaison XL analyzer, and receiver operating characteristics (ROC) analysis was performed to identify the PACIA cutoff.ResultsROC revealed good performance (area under the curve = 0.893; P < .001) of 4-hour postsaline PACIA for diagnosis of PA and an optimal diagnostic cutoff of 171 pmol/L, with sensitivity and specificity of 95.4% and 80.0%, respectively. A higher cutoff of 217 pmol/L improved specificity (86.7%) with lower sensitivity (86.2%). PACIA measurements strongly correlated with PAC measured by HPLC-MS (r = 0.94, P < .001).ConclusionsA higher diagnostic cutoff for SSST should be employed when PAC is measured by immunoassay rather than HPLC-MS/MS. The results suggest that (i) PA can be excluded if 4-hour PACIA is less than 171 pmol/L, and (ii) PA is highly likely if the PACIA is greater than 217 pmol/L by chemiluminescence immunoassay. A gray zone exists between the cutoffs of 171 and 217 pmol/L, likely reflecting a lower specificity of immunoassay.
      PubDate: Sat, 02 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz150
      Issue No: Vol. 105, No. 3 (2019)
  • Bone Mineral Density Response With Denosumab in Combination With Standard
           or High-Dose Teriparatide: The DATA-HD RCT
    • Authors: Ramchand S; David N, Leder B, et al.
      Abstract: AbstractContextIn the Denosumab and High-Dose Teriparatide Administration (DATA-HD) study, we reported that 15 months of combined high-dose (HD) teriparatide and denosumab increased mean areal bone mineral density (aBMD) at the hip and spine more than combined denosumab and standard-dose (SD) teriparatide.ObjectiveIn the current analysis, we compare the individual rates of aBMD response between the treatment groups.DesignSingle-site, open-label, randomized controlled trial in which postmenopausal women received either teriparatide 20-μg daily (SD) or 40-μg daily (HD) given months 0 through 9, overlapped with denosumab 60 mg, given months 3 through 15 (15 months’ total duration). The proportion of participants in the SD and HD groups experiencing total hip, femoral neck, and lumbar spine aBMD gains of >3%, >6%, and >9% were compared.ParticipantsPostmenopausal women with osteoporosis completing all study visits (n = 60).Main outcome measure(s)aBMD (dual x-ray absorptiometry).ResultsAt the end of the 15-month treatment period, a higher proportion of women in the HD group had aBMD increases >3% (83% vs. 58%, P = .037) and >6% (45% vs. 19%, P = .034) at the total hip, and >3% at the femoral neck (86% vs. 63%, P = .044). At the lumbar spine, >3% response rates were similar, whereas the >6% and >9% response rates were greater in the HD group (100% vs. 79%, P = .012 and 93% vs. 59%, P = .003, respectively).ConclusionCompared with the SD regimen, more women treated with the HD regimen achieved clinically meaningful and rapid gains in hip and spine aBMD. These results suggest that this approach may provide unique benefits in the treatment of postmenopausal osteoporosis.
      PubDate: Fri, 01 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz163
      Issue No: Vol. 105, No. 3 (2019)
  • Response to Letter to the Editor: “Impaired Glucose Metabolism in
           Primary Aldosteronism Is Associated with Cortisol Cosecretion”
    • Authors: Gerards J; Reincke M, Quinkler M.
      Abstract: We thank Drs. Zignashina and Gosmanov for their interest in and comments on our work.
      PubDate: Fri, 01 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz159
      Issue No: Vol. 105, No. 3 (2019)
  • Letter to the Editor: “Impaired Glucose Metabolism in Primary
           Aldosteronism Is Associated With Cortisol Cosecretion”
    • Authors: Ziganshina A; Gosmanov A.
      Abstract: Primary aldosteronism (PA) is not an uncommon diagnosis in routine endocrine practice. About half of patients have PA due to autonomous production of aldosterone from adrenal nodule(s), and current guidelines recommend curative adrenalectomy in this cohort to improve long-term vascular outcomes (1). However, sometimes patients instead elect to receive pharmacological therapy that includes a mineralocorticoid receptor antagonist (MRA). In this regard, the results of the study by Gerards et al (2) may further strengthen our discussions in the clinic why adrenalectomy is the procedure of choice for those who have unilateral PA. In a carefully selected cohort of patients, the authors found modest but significant increases in the frequency of type 2 diabetes and metabolic parameters indicative of insulin resistance in patients who had concomitant PA and biochemical evidence of autonomous cortisol production compared with the patients without PA or the patients with PA and without biochemical hypercortisolism. The results were adjusted for multiple covariates including age, sex, and body mass index. However, upon further review of the study design we would like to inquire if in their analyses the authors considered prevalence and type of MRA therapy and associated use of beta-blockers and thiazide diuretics in the studied patients.
      PubDate: Fri, 01 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz152
      Issue No: Vol. 105, No. 3 (2019)
  • The Macrophage Activation Marker Soluble CD163 is Longitudinally
           Associated With Insulin Sensitivity and β-cell Function
    • Authors: Semnani-Azad Z; Connelly P, Johnston L, et al.
      Abstract: AbstractContextChronic inflammation arising from adipose tissue macrophage (ATM) activation may be central in type 2 diabetes etiology. Our objective was to assess the longitudinal associations of soluble CD163 (sCD163), a novel biomarker of ATM activation, with insulin sensitivity, β-cell function, and dysglycemia in high-risk subjects.MethodsAdults at risk for type 2 diabetes in the Prospective Metabolism and Islet Cell Evaluation (PROMISE) study had 3 assessments over 6 years (n = 408). Levels of sCD163 were measured using fasting serum. Insulin sensitivity was assessed by HOMA2-%S and the Matsuda index (ISI). β-cell function was determined by insulinogenic index (IGI) over HOMA-IR and insulin secretion-sensitivity index-2 (ISSI-2). Incident dysglycemia was defined as the onset of impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes. Generalized estimating equations (GEE) evaluated longitudinal associations of sCD163 with insulin sensitivity, β-cell function, and incident dysglycemia adjusting for demographic and lifestyle covariates. Areas under receiver-operating-characteristic curve (AROC) tested whether sCD163 improved dysglycemia prediction in a clinical model.ResultsLongitudinal analyses showed significant inverse associations between sCD163 and insulin sensitivity (% difference per standard deviation increase of sCD163 for HOMA2-%S (β = −7.01; 95% CI, −12.26 to −1.44) and ISI (β = −7.60; 95% CI, −11.09 to −3.97) and β-cell function (ISSI-2 (β = −4.67; 95 %CI, −8.59 to −0.58) and IGI/HOMA-IR (β = −8.75; 95% CI, −15.42 to −1.56)). Increased sCD163 was associated with greater risk for incident dysglycemia (odds ratio = 1.04; 95% CI, 1.02-1.06; P < 0.001). Adding sCD163 data to a model with clinical variables improved prediction of incident dysglycemia (AROC=0.6731 vs 0.638; P < 0.05).ConclusionssCD163 was longitudinally associated with core disorders that precede the onset of type 2 diabetes.
      PubDate: Fri, 01 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz166
      Issue No: Vol. 105, No. 3 (2019)
  • Endometrial Liquid Biopsy Provides a miRNA Roadmap of the Secretory Phase
           of the Human Endometrium
    • Authors: Grasso A; Navarro R, Balaguer N, et al.
      Abstract: AbstractContextEndometrial liquid biopsy (ELB) is a minimally invasive alternative for research and diagnosis in endometrial biology.ObjectiveWe sought to establish an endometrial micro ribonucleic acid (miRNA) roadmap based on ELB during the secretory phase of the menstrual cycle in both natural and hormonal replacement therapy (HRT) cycles.DesignHuman ELB samples (n = 58) were obtained from healthy ovum donors undergoing a natural and an HRT cycle consecutively. miRNA profiles were identified using next-generation sequencing (NGS). For functional analysis, messenger ribonucleic acid targets were chosen among those reported in the endometrial receptivity analysis.ResultsThe human endometrial secretory phase is characterized by a dynamic miRNA secretion pattern that varies from the prereceptive to the receptive stages. No differences in miRNA profiles were found among natural versus HRT cycles in the same women, reinforcing the similarities in functional and clinical outcomes in natural versus medicated cycles. Bioinformatic analysis revealed 62 validated interactions and 81 predicted interactions of miRNAs differentially expressed in the HRT cycle. Annotation of these genes linked them to 51 different pathways involved in endometrial receptivity.ConclusionThis NGS-based study describes the miRNA signature in human ELB during the secretory phase of natural and HRT cycles. A consistent endometrial miRNA signature was observed in the acquisition of endometrial receptivity. Interestingly, no significant differences in miRNA expression were found in natural versus HRT cycles reinforcing the functional clinical similarities between both approaches.
      PubDate: Tue, 29 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz146
      Issue No: Vol. 105, No. 3 (2019)
  • Urine Steroid Metabolomics as a Novel Tool for Detection of Recurrent
           Adrenocortical Carcinoma
    • Authors: Chortis V; Bancos I, Nijman T, et al.
      Abstract: AbstractContextUrine steroid metabolomics, combining mass spectrometry-based steroid profiling and machine learning, has been described as a novel diagnostic tool for detection of adrenocortical carcinoma (ACC).Objective, Design, SettingThis proof-of-concept study evaluated the performance of urine steroid metabolomics as a tool for postoperative recurrence detection after microscopically complete (R0) resection of ACC.Patients and Methods135 patients from 14 clinical centers provided postoperative urine samples, which were analyzed by gas chromatography–mass spectrometry. We assessed the utility of these urine steroid profiles in detecting ACC recurrence, either when interpreted by expert clinicians or when analyzed by random forest, a machine learning-based classifier. Radiological recurrence detection served as the reference standard.ResultsImaging detected recurrent disease in 42 of 135 patients; 32 had provided pre- and post-recurrence urine samples. 39 patients remained disease-free for ≥3 years. The urine “steroid fingerprint” at recurrence resembled that observed before R0 resection in the majority of cases. Review of longitudinally collected urine steroid profiles by 3 blinded experts detected recurrence by the time of radiological diagnosis in 50% to 72% of cases, improving to 69% to 92%, if a preoperative urine steroid result was available. Recurrence detection by steroid profiling preceded detection by imaging by more than 2 months in 22% to 39% of patients. Specificities varied considerably, ranging from 61% to 97%. The computational classifier detected ACC recurrence with superior accuracy (sensitivity = specificity = 81%).ConclusionUrine steroid metabolomics is a promising tool for postoperative recurrence detection in ACC; availability of a preoperative urine considerably improves the ability to detect ACC recurrence.
      PubDate: Tue, 29 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz141
      Issue No: Vol. 105, No. 3 (2019)
  • The External Genitalia Score (EGS): A European Multicenter Validation
    • Authors: van der Straaten S; Springer A, Zecic A, et al.
      Abstract: AbstractContextStandardized description of external genitalia is needed in the assessment of children with atypical genitalia.ObjectivesTo validate the External Genitalia Score (EGS), to present reference values for preterm and term babies up to 24 months and correlate obtained scores with anogenital distances (AGDs).Design, SettingA European multicenter (n = 8) validation study was conducted from July 2016 to July 2018.Patients and MethodsEGS is based on the external masculinization score but uses a gradual scale from female to male (range, 0–12) and terminology appropriate for both sexes. The reliability of EGS and AGDs was determined by the interclass correlation coefficient (ICC). Cross-sectional data were obtained in 686 term babies (0–24 months) and 181 preterm babies, and 111 babies with atypical genitalia.ResultsThe ICC of EGS in typical and atypical genitalia is excellent and good, respectively. Median EGS (10th to 90th centile) in males < 28 weeks gestation is 10 (8.6–11.5); in males 28–32 weeks 11.5 (9.2–12); in males 33–36 weeks 11.5 (10.5–12) and in full-term males 12 (10.5–12). In all female babies, EGS is 0 (0-0). The mean (SD) lower/upper AGD ratio (AGDl/u) is 0.45 (0.1), with significant difference between AGDl/u in males 0.49 (0.1) and females 0.39 (0.1) and intermediate values in differences of sex development (DSDs) 0.43 (0.1). The AGDl/u correlates with EGS in males with typical genitalia and in atypical genitalia.ConclusionsEGS is a reliable and valid tool to describe external genitalia in premature and term babies up to 24 months. EGS correlates with AGDl/u in males. It facilitates standardized assessment, clinical decision-making and multicenter research.
      PubDate: Tue, 29 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz142
      Issue No: Vol. 105, No. 3 (2019)
  • Elevated Cholesteryl Ester Transfer Protein Activity Early in Pregnancy
           Predicts Prediabetes 5 Years Later
    • Authors: Ueland T; Roland M, Michelsen A, et al.
      Abstract: AbstractContextCholesteryl ester transfer protein (CETP) regulates high-density lipoprotein (HDL) cholesterol levels and interaction between glucose, and HDL metabolism is central in the development of diabetes.ObjectiveWe hypothesized that CETP levels would be regulated in diabetic pregnancies. We tested the hypothesis by evaluating CETP activity measured multiple times during pregnancy and at 5 years’ follow-up in a prospective cohort (STORK) and investigated its association with gestational diabetes mellitus (GDM) during pregnancy or development of prediabetes 5 years after pregnancy. We also evaluated the strongest correlation of CETP activity among measures of adipocity and glucose metabolism, lipoproteins, adipokines, and monocyte/macrophage activation markers.DesignA population-based longitudinal cohort study was conducted from 2001 to 2013.SettingThe study setting was Oslo University Hospital.Patients or Other ParticipantsA total of 300 women during pregnancy and at 5 years postpartum participated in this study.Main Outcome MeasuresCETP activity was measured at 14 to 16, 22 to 24, 30 to 32, and 36 to 38 weeks’ gestation, and at 5 years’ follow-up.ResultsWe found higher CETP activity in pregnancy in women developing prediabetes but no association with GDM. CETP activity decreased throughout pregnancy and remained low at follow-up. High CETP activity was associated with sCD14 levels, in particular in women who developed prediabetes. These data show that enhanced CETP activity during pregnancy is associated with systemic indices of monocyte/macrophage activation, in particular in women who develop prediabetes later in life.ConclusionsCETP activity during pregnancy identifies women at risk for later diabetes development.
      PubDate: Tue, 29 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz119
      Issue No: Vol. 105, No. 3 (2019)
  • Associations of Exposure to Perfluoroalkyl Substances With Thyroid Hormone
           Concentrations and Birth Size
    • Authors: Xiao C; Grandjean P, Valvi D, et al.
      Abstract: AbstractBackgroundAdequate thyroid function during pregnancy is essential for optimal fetal growth. Gestational exposure to perfluoroalkyl substances (PFAS) can negatively affect birth size and disrupt maternal and neonatal thyroid function, although the interrelationship is unclear.ObjectiveWe aimed to quantify the associations between maternal serum–PFAS concentrations and birth weight, birth length, and cranial circumference. We also aimed to estimate associations between PFAS and thyroid hormone (TH) concentrations, thereby elucidating whether THs potentially mediate the associations between PFAS concentrations and birth size.MethodsWe studied a population-based prospective cohort of 172 mother-singleton pairs from the Faroe Islands. Twelve PFAS were measured in maternal serum obtained at 34 weeks of gestation. THs were measured in maternal and cord serum. Associations between PFAS concentrations and birth size and TH concentrations were estimated using multivariable linear regressions. Sex-stratified analyses along with a mediation analysis were performed to estimate potential mediating effects of THs in the association between PFAS and birth outcomes.ResultsSeveral PFASs were negatively associated with birth weight, length, and head circumference, and a general positive association between maternal serum–PFASs and cord serum–thyroid-stimulating hormone (TSH; also known as thyrotropin) was found. For instance, a doubling in perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) was associated with a 53% (95% CI, 18%-99%) and 40% (95% CI, 8%-81%) increases in TSH concentrations, respectively. There was little evidence of sexually dimorphic associations. Overall, THs were not found to mediate associations between PFASs and birth size.ConclusionIn this study, several PFASs were negatively associated with birth size and increased THs; however, this did not explain lower birth weight among children exposed to PFAS.
      PubDate: Tue, 29 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz147
      Issue No: Vol. 105, No. 3 (2019)
  • The Selective Progesterone Receptor Modulator Ulipristal Acetate Inhibits
           the Activity of the Glucocorticoid Receptor
    • Authors: Small B; Millard C, Kisanga E, et al.
      Abstract: AbstractContextThe selective progesterone modulator ulipristal acetate (ulipristal) offers a much-needed therapeutic option for the clinical management of uterine fibroids. Although ulipristal initially passed safety evaluations in Europe, postmarketing analysis identified cases of hepatic injury and failure, leading to restrictions on the long-term use of ulipristal. One of the factors potentially contributing to significant side effects with the selective progesterone modulators is cross-reactivity with other steroid receptors.ObjectiveTo determine whether ulipristal can alter the activity of the endogenous glucocorticoid receptor (GR) in relevant cell types.DesignImmortalized human uterine fibroid cells (UtLM) and hepatocytes (HepG2) were treated with the synthetic glucocorticoid dexamethasone and/or ulipristal. Primary uterine fibroid tissue was isolated from patients undergoing elective gynecological surgery and treated ex vivo with dexamethasone and/or ulipristal. In vivo ulipristal exposure was performed in C57Bl/6 mice to measure the effect on basal gene expression in target tissues throughout the body.ResultsDexamethasone induced the expression of established glucocorticoid-target genes period 1 (PER1), FK506 binding protein 51 (FKBP5), and glucocorticoid-induced leucine zipper (GILZ) in UtLM and HepG2 cells, whereas cotreatment with ulipristal blocked the transcriptional response to glucocorticoids in a dose-dependent manner. Ulipristal inhibited glucocorticoid-mediated phosphorylation, nuclear translocation, and DNA interactions of GR. Glucocorticoid stimulation of PER1, FKBP5, and GILZ was abolished by cotreatment with ulipristal in primary uterine fibroid tissue. The expression of glucocorticoid-responsive genes was decreased in the lung, liver, and uterus of mice exposed to 2 mg/kg ulipristal. Interestingly, transcript levels of Fkbp5 and Gilz were increased in the hippocampus and pituitary.ConclusionsThese studies demonstrate that ulipristal inhibits endogenous glucocorticoid signaling in human fibroid and liver cells, which is an important consideration for its use as a long-term therapeutic agent.
      PubDate: Tue, 29 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz139
      Issue No: Vol. 105, No. 3 (2019)
  • Time to Diagnosis in Cushing’s Syndrome: A Meta-Analysis Based on
           5367 Patients
    • Authors: Rubinstein G; Osswald A, Hoster E, et al.
      Abstract: AbstractContextSigns and symptoms of Cushing’s syndrome (CS) overlap with common diseases, such as the metabolic syndrome, obesity, osteoporosis, and depression. Therefore, it can take years to finally diagnose CS, although early diagnosis is important for prevention of complications.ObjectiveThe aim of this study was to assess the time span between first symptoms and diagnosis of CS in different populations to identify factors associated with an early diagnosis.Data SourcesA systematic literature search via PubMed was performed to identify studies reporting on time to diagnosis in CS. In addition, unpublished data from patients of our tertiary care center and 4 other centers were included.Study SelectionClinical studies reporting on the time to diagnosis of CS were eligible. Corresponding authors were contacted to obtain additional information relevant to the research question.Data ExtractionData were extracted from the text of the retrieved articles and from additional information provided by authors contacted successfully. From initially 3326 screened studies 44 were included.Data SynthesisMean time to diagnosis for patients with CS was 34 months (ectopic CS: 14 months; adrenal CS: 30 months; and pituitary CS: 38 months; P < .001). No difference was found for gender, age (<18 and ≥18 years), and year of diagnosis (before and after 2000). Patients with pituitary CS had a longer time to diagnosis in Germany than elsewhere.ConclusionsTime to diagnosis differs for subtypes of CS but not for gender and age. Time to diagnosis remains to be long and requires to be improved.
      PubDate: Tue, 29 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz136
      Issue No: Vol. 105, No. 3 (2019)
  • Controlled Antenatal Thyroid Screening II: Effect of Treating Maternal
           Suboptimal Thyroid Function on Child Behavior
    • Authors: Hales C; Taylor P, Channon S, et al.
      Abstract: AbstractContext & ObjectivesThe Controlled Antenatal Thyroid Screening (CATS) study was the first randomized controlled trial to investigate effects of treating suboptimal gestational thyroid function (SGTF) on child cognition. Since observational studies indicated that SGTF may also increase symptoms of autism and attention-deficit/hyperactivity disorder (ADHD), the CATS cohort was used to investigate whether treatment of mothers affected their children’s behavior.Design & ParticipantsMothers (N = 475) completed 3 questionnaires: the Strengths and Difficulties Questionnaire (SDQ), the Child ADHD Questionnaire, and the Social Communication Questionnaire (SCQ, used as a screen for autism spectrum disorder [ASD]), about their children (mean age 9.5 years). Group comparisons of total scores, numbers of children above clinical thresholds, and association between high maternal free thyroxine (FT4) (> 97.5th percentile of the UK cohort, “overtreated”) and child neurodevelopment were reported.ResultsThere were no differences in total scores between normal gestational thyroid function (GTF) (n = 246), treated (n = 125), and untreated (n = 104) SGTF groups. More children of treated mothers scored above clinical thresholds, particularly the overtreated. Scores were above thresholds in SDQ conduct (22% vs 7%), SCQ total scores (7% vs 1%), and ADHD hyperactivity (17% vs 5%) when comparing overtreated (n = 40) and untreated (N = 100), respectively. We identified significantly higher mean scores for SDQ conduct (adjusted mean difference [AMD] 0.74; 95% confidence interval [CI], 0.021-1.431; P = 0.040, effect size 0.018) and ADHD hyperactivity (AMD 1.60, 95% CI, 0.361-2.633; P = 0.003, effect size 0.028) comparing overtreated with normal-GTF children.ConclusionsThere was no overall association between SGTF and offspring ADHD, ASD, or behavior questionnaire scores. However, children of “overtreated” mothers displayed significantly more ADHD symptoms and behavioral difficulties than those of normal-GTF mothers. Thyroxine supplementation during pregnancy requires monitoring to avoid overtreatment.
      PubDate: Tue, 29 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz098
      Issue No: Vol. 105, No. 3 (2019)
  • Heterogenous Responses to Cosyntropin in Primary AldosteronismCommentary
           to: Three Discrete Patterns of Primary Aldosteronism Lateralization in
           Response to Cosyntropin during Adrenal Vein Sampling
    • Authors: Rossi G.
      Abstract: Compelling evidence indicates that even the most refined imaging technology, including functional imaging with C11 metomidate (1), or 18F-labelled aldosterone synthase inhibitors, are either inadequate or unavailable for identification of the “culprit” adrenal in patients with primary aldosteronism (PA). Hence, adrenal vein sampling (AVS) is still recommended by all guidelines (2) for subtyping these patients, ie, for identifying those with unilateral PA that can benefit from laparoscopic adrenalectomy (3). Unfortunately, AVS is a technically challenging invasive technique that requires considerable expertise both for performing it and for interpreting the hormonal results (3). Moreover, the interpretations of AVS remained somewhat fickle, and even referral centers used absolute hormonal values for the clinical decision making, in that overlooking the confounding effects of proximity of the catheter’s tip to the adrenal cortex and of dilution from accessory veins of hormonal values, until 2001, when the Selectivity Index (SI) and the Lateralization Index (LI) were introduced as tools to assess successful adrenal vein catheterization and to establish lateralization, respectively (4).
      PubDate: Mon, 28 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz133
      Issue No: Vol. 105, No. 3 (2019)
  • Clinically Silent Thyroid Cancers: Drop Those Needles and Scalpels!
    • Authors: Durante C; Grani G.
      Abstract: papillary thyroid carcinomamicrocarcinomaincidentalomascreeningmanagement
      PubDate: Mon, 28 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz129
      Issue No: Vol. 105, No. 3 (2019)
  • Evaluation of the 2015 ATA Guidelines in Patients With Distant Metastatic
           Differentiated Thyroid Cancer
    • Authors: van Velsen E; Stegenga M, van Kemenade F, et al.
      Abstract: AbstractContextCurrent American Thyroid Association (ATA) Management Guidelines for the treatment of differentiated thyroid cancer (DTC) stratify patients to decide on additional radioiodine (RAI) therapy after surgery, and to predict recurring/persisting disease. However, studies evaluating the detection of distant metastases and how these guidelines perform in patients with distant metastases are scarce.ObjectiveTo evaluate the 2015 ATA Guidelines in DTC patients with respect to 1) the detection of distant metastases, and 2) the accuracy of its Risk Stratification System in patients with distant metastases.Patients and Main Outcome MeasuresWe retrospectively included 83 DTC patients who were diagnosed with distant metastases around the time of initial therapy, and a control population of 472 patients (312 low-risk, 160 intermediate-risk) who did not have a routine indication for RAI therapy. We used the control group to assess the percentage of distant metastases that would have been missed if no RAI therapy was given.ResultsTwo hundred forty-six patients had no routine indication for RAI therapy of which 4 (1.6%) had distant metastases. Furthermore, among the 83 patients with distant metastases, 14 patients (17%) had excellent response, while 55 (67%) had structural disease after a median follow-up of 62 months. None of the 14 patients that achieved an excellent response had a recurrence.ConclusionsIn patients without a routine indication for RAI therapy according to the 2015 ATA Guidelines, distant metastases would initially have been missed in 1.6% of the patients. Furthermore, in patients with distant metastases upon diagnosis, the 2015 ATA Guidelines are an excellent predictor of both persistent disease and recurrence.
      PubDate: Mon, 28 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz137
      Issue No: Vol. 105, No. 3 (2019)
  • Response to Letter to the Editor: “Hypernatremic Hydrophobic Transient
           Adipsia without Organic or Severe Psychiatric Disorder”
    • Authors: Rodriguez A; Fogelfeld L, Robertson G.
      Abstract: We agree with Dr. Novak that a urine osmolarity of 474 mOsm/L is not as high as it should be when plasma osmolarity and sodium are above the normal range. However, this defect alone does not justify a diagnosis of partial diabetes insipidus, because this syndrome is defined as the excretion of abnormally large volumes of dilute urine and neither of these abnormalities was observed or reported by the patient (1). It is less clear, however, whether the patient’s failure to concentrate her urine to higher levels was due to a defect in the secretion or action of vasopressin because the hormone was not measured. Nevertheless, we think a decrease in secretion is most likely since the magnetic resonance imaging (MRI) revealed persistence of the normal posterior pituitary bright spot despite a strong, prolonged hypertonic stimulus that ought to have eliminated the signal by depleting pituitary stores of the hormone as it invariably does in patients with nephrogenic diabetes insipidus (2, 3). Thus, the failure of hypertonicity to stimulate the release of vasopressin in amounts sufficient to both maximally concentrate the urine and to eliminate the MRI signal can be attributed to a defect in the anterior hypothalamic neurons that osmoregulate the secretion of vasopressin by the posterior pituitary. Since these neurons also osmoregulate the sensation of thirst, a defect there could also explain the adipsia and hypernatremia in this patient. How this defect might be related to depression is unclear. A similar constellation of abnormalities has been observed in association with a variety of known lesions in the anterior hypothalamus and, in many of them, the defect in vasopressin secretion is limited to osmotic stimulation and does not impair the effect of emetic or hypovolemic stimuli (2). Further studies of vasopressin function in other patients with psychogenic adipsia may clarify this issue and shed light on the link between emotional disorders and disruption of these vital functions.
      PubDate: Mon, 28 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz128
      Issue No: Vol. 105, No. 3 (2019)
  • The Thyroid Nodule Conundrum: Evaluate or Leave it Alone'
    • Authors: Sipos J.
      Abstract: Thyroid nodules create a conundrum for healthcare providers across the entire spectrum of medical specialties because of their high prevalence in adults. While the majority represent a benign neoplasm, the risk of malignancy (ROM) is high enough that simply ignoring the incidentally detected thyroid nodule is not an optimal approach. Spending inordinate financial resources evaluating every single nodule to identify those few clinically significant cancers is also not an ideal strategy, particularly in this era of soaring medical care costs.
      PubDate: Mon, 28 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz124
      Issue No: Vol. 105, No. 3 (2019)
  • Vitamin D Therapy and the Era of Precision Medicine
    • Authors: Roizen J; Levine M.
      Abstract: Vitamin DCYP2R1GC, precision genetics
      PubDate: Mon, 28 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz120
      Issue No: Vol. 105, No. 3 (2019)
  • Glucose-Dependent Insulinotropic Polypeptide Is a Pancreatic Polypeptide
           Secretagogue in Humans
    • Authors: Veedfald S; Vedtofte L, Skov-Jeppesen K, et al.
      Abstract: AbstractBackgroundGlucose-dependent insulinotropic polypeptide (GIP) has been suggested to stimulate the secretion of pancreatic polypeptide (PP), an islet hormone thought to regulate gut motility, appetite, and glycemia.ObjectiveTo determine whether human GIP1-42 (hGIP) stimulates PP secretion.MethodAs glycemia modulates the secretion of PP, we measured plasma PP concentrations from 2 studies in healthy men (n = 10) and in patients with type 2 diabetes (T2D) (n = 12), where hGIP1-42 had been administered intravenously during fasting glycemia, hyperglycemia (12 mmol/L), and insulin-induced hypoglycemia (targets: 2.5 mmol/L [healthy]; 3.5 mmol/L [T2D]). Porcine GIP1-42 (pGIP) was also infused intra-arterially in isolated porcine pancreata (n = 4).ResultsMean fasting plasma glucose concentrations were approximately 5 mmol/L (healthy) and approximately 8 mmol/L (T2D). At fasting glycemia, PP concentrations were higher during intravenous hGIP1-42 infusion compared with saline in healthy men (mean [standard error of the mean, SEM], net incremental areas under the curves (iAUCs)[0-30min], 403 [116] vs –6 [57] pmol/L × min; P = 0.004) and in patients with T2D (905 [177] vs –96 [86] pmol/L × min; P = 0.009). During hyperglycemic clamping, mean [SEM] PP concentrations were significantly higher during hGIP1-42 infusion compared with saline in patients with T2D (771 [160] vs –183 [117] pmol/L × min; P = 0.001), but not in healthy individuals (–8 [86] vs –57 [53] pmol/L × min; P = 0.69). When plasma glucose levels were declining in response to exogenous insulin, mean [SEM] PP concentrations were higher during hGIP1-42 infusion compared with saline in healthy individuals (294 [88] vs –82 [53] pmol/L × min; P = 0.0025), but not significantly higher in patients with T2D (586 [314] vs –120 [53]; P = 0.070). At target hypoglycemia, PP levels surged in both groups during both hGIP1-42 and saline infusions. In isolated pancreata, pGIP1-42 increased mean [SEM] PP output in the pancreatic venous effluent (baseline vs infusion, 24[5] vs 79 [16] pmol/min x min; P = 0.044).ConclusionGIP1-42 increases plasma PP secretion in healthy individuals, patients with T2D, and isolated porcine pancreata. Hyperglycemia blunts the stimulatory effect of hGIP1-42 in healthy individuals, but not in patients with T2D.
      PubDate: Sat, 26 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz097
      Issue No: Vol. 105, No. 3 (2019)
  • Letter to the Editor: “Hypernatremic Hydrophobic Transient Adipsia
           without Organic or Severe Psychiatric Disorder”
    • Authors: Novak J.
      Abstract: I read with interest the case of psychogenic adipsic hypernatremia by Rodriguez et al. (1). In this report, the authors ascribe hypernatremia to water avoidance, and antidepressant therapy ultimately resulted in serum sodium correction. However, the authors also note urinary water loss as a contributing factor; specifically, the urine osmolality of 474 to 501 mOsm/kg was inappropriately dilute for the serum osmolality of 338 to 345 mOsm/kg. Indeed, such a severely hypernatremic patient with intact medullary concentrating ability should have been able to concentrate her urine to 1200 mOsm/kg (2). The authors attribute this inappropriate urinary water loss—in effect, partial diabetes insipidus (DI)—to inadequate arginine vasopressin (AVP) secretion.
      PubDate: Sat, 26 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz126
      Issue No: Vol. 105, No. 3 (2019)
  • Real-world Comparison of Afirma GEC and GSC for the Assessment of
           Cytologically Indeterminate Thyroid Nodules
    • Authors: San Martin V; Lawrence L, Bena J, et al.
      Abstract: AbstractContextMolecular tests have improved the accuracy of preoperative diagnosis of indeterminate thyroid nodules. The Afirma Gene Sequencing Classifier (GSC) was developed to improve the specificity of the Gene Expression Classifier (GEC). Independent studies are needed to assess the performance of GSC.ObjectiveThe aim was to compare the performance of GEC and GSC in the assessment of indeterminate nodules.Design, Settings, and ParticipantsRetrospective analysis of Bethesda III and IV nodules tested with GEC or GSC in an academic center between December 2011 and September 2018. Benign call rates (BCRs) and surgical outcomes were compared. Histopathologic data were collected on nodules that were surgically resected to calculate measures of test performance.ResultsThe BCR was 41% (73/178) for GEC and 67.8% (82/121) for GSC (P < .001). Among specimens with dominant Hürthle cell cytology, the BCR was 22% (6/27) for GEC and 63.2% (12/19) for GSC (P = .005). The overall surgery rate decreased from 47.8% in the GEC group to 34.7% in the GSC group (P = .025). One GEC-benign and 3 GSC-benign nodules proved to be malignant on surgical excision. GSC had a statistically significant higher specificity (94% vs 60%, P < .001) and positive predictive value (PPV) (85.3% vs 40%, P < .001) than GEC. While sensitivity and negative predictive value (NPV) dropped with GSC (97.0% vs 90.6% and 98.6% vs 96.3%, respectively), these differences were not significant.ConclusionsGSC reclassified more indeterminate nodules as benign and improved the specificity and PPV of the test. These enhancements appear to be resulting in fewer diagnostic surgeries.
      PubDate: Sat, 26 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz099
      Issue No: Vol. 105, No. 3 (2019)
  • Active Surveillance in Papillary Thyroid Microcarcinomas is Feasible and
           Safe: Experience at a Single Italian Center
    • Authors: Molinaro E; Campopiano M, Pieruzzi L, et al.
      Abstract: AbstractContextThe dramatic rise in the incidence of thyroid cancer over the last 30 years is largely attributable to the increasing diagnosis of papillary microcarcinomas (mPTCs). Current guidelines endorse an observational management approach in properly selected cases. ObjectiveTo evaluate the feasibility of active surveillance in mPTC in Italy, its impact on real life, and to identify risk factors of progression.Design and settingIn 2014 we started a prospective–observational study of active surveillance in mPTC patients.PatientsIncluded patients demonstrated a single Thy4 or Thy5 thyroid nodule, with largest diameter ≤1.3 cm, and no suspicious laterocervical lymph nodes by neck ultrasonography. Of 185 eligible subjects, 50.3% (93/185) enrolled in the observational management protocol while the others opted for surgery and were excluded from this analysis.InterventionEnrolled patients were followed with neck ultrasound at 6- to 12-month intervals. Disease progression was defined as the appearance of abnormal lymph nodes or nodule enlargement during follow-up. In these cases, patients were directed to surgery.ResultsThree patients (3/93, 3%) showed clinical progression and required surgery. Another 19 patients (19/93, 20%) decided to transition to surgical intervention even though there was no evidence of disease progression. All operated patients had excellent response to initial treatment despite the delayed surgery.ConclusionsWithin an Italian medical context, active surveillance appears to be a feasible and safe alternative to immediate surgery in healthy mPTC patients. Only 3% of mPTC demonstrated disease progression during a median follow-up of 19 months (range 6–54) and importantly demonstrated excellent outcomes after surgical intervention in a short-term follow-up.
      PubDate: Fri, 25 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz113
      Issue No: Vol. 105, No. 3 (2019)
  • Biphasic Glucocorticoid Rhythm in One-Month-Old Infants: Reflection of a
           Developing HPA-Axis'
    • Authors: Hollanders J; van der Voorn B, de Goede P, et al.
      Abstract: AbstractContextThe hypothalamus-pituitary-adrenal (HPA) axis displays a diurnal rhythm. However, little is known about its development in early life.ObjectiveTo describe HPA-axis activity and study possible influencing factors in 1-month-old infants.DesignObservational.SettingAmsterdam University Medical Center, location VU University Medical Center (VUMC), and Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam.ParticipantsFifty-five mother-infant pairs.InterventionsCollection of breast milk and infants’ saliva 1 month postpartum for analysis of glucocorticoids (GCs; ie, cortisol and cortisone) using liquid chromatography– tandem mass spectrometry.Main Outcome MeasureGC rhythm in infants’ saliva and associations with vulnerability for maternal psychological distress (increased Hospital Anxiety and Depression Scale [HADS] score) or consultation at the Psychiatric Obstetric Pediatric (POP clinic), season at sampling, sex, and breast milk GC rhythmicity analyzed with SigmaPlot 14.0 software (Systat Software, San Jose, CA, USA) and regression analyses.ResultsA significant biphasic GC rhythm was detected in infants, with mean peaks [standard error of the mean, SEM] at 6:53 am [1:01] and 18:36 pm [1:49] for cortisol, and at 8:50 am [1:11] and 19:57 pm [1:13] for cortisone. HADS score, POP consultation, season at sampling, and sex were not associated with the infants’ GC rhythm. Breast milk cortisol maximum was positively associated with infants’ cortisol area-under-the-curve (AUC) increase and maximum. Higher breast milk cortisone AUC increase, AUC ground, and maximum were associated with an earlier maximum in infants. Breast milk and infant GC concentrations were associated between 6:00 am and 9:00 am.ConclusionsA biphasic GC rhythm, peaking in the morning and evening, was seen in 1-month-old infants at a group level. Breast milk GC parameters might be associated with the infants’ GC rhythm, possibly caused by a signaling effect of breast milk GCs, or as an associative effect of increased mother-infant synchrony. These results contribute to an increased understanding of early life HPA-axis development.
      PubDate: Fri, 25 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz089
      Issue No: Vol. 105, No. 3 (2019)
  • Elagolix Suppresses Ovulation in a Dose-Dependent Manner: Results From a
           3-Month, Randomized Study in Ovulatory Women
    • Authors: Archer D; Ng J, Chwalisz K, et al.
      Abstract: AbstractContextElagolix is an oral gonadotropin-releasing hormone (GnRH) antagonist recently approved for the treatment of endometriosis-associated pain and being developed for heavy menstrual bleeding associated with uterine fibroids.ObjectiveThe objective was to evaluate the effects of elagolix on ovulation and ovarian sex hormones.Design and SettingThis was a randomized, open-label, multicenter study.ParticipantsParticipants were healthy ovulatory women aged 18 to 40 years.InterventionsElagolix was administered orally for 3 continuous 28-day dosing intervals at 100 to 200 mg once daily (QD), 100 to 300 mg twice daily (BID), and 300 mg BID plus estradiol/norethindrone acetate (E2/NETA) 1/0.5 mg QD. Main Outcome MeasuresThe main outcomes measures were ovulation rates measured by transvaginal ultrasound, progesterone concentrations, and hormone suppression.ResultsElagolix suppressed ovulation in a dose-dependent manner. The percentage of women who ovulated was highest at 100 mg QD (78%), intermediate at 150 and 200 mg QD and 100 mg BID (47%–57%), and lowest at 200 and 300 mg BID (32% and 27%, respectively). Addition of E2/NETA to elagolix 300 mg BID further suppressed the ovulation rate to 10%. Elagolix also suppressed luteinizing hormone and follicle stimulating hormone in a dose-dependent manner, leading to dose-dependent suppression of estradiol and progesterone. Elagolix had no effect on serum biomarker of ovarian reserve, and reduced endometrial thickness compared to the screening cycle.ConclusionWomen being treated with elagolix may ovulate and should use effective methods of contraception. The rate of ovulation was lowest with elagolix 300 mg BID plus E2/NETA 1/0.5 mg QD.
      PubDate: Fri, 25 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz086
      Issue No: Vol. 105, No. 3 (2019)
  • U-Shaped Association of Serum Uric Acid With All-Cause and Cause-Specific
           Mortality in US Adults: A Cohort Study
    • Authors: Hu L; Hu G, Xu B, et al.
      Abstract: AbstractBackgroundIn addition to the controversy regarding the association of hyperuricemia with mortality, uncertainty also remains regarding the association between low serum uric acid (SUA) and mortality. We aimed to assess the relationship between SUA and all-cause and cause-specific mortality.MethodsThis cohort study included 9118 US adults from the National Health and Nutrition Examination Survey (1999-2002). Multivariable Cox proportional hazards models were used to evaluate the relationship between SUA and mortality. Our analysis included the use of a generalized additive model and smooth curve fitting (penalized spline method), and 2-piecewise Cox proportional hazards models, to address the nonlinearity between SUA and mortality.ResultsDuring a median follow-up of 5.83 years, 448 all-cause deaths occurred, with 100 cardiovascular disease (CVD) deaths, 118 cancer deaths, and 37 respiratory disease deaths. Compared with the reference group, there was an increased risk of all-cause, CVD, cancer, and respiratory disease mortality for participants in the first and third tertiles of SUA. We further found a nonlinear and U-shaped association between SUA and mortality. The inflection point for the curve was found at a SUA level of 5.7 mg/dL. The hazard ratios (95% confidence intervals) for all-cause mortality were 0.80 (0.65-0.97) and 1.24 (1.10-1.40) to the left and right of the inflection point, respectively. This U-shaped association was observed in both sexes; the inflection point for SUA was 6 mg/dL in males and 4 mg/dL in females.ConclusionBoth low and high SUA levels were associated with increased all-cause and cause-specific mortality, supporting a U-shaped association between SUA and mortality.
      PubDate: Fri, 25 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz068
      Issue No: Vol. 105, No. 3 (2019)
  • Fertility and Pregnancy in Women With Hypopituitarism: A Systematic
           Literature Review
    • Authors: Vila G; Fleseriu M.
      Abstract: AbstractContextHuman reproduction is mainly governed from the hypothalamic–adrenal–gonadal (HPG) axis, which controls both ovarian morphology and function. Disturbances in the secretion of other anterior pituitary hormones (and their respective endocrine axes) interfere with HPG activity and have been linked to fertility problems. In normal pregnancy, maintenance of homeostasis is associated with continuous changes in pituitary morphology and function, which need to be considered during hormone replacement in patients with hypopituitarism.DesignWe conducted a systematic PubMed literature review from 1969 to 2019, with the following keywords: fertility and hypopituitarism, pregnancy and hypopituitarism, and ovulation induction and hypopituitarism. Case reports or single-case series of up to 2 patients/4 pregnancies were excluded.ResultsEleven publications described data on fertility (n = 6) and/or pregnancy (n = 7) in women with hypopituitarism. Women with hypopituitarism often need assisted reproductive treatment, with pregnancy rates ranging from 47% to 100%. In patients achieving pregnancy, live birth rate ranged from 61% to 100%. While glucocorticoids, levothyroxine, and desmopressin are safely prescribed during pregnancy, growth hormone treatment regimens vary significantly between countries, and several publications support a positive effect in women seeking fertility.ConclusionsIn this first systematic review on fertility, ovulation induction, and pregnancy in patients with hypopituitarism, we show that while literature is scarce, birth rates are high in patients achieving pregnancy. However, prospective studies are needed for evaluating outcomes in relationship to treatment patterns. Replacement therapy in hypopituitarism should always mimic normal physiology, and this becomes challenging with changing demands during pregnancy evolution.
      PubDate: Fri, 25 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz112
      Issue No: Vol. 105, No. 3 (2019)
  • IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory
    • Authors: Joustra S; Roelfsema F, van Trotsenburg A, et al.
      Abstract: AbstractContextThe X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition.ObjectiveWe aimed to evaluate the role of IGSF1 in human and murine somatotrope function.Patients, Design, and SettingWe evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting.Main Outcome MeasuresWe compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates.ResultsIGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels.ConclusionsWe demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure.
      PubDate: Fri, 25 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz093
      Issue No: Vol. 105, No. 3 (2019)
  • Association of Genetic Variants Related to Serum Calcium Levels with
           Reduced Bone Mineral Density
    • Authors: Li G; Robinson-Cohen C, Sahni S, et al.
      Abstract: AbstractContextThe role of serum calcium in bone metabolism is unknown, even though calcium/vitamin D supplementations have been widely used and are expected to improve bone health. We aim to determine the independent role of serum calcium in bone mineral density (BMD).Design and settingTwo epidemiological analyses with 5478 and 5556 participants from the National Health and Nutrition Examination Survey (NHANES) 2003 to 2006 and the Hong Kong Osteoporosis Study (HKOS) to evaluate the cross-sectional association of serum calcium with BMD. Two-sample Mendelian randomization (MR) studies using genetic variations as instrumental variables to infer causality. Summary statistics of genome-wide association study of serum calcium (N = 39 400) and lifelong whole-body BMD (N = 66 628) were used.Main outcome measureBMD measured by dual-energy X-ray absorptiometryResultsIn NHANES 2003–6 and HKOS, each standard deviation (SD) increase in serum calcium was significantly associated with 0.036–0.092 SD decrease in BMD at various sites (all P < .05). In multivariable inverse-variance weighted MR analysis, genetic predisposition to higher serum calcium level was inversely associated with whole-body BMD after adjustment for serum parathyroid hormone, vitamin D, and phosphate (–0.431 SD per SD increase in serum calcium; 95% CI: –0.773 to –0.089, P = .014). Similar estimates were obtained in sensitivity analyses.ConclusionsOur study reveals that genetic predisposition to higher serum calcium level per se may have a negative impact on bone metabolism. Whether increased serum calcium caused by calcium/vitamin D supplementations would have the same negative effect on bone remains unknown, which warrants further investigation. In addition to other adverse clinical outcomes, careful use of high-dose supplementations is required.
      PubDate: Fri, 25 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz088
      Issue No: Vol. 105, No. 3 (2019)
  • Letter to the Editor: “Comparison of Teriparatide and Denosumab in
           Patients Switching from Long-Term Bisphosphonate Use”
    • Authors: Geusens P; Marín F, Kendler D.
      Abstract: In a retrospective cohort analysis of 215 patients, Lyu and colleagues (1) reported that patients who switched from bisphosphonate (BP) to denosumab had a greater increase in total hip (TH) and femoral neck (FN) bone mineral density (BMD) than those who switched from BP to teriparatide. Based on changes in BMD at the TH (transient loss of 1%) and FN (unchanged after 1 year followed by a 2% increase after 2 years of teriparatide therapy), they concluded that “among patients who use long-term bisphosphonates, the decision of switching to teriparatide should be made with caution, especially for patients at high risk of hip fracture.” Fracture data were not reported in their study, except for a comment that fracture risk was low.
      PubDate: Fri, 25 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz122
      Issue No: Vol. 105, No. 3 (2019)
  • Results of a Study Comparing Glycated Albumin to Other Glycemic Indices
    • Authors: Desouza C; Holcomb R, Rosenstock J, et al.
      Abstract: AbstractContextIntermediate-term glycemic control metrics fulfill a need for measures beyond hemoglobin A1C.ObjectiveCompare glycated albumin (GA), a 14-day blood glucose measure, with other glycemic indices.Design24-week prospective study of assay performance.Setting8 US clinics.ParticipantsSubjects with type 1 (n = 73) and type 2 diabetes (n = 77) undergoing changes to improve glycemic control (n = 98) or with stable diabetes therapy (n = 52).InterventionsGA, fructosamine, and A1C measured at prespecified intervals. Mean blood glucose (MBG) calculated using weekly self-monitored blood glucose profiles.Main Outcome MeasuresPrimary: Pearson correlation between GA and fructosamine. Secondary: magnitude (Spearman correlation) and direction (Kendall correlation) of change of glycemic indices in the first 3 months after a change in diabetes management.ResultsGA was more concordant (60.8%) with changes in MBG than fructosamine (55.5%) or A1C (45.5%). Across all subjects and visits, the GA Pearson correlation with fructosamine was 0.920. Pearson correlations with A1C were 0.655 for GA and 0.515 for fructosamine (P < .001) and with MBG were 0.590 and 0.454, respectively (P < .001). At the individual subject level, Pearson correlations with both A1C and MBG were higher for GA than for fructosamine in 56% of subjects; only 4% of subjects had higher fructosamine correlations with A1C and MBG. GA had a higher Pearson correlation with A1C and MBG in 82% and 70% of subjects, respectively.ConclusionsCompared with fructosamine, GA correlates significantly better with both short-term MBG and long-term A1C and may be more useful than fructosamine in clinical situations requiring monitoring of intermediate-term glycemic control (NCT02489773).
      PubDate: Fri, 25 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz087
      Issue No: Vol. 105, No. 3 (2019)
  • Divergent Metastatic Patterns Between Subtypes of Thyroid Carcinoma
           Results From the Nationwide Dutch Pathology Registry
    • Authors: Hugen N; Sloot Y, Netea-Maier R, et al.
      Abstract: AbstractBackgroundMetastatic disease is the main cause of cancer-related mortality in thyroid carcinoma (TC) patients. Clinical studies have suggested differences in metastatic patterns between the different subtypes of TC. This study systematically evaluates the metastatic patterns of different subtypes in TC patients.MethodsA nationwide review of pathological records of all 650 patients diagnosed with a primary malignancy in the thyroid who underwent an autopsy between 1991 and 2010 was performed. Patients were selected from the Dutch pathology registry (PALGA).ResultsMetastatic disease was present in 228 (35.1%) patients and was found in 38.7%, 17.3%, 75.4%, and 47.8% of patients with follicular, papillary, anaplastic, and medullary types of TC, respectively (P < .0001). The majority of patients had more than 1 metastasis. The most common site of metastatic disease was the lung for papillary (79.7%), follicular (72.9%), and anaplastic (92.1%) carcinoma but not for medullary carcinoma (56.3%), P < .0001. Medullary carcinoma patients most frequently had metastases to the liver (81.3%). The combination of metastases also differed between subtypes.ConclusionThere are major differences in metastatic patterns between different subtypes of TC. The patterns and frequencies identified in this autopsy study may reflect the underlying biology of metastatic thyroid cancer and have potential to influence future monitoring and treatment strategies depending on clinical correlations.
      PubDate: Wed, 23 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz078
      Issue No: Vol. 105, No. 3 (2019)
  • Lipoprotein(a): The Renaissance of an Enigmatic Lipoprotein
    • Authors: Dullaart R.
      Abstract: apolipoprotein(a)apolipoprotein(a) production ratelipoprotein(a)LPA genecardiovascular disease
      PubDate: Wed, 23 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz111
      Issue No: Vol. 105, No. 3 (2019)
  • Altered Expression of Adrenomedullin 2 and its Receptor in the Adipose
           Tissue of Obese Patients
    • Authors: Kim J; Lee S, Kim D, et al.
      Abstract: AbstractContextAdrenomedullin 2 (AM2) plays protective roles in the renal and cardiovascular systems. Recent studies in experimental animals demonstrated that AM2 is an adipokine with beneficial effects on energy metabolism. However, there is little information regarding AM2 expression in human adipose tissue.ObjectiveTo investigate the pattern and regulation of the expression of AM2 and its receptor component in human adipose tissue, in the context of obesity and type 2 diabetes.MethodsWe measured metabolic parameters, serum AM2, and expression of ADM2 and its receptor component genes in abdominal subcutaneous and visceral adipose tissue in obese (with or without type 2 diabetes) and normal-weight women. Serum AM2 was assessed before and 6 to 9 months after bariatric surgery. Expression/secretion of AM2 and its receptor were assessed in human adipocytes.ResultsADM2 mRNA in both fat depots was higher in obese patients, whether diabetic or not. Although serum AM2 was significantly lower in obese patients, it was not changed after bariatric surgery. AM2 and its receptor complex were predominantly expressed by adipocytes, and the expression of CALCRL, encoding a component of the AM2 receptor complex, was lower in both fat depots of obese patients. Incubating adipocytes with substances mimicking the microenvironment of obese adipose tissue increased ADM2 mRNA but reduced both AM2 secretion into culture media and CALCRL mRNA expression.ConclusionsOur data indicate that AM2 signaling is suppressed in adipose tissue in obesity, involving lower receptor expression and ligand availability, likely contributing to insulin resistance and other aspects of the pathophysiology associated with obesity.
      PubDate: Wed, 23 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz066
      Issue No: Vol. 105, No. 3 (2019)
  • Letter to the Editor: “Exercise Mitigates Bone Loss in Women With Severe
           Obesity After Roux-en-Y Gastric Bypass: A Randomized Controlled Trial”
    • Authors: Sugiyama T.
      Abstract: On the basis of their results from a randomized controlled trial, Murai and colleagues concluded that care management of patients after bariatric surgery should include exercise for cardiometabolic and bone health (1). This is a timely and important topic (2) that needs further discussion.
      PubDate: Wed, 23 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz108
      Issue No: Vol. 105, No. 3 (2019)
  • Response to Letter to the Editor: “Exercise Mitigates Bone Loss in Women
           With Severe Obesity After Roux-en-Y Gastric Bypass: A Randomized
           Controlled Trial”
    • Authors: Murai I; Roschel H, Gualano B.
      Abstract: We appreciate the interest of Dr. Sugiyama in our manuscript “Exercise mitigates bone loss in women with severe obesity after Roux-en-Y gastric bypass: a randomized controlled trial.”
      PubDate: Wed, 23 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz109
      Issue No: Vol. 105, No. 3 (2019)
  • Circulating IGF-1 Independently Predicts Blood Pressure in Children With
           Higher Calcium-Phosphorus Product Levels
    • Authors: Xargay-Torrent S; Dorado-Ceballos E, Benavides-Boixader A, et al.
      Abstract: AbstractObjectiveTo study the association between insulin-like growth factor 1 (IGF-1) and blood pressure in children, in particular, the potential interaction with the serum calcium-phosphorus product (Ca*P).MethodsA longitudinal study included 521 children (age 8.8 ± 0.1) from northeastern Spain, of whom 158 were followed-up after 5 years. IGF-1, insulin-like growth factor-binding protein 3 (IGFBP-3), and serum calcium and phosphorus were measured at baseline. Anthropometric (body-mass index [BMI] and waist) and cardiometabolic variables (systolic [SBP] and diastolic blood pressure), pulse pressure, insulin, homeostatic model assessment of insulin resistance [HOMA-IR], high-density lipoprotein [HDL]-cholesterol, and triglycerides) were assessed at baseline and at the end of follow-up. Statistical analysis included Pearson correlations followed by multivariable linear regression analyses.ResultsBaseline IGF-1 and IGF-1/IGFBP-3 molar ratio positively correlated with baseline and follow-up BMI, waist, SBP, pulse pressure, insulin, HOMA-IR and triglycerides (r 0.138-0.603; all P < 0.05). The associations with SBP were stronger with increasing Ca*P (r 0.261-0.625 for IGF-1; and r 0.174-0.583 for IGF-1/IGFBP-3). After adjusting for confounding variables, baseline IGF-1 and IGF-1/IGFBP-3 remained independently associated with both baseline and follow-up SBP in children in the highest Ca*P tertile (β = 0.245-0.381; P < 0.01; model R2 = 0.246-0.566).ConclusionsOur results suggest that IGF-1 in childhood is an independent predictor of SBP in apparently healthy children, especially in those with high Ca*P levels.
      PubDate: Mon, 21 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz101
      Issue No: Vol. 105, No. 3 (2019)
  • Preventive Role of Vitamin D Supplementation for Acute Phase Reaction
           after Bisphosphonate Infusion in Paget’s Disease
    • Authors: Merlotti D; Rendina D, Muscariello R, et al.
      Abstract: AbstractContextIntravenous aminobisphosphonates (N-BPs) can induce an acute phase reaction (APR) in up to 40% to 70% of first infusions, causing discomfort and often requiring intervention with analgesics or antipyretics.ObjectiveOur aim was to explore the risk factors of APR in a large sample of patients with Paget’s disease of bone (PDB) and to assess the possible preventive effects of vitamin D administration.MethodsAn observational analysis was performed in 330 patients with PDB at the time of N-BP infusion. Then, an interventional study was performed in 66 patients with active, untreated PDB to evaluate if vitamin D administration (oral cholecalciferol 50 000 IU/weekly for 8 weeks before infusion) may prevent APR.ResultsIn a retrospective study, APR occurred in 47.6% and 18.3% of naive or previously treated patients, respectively. Its prevalence progressively increased in relation to the severity of vitamin D deficiency, reaching 80.0% in patients with 25-hydroxyvitamin D (25OHD) levels below 10 ng/mL (relative risk (RR) = 3.7; 95% confidence interval (CI) 2.8–4.7, P < .0001), even in cases previously treated with N-BPs. Moreover, APR occurred more frequently in patients who experienced a previous APR (RR = 2.8; 95% CI 1.5–5.2; P < .001) or in carriers of SQSTM1 mutation (RR = 2.3; 95% CI 1.3–4.2; P = .005). In the interventional study, vitamin D supplementation prevented APR in most cases, equivalent to a RR of 0.31 (95% CI 0.14–0.67; P < .005) with respect to prevalence rates of the observational cohort. A similar trend was observed concerning the occurrence of hypocalcemia.ConclusionsThe achievement of adequate 25OHD levels is recommended before N-BP infusion in order to minimize the risk of APR or hypocalcemia in PDB.
      PubDate: Mon, 21 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz138
      Issue No: Vol. 105, No. 3 (2019)
  • A Balanced Translocation in Kallmann Syndrome Implicates a Long Noncoding
           RNA, RMST, as a GnRH Neuronal Regulator
    • Authors: Stamou M; Ng S, Brand H, et al.
      Abstract: AbstractContextKallmann syndrome (KS) is a rare, genetically heterogeneous Mendelian disorder. Structural defects in KS patients have helped define the genetic architecture of gonadotropin-releasing hormone (GnRH) neuronal development in this condition.ObjectiveExamine the functional role a novel structural defect affecting a long noncoding RNA (lncRNA), RMST, found in a KS patient.DesignWhole genome sequencing, induced pluripotent stem cells and derived neural crest cells (NCC) from the KS patient were contrasted with controls.SettingThe Harvard Reproductive Sciences Center, Massachusetts General Hospital Center for Genomic Medicine, and Singapore Genome Institute.PatientA KS patient with a unique translocation, t(7;12)(q22;q24).Interventions/Main Outcome Measure/ResultsA novel translocation was detected affecting the lncRNA, RMST, on chromosome 12 in the absence of any other KS mutations. Compared with controls, the patient’s induced pluripotent stem cells and NCC provided functional information regarding RMST. Whereas RMST expression increased during NCC differentiation in controls, it was substantially reduced in the KS patient’s NCC coincident with abrogated NCC morphological development and abnormal expression of several “downstream” genes essential for GnRH ontogeny (SOX2, PAX3, CHD7, TUBB3, and MKRN3). Additionally, an intronic single nucleotide polymorphism in RMST was significantly implicated in a genome-wide association study associated with age of menarche.ConclusionsA novel deletion in RMST implicates the loss of function of a lncRNA as a unique cause of KS and suggests it plays a critical role in the ontogeny of GnRH neurons and puberty.
      PubDate: Sat, 19 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz011
      Issue No: Vol. 105, No. 3 (2019)
  • Exposure to Glucocorticoids in the First Part of Fetal Life is Associated
           with Insulin Secretory Defect in Adult Humans
    • Authors: Riveline J; Baz B, Nguewa J, et al.
      Abstract: AbstractObjectiveHigh glucocorticoid levels in rodents inhibit development of beta cells during fetal life and lead to insulin deficiency in adulthood. To test whether similar phenomena occur in humans, we compared beta-cell function in adults who were exposed to glucocorticoids during the first part of fetal life with that of nonexposed subjects.Research Design and MethodsThe study was conducted in 16 adult participants exposed to glucocorticoids during the first part of fetal life and in 16 nonexposed healthy participants with normal glucose tolerance who were matched for age, sex, and body mass index (BMI). Exposed participants had been born to mothers who were treated with dexamethasone 1 to 1.5 mg/day from the sixth gestational week (GW) to prevent genital virilization in children at risk of 21-hydroxylase deficiency. We selected offspring of mothers who stopped dexamethasone before the 18th GW following negative genotyping of the fetus. Insulin and glucagon secretion were measured during an oral glucose tolerance test (OGTT) and graded intravenous (IV) glucose and arginine tests. Insulin sensitivity was measured by hyperinsulinemic-euglycemic-clamp.ResultsAge, BMI, and anthropometric characteristics were similar in the 2 groups. Insulinogenic index during OGTT and insulin sensitivity during the clamp were similar in the 2 groups. In exposed subjects, insulin secretion during graded IV glucose infusion and after arginine administration decreased by 17% (P = 0.02) and 22% (P = 0.002), respectively, while glucagon secretion after arginine increased.ConclusionOverexposure to glucocorticoids during the first part of fetal life is associated with lower insulin secretion at adult age, which may lead to abnormal glucose tolerance later in life.
      PubDate: Sat, 19 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz145
      Issue No: Vol. 105, No. 3 (2019)
  • Effects of Peptide YY on the Hypothalamic-Pituitary-Gonadal Axis in
           Healthy Men
    • Authors: Izzi-Engbeaya C; Jones S, Crustna Y, et al.
      Abstract: AbstractContextCentral and peripheral administration of peptide YY (PYY) has potent anorectic effects, and PYY analogs are under development as antiobesity treatments. Recent animal data suggest PYY may also influence the reproductive axis; however the effects of PYY on the human reproductive system are unknown.ObjectiveTo investigate the effects of PYY administration on the reproductive axis in healthy young men.DesignSingle-blind, randomized, placebo-controlled crossover study.SettingClinical Research Facility, Imperial College Healthcare NHS Trust.ParticipantsEighteen healthy eugonadal men (mean age 24.1 ± 0.9 years, mean body mass index 22.2 ± 0.4 kg/m2).InterventionEight-hour intravenous infusion of 0.4 pmol/kg/min PYY3-36 or rate-matched vehicle infusion.Main Outcome MeasuresNumber of luteinizing hormone (LH) pulses, LH, follicle stimulating hormone (FSH), and testosterone levels.ResultsThe number of LH pulses (mean number of LH pulses/8 hours: PYY 4.4 ± 0.3 vs vehicle 4.4 ± 0.4, P > .99), LH area under the curve (AUC) (PYY 1503 ± 79 IU.min/L vs vehicle 1574 ± 86 IU.min/L, P = .36), FSH AUC (PYY 1158 ± 513 IU.min/L vs vehicle 1199 ± 476 IU.min/L, P = .49) and testosterone AUC (PYY 10 485 ± 684 IU.min/L vs vehicle 11 133 ± 803 IU.min/L, P = .24) were similar during PYY and vehicle infusions.ConclusionsAcute intravenous infusion of 0.4 pmol/kg/min PYY does not affect the reproductive axis in healthy men.
      PubDate: Sat, 19 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz103
      Issue No: Vol. 105, No. 3 (2019)
  • Lipid Metabolism Links Nutrient-Exercise Timing to Insulin Sensitivity in
           Men Classified as Overweight or Obese
    • Authors: Edinburgh R; Bradley H, Abdullah N, et al.
      Abstract: AbstractContextPre-exercise nutrient availability alters acute metabolic responses to exercise, which could modulate training responsiveness.ObjectiveTo assess acute and chronic effects of exercise performed before versus after nutrient ingestion on whole-body and intramuscular lipid utilization and postprandial glucose metabolism.Design(1) Acute, randomized, crossover design (Acute Study); (2) 6-week, randomized, controlled design (Training Study).SettingGeneral community.ParticipantsMen with overweight/obesity (mean ± standard deviation, body mass index: 30.2 ± 3.5 kg⋅m-2 for Acute Study, 30.9 ± 4.5 kg⋅m-2 for Training Study).InterventionsModerate-intensity cycling performed before versus after mixed-macronutrient breakfast (Acute Study) or carbohydrate (Training Study) ingestion.ResultsAcute Study—exercise before versus after breakfast consumption increased net intramuscular lipid utilization in type I (net change: –3.44 ± 2.63% versus 1.44 ± 4.18% area lipid staining, P < 0.01) and type II fibers (–1.89 ± 2.48% versus 1.83 ± 1.92% area lipid staining, P < 0.05). Training Study—postprandial glycemia was not differentially affected by 6 weeks of exercise training performed before versus after carbohydrate intake (P > 0.05). However, postprandial insulinemia was reduced with exercise training performed before but not after carbohydrate ingestion (P = 0.03). This resulted in increased oral glucose insulin sensitivity (25 ± 38 vs –21 ± 32 mL⋅min-1⋅m-2; P = 0.01), associated with increased lipid utilization during exercise (r = 0.50, P = 0.02). Regular exercise before nutrient provision also augmented remodeling of skeletal muscle phospholipids and protein content of the glucose transport protein GLUT4 (P < 0.05).ConclusionsExperiments investigating exercise training and metabolic health should consider nutrient-exercise timing, and exercise performed before versus after nutrient intake (ie, in the fasted state) may exert beneficial effects on lipid utilization and reduce postprandial insulinemia.
      PubDate: Sat, 19 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz104
      Issue No: Vol. 105, No. 3 (2019)
  • Scaffold-Free Endometrial Organoids Respond to Excess Androgens Associated
           With Polycystic Ovarian Syndrome
    • Authors: Wiwatpanit T; Murphy A, Lu Z, et al.
      Abstract: AbstractContextPolycystic ovary syndrome (PCOS) is a prevalent disorder in reproductive aged women associated with a number of endocrine and metabolic complications, including increased risk of endometrial cancer.ObjectiveTo study the effect of the characteristic increased androgen levels in PCOS on the endometrium, a novel scaffold-free multicellular endometrial organoid was established.DesignHuman endometrial organoids were constructed using primary endometrial epithelial and stromal cells from endometrial tissues. Organoids were treated for 14 days with physiologic levels of estradiol and testosterone to mimic a normal follicular phase or PCOS hormone profiles. Organoids were harvested for immunostaining and ribonucleic acid sequencing.SettingAcademic institution.PatientsEndometrial tissues from 10 premenopausal women undergoing hysterectomy for benign pathologies were obtained following written consent.Main Outcome MeasuresOrganoid architecture, cell specific markers, functional markers, proliferation, and gene expression were measured.ResultsA method to generate scaffold-free endometrial organoids containing epithelial and stromal cells was established. These organoids exhibited distinct organization with epithelial cells lining the outer surface and stromal cells in the center of the organoids. Epithelial cells were polarized, organoids expressed cell type specific and functional markers, as well as androgen, estrogen, and progesterone receptors. Treatment with PCOS hormones increased cell proliferation and dysregulated genes in endometrial organoids.ConclusionsA new multicellular, scaffold-free endometrial organoid system was established that resembled physiology of the native endometrium. Excess androgens in PCOS promoted cell proliferation in endometrial organoids, revealing new mechanisms of PCOS-associated with risk of endometrial neoplasia.
      PubDate: Wed, 16 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz100
      Issue No: Vol. 105, No. 3 (2019)
  • Effect of Dosage of 17ß-Estradiol on Uterine Growth in Turner
           Syndrome—A Randomized Controlled Clinical Pilot Trial
    • Authors: Cleemann L; Holm K, Fallentin E, et al.
      Abstract: AbstractContextMost Turner syndrome (TS) girls need exogenous estrogen treatment to induce puberty and normal uterine growth. After puberty, the optimal estrogen treatment protocol has not been determined.ObjectiveTo compare 2 doses of oral 17ß-estradiol on uterine size.DesignA double-blind, 5-year randomized controlled clinical trial.SettingAmbulatory care.ParticipantsTwenty young TS women (19.2 ± 2.5 years, range 16.0–24.9) participated. Sixteen patients completed the study. No patients withdrew due to adverse effects.InterventionThe lower dose (LD) group took 2 mg 17ß-estradiol/d orally and placebo. The higher dose (HD) group took 4 mg 17ß-estradiol/d orally.Main Outcome Measure(s)Uterine volume evaluated by transabdominal ultrasound yearly.ResultsUterine size increased significantly more in the HD group compared with the LD group (P = 0.038), with a gain in uterine volume within the first 3 years of treatment of 19.6 mL (95% confidence interval [CI] = 4.0-19.0) in the HD group compared with 11.5 mL (95% CI = 11.2-27.9) in the LD group. The difference in 3-year gain was 8.1 mL (95% CI = 0.7-15.9). At the last visit, there were no significant differences in uterine volume between the groups.ConclusionHD oral 17ß-estradiol induces a steeper increase in uterine volume within the first years of treatment compared with the LD. However, the uterine growth potential seems to be the same in most young TS women making the duration of treatment equally significant as estrogen dose, although a few TS women did not experience sufficient uterine growth on 2 mg of estradiol.ClinicalTrials.govNCT00134745Abbreviations: BMI, body mass index; BSA, body surface area; DHEAS, dihydroepiandrosteronesulfate; HD, higher dose; HRT, hormone replacement therapy; LD, lower dose; TS, Turner syndrome; US, ultrasound
      PubDate: Tue, 15 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz061
      Issue No: Vol. 105, No. 3 (2019)
  • Effects of Pegvisomant and Pasireotide LAR on Vertebral Fractures in
           Acromegaly Resistant to First-generation SRLs
    • Authors: Chiloiro S; Giampietro A, Frara S, et al.
      Abstract: AbstractPurposeOsteopathy is an emerging complication of acromegaly. In somatostatin receptor ligands (SRL)-resistant patients, pegvisomant (PegV) and pasireotide LAR (Pasi) are used for acromegaly treatment, but their effect on skeletal health is still not defined.MethodsIn a longitudinal retrospective international study, we evaluated incidence of radiological vertebral fractures (VFs) in 55 patients with acromegaly resistant to first-generation SRL.ResultsAt study entry, prevalent VFs occurred in 23 patients (41.8%). Biochemical acromegaly control was reached in 66.7% of patients on PegV and in 66.7% of patients on Pasi. During the follow-up, incident VFs (iVFs) were detected in 16 patients (29.1%). Occurrence of iVFs was associated with prevalent VFs (P = .002), persistence of active acromegaly (P = .01) and higher value of insulin-like growth factor 1 (IGF-1) during follow-up (P = .03). Among patients with active disease at last visit, iVFs occurred less frequently in patients on treatment with Pasi (25%) compared to PegV (77.8% P = .04), independently of the IGF-1 values (P = .90). In patients who reached biochemical control, 22.7% on PegV and 12.5% on Pasi had iVFs (P = .40). Among both treatment groups, the presence of pre-existent VFs was the main determinant for iVFs.ConclusionOur data show for the first time that patients with biochemically active disease treated with Pasi had lower risk of iVFs versus those treated with PegV. It also confirms that the presence of pre-existent VFs was the main determinant for iVFs. Additional studies on larger populations and with longer follow-up are needed to confirm our data and disclose the mechanisms underlying our findings.
      PubDate: Tue, 15 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz054
      Issue No: Vol. 105, No. 3 (2019)
  • Effect of the Incretin Hormones on the Endocrine Pancreas in End-Stage
           Renal Disease
    • Authors: Jørgensen M; Idorn T, Rydahl C, et al.
      Abstract: AbstractContextThe insulin-stimulating and glucagon-regulating effects of the 2 incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), contribute to maintain normal glucose homeostasis. Impaired glucose tolerance occurs with high prevalence among patients with end-stage renal disease (ESRD).ObjectiveTo evaluate the effect of the incretin hormones on endocrine pancreatic function in patients with ESRD.Design and SettingTwelve ESRD patients on chronic hemodialysis and 12 matched healthy controls, all with normal oral glucose tolerance test, were included. On 3 separate days, a 2-hour euglycemic clamp followed by a 2-hour hyperglycemic clamp (3 mM above fasting level) was performed with concomitant infusion of GLP-1 (1 pmol/kg/min), GIP (2 pmol/kg/min), or saline administered in a randomized, double-blinded fashion. A 30% lower infusion rate was used in the ESRD group to obtain comparable incretin hormone plasma levels.ResultsDuring clamps, comparable plasma glucose and intact incretin hormone concentrations were achieved. The effect of GLP-1 to increase insulin concentrations relative to placebo levels tended to be lower during euglycemia in ESRD and was significantly reduced during hyperglycemia (50 [8–72]%, P = 0.03). Similarly, the effect of GIP relative to placebo levels tended to be lower during euglycemia in ESRD and was significantly reduced during hyperglycemia (34 [13–50]%, P = 0.005). Glucagon was suppressed in both groups, with controls reaching lower concentrations than ESRD patients.ConclusionsThe effect of incretin hormones to increase insulin release is reduced in ESRD, which, together with elevated glucagon levels, could contribute to the high prevalence of impaired glucose tolerance among ESRD patients.
      PubDate: Mon, 14 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz048
      Issue No: Vol. 105, No. 3 (2019)
  • Efficacy, Safety, and Mechanistic Insights of Cotadutide, a Dual Receptor
           Glucagon-Like Peptide-1 and Glucagon Agonist
    • Authors: Parker V; Robertson D, Wang T, et al.
      Abstract: AbstractContextCotadutide is a dual receptor agonist with balanced glucagon-like peptide-1 and glucagon activity.ObjectiveTo evaluate different doses of cotadutide and investigate underlying mechanisms for its glucose-lowering effects.Design/settingRandomized, double-blind, phase 2a study conducted in 2 cohorts at 5 clinical trial sites.PatientsParticipants were 65 adult overweight/obese patients with type 2 diabetes mellitus; 63 completed the study; 2 were withdrawn due to AEs.InterventionOnce-daily subcutaneous cotadutide or placebo for 49 days. Doses (50–300 µg) were uptitrated weekly (cohort 1) or biweekly (cohort 2).Main outcome measuresCo-primary end points (cohort 1) were percentage changes from baseline to end of treatment in glucose (area under the curve from 0 to 4 hours [AUC0–4h]) post–mixed-meal tolerance test (MMTT) and weight. Exploratory measures included postprandial insulin and gastric emptying time (GET; cohort 2).ResultsPatients received cotadutide (cohort 1, n = 26; cohort 2, n = 20) or placebo (cohort 1, n = 13; cohort 2, n = 6). Significant reductions were observed with cotadutide vs placebo in glucose AUC0–4h post MMTT (least squares mean [90% CI], −21.52% [−25.68, −17.37] vs 6.32% [0.45, 12.20]; P < 0.001) and body weight (−3.41% [−4.37, −2.44] vs −0.08% [−1.45, 1.28]; P = 0.002). A significant increase in insulin AUC0–4h post MMTT was observed with cotadutide (19.3 mU.h/L [5.9, 32.6]; P = 0.008) and GET was prolonged on day 43 with cotadutide vs placebo (t½: 117.2 minutes vs −42.9 minutes; P = 0.0392).ConclusionThese results suggest that the glucose-lowering effects of cotadutide are mediated by enhanced insulin secretion and delayed gastric emptying.Trial, NCT03244800.
      PubDate: Mon, 14 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz047
      Issue No: Vol. 105, No. 3 (2019)
  • A Role for Oncostatin M in the Impairment of Glucose Homeostasis in
    • Authors: Piquer-Garcia I; Campderros L, Taxerås S, et al.
      Abstract: AbstractContextOncostatin M (OSM) plays a key role in inflammation, but its regulation and function during obesity is not fully understood.ObjectiveThe aim of this study was to evaluate the relationship of OSM with the inflammatory state that leads to impaired glucose homeostasis in obesity. We also assessed whether OSM immunoneutralization could revert metabolic disturbances caused by a high-fat diet (HFD) in mice.Design28 patients with severe obesity were included and stratified into two groups: (1) glucose levels <100 mg/dL and (2) glucose levels >100 mg/dL. White adipose tissue was obtained to examine OSM gene expression. Human adipocytes were used to evaluate the effect of OSM in the inflammatory response, and HFD-fed C57BL/6J mice were injected with anti-OSM antibody to evaluate its effects.ResultsOSM expression was elevated in subcutaneous and visceral fat from patients with obesity and hyperglycemia, and correlated with Glut4 mRNA levels, serum insulin, homeostatic model assessment of insulin resistance, and inflammatory markers. OSM inhibited adipogenesis and induced inflammation in human adipocytes. Finally, OSM receptor knockout mice had increased Glut4 mRNA levels in adipose tissue, and OSM immunoneutralization resulted in a reduction of glucose levels and Ccl2 expression in adipose tissue from HFD-fed mice.ConclusionsOSM contributes to the inflammatory state during obesity and may be involved in the development of insulin resistance.
      PubDate: Sun, 13 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz090
      Issue No: Vol. 105, No. 3 (2019)
  • Long-Term Outcomes of 125 Patients With Metastatic Pheochromocytoma or
           Paraganglioma Treated With 131-I MIBG
    • Authors: Thorpe M; Kane A, Zhu J, et al.
      Abstract: AbstractContextPrognosis of metastatic pheochromocytoma/paraganglioma following 131-Iodine metaiodobenzylguanidine (MIBG) is incompletely characterized due to small samples and shorter follow-up in these rare, often indolent tumors.ObjectiveTo describe long-term survival, frequency, and prognostic impact of imaging, biochemical, and symptomatic response to 131-I MIBG.DesignRetrospective chart and imaging review at a tertiary referral center.PatientsSix hundred sixty-eight person-years of follow-up in 125 patients with metastatic pheochromocytoma/paraganglioma with progression through prior multimodal treatment.InterventionMedian 18 800 MBq 131-I MIBG.Main Outcome MeasuresOverall survival, Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) imaging response, symptomatic response per chart review, and biochemical response (20% change over 2 consecutive assays of catecholamines, vanillylmandelic acid, metanephrines, or chromogranin A).ResultsMedian survival standard deviation [SD] from diagnosis was 11.5 years [2.4]; following metastasis, 6.5 years [0.8]; post treatment, 4.3 years [0.7]. Among 88 participants with follow-up imaging, 1% experienced complete response, 33% partial response, 53% stability, and 13% progression. Fifty-one percent showed subsequent progression, median progression-free survival [SD] of 2.0 years [0.6]. Stability/response vs progression at first imaging follow-up (3–6 months) predicted improved survival, 6.3 vs 2.4 years (P = 0.021). Fifty-nine percent of 54 patients demonstrated biochemical response. Fifty percent of these relapsed, with median time to laboratory progression [SD] of 2.8 years [0.7]. Biochemical response did not predict extended survival. Seventy-five percent of 83 patients reported improvement in pretreatment symptoms, consisting primarily of pain (42%), fatigue (27%), and hypertension (14%). Sixty-one percent of these patients experienced subsequent symptomatic progression at median [SD] 1.8 years [0.4]. Symptomatic response did not predict extended survival.ConclusionsImaging, symptomatic, and laboratory response to multimodal treatment including high-dose 131-I MIBG were achieved on long-term follow-up in metastatic pheochromocytoma or paraganglioma. Imaging response at 3 to 6 months was prognostic.
      PubDate: Fri, 11 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz074
      Issue No: Vol. 105, No. 3 (2019)
  • Prevalence of Insomnia (Symptoms) in T2D and Association With Metabolic
           Parameters and Glycemic Control: Meta-Analysis
    • Authors: Koopman A; Beulens J, Dijkstra T, et al.
      Abstract: ObjectiveWe aimed to determine the prevalence of insomnia and insomnia symptoms and its association with metabolic parameters and glycemic control in people with type 2 diabetes (T2D) in a systematic review and meta-analysis.Data SourcesA systematic literature search was conducted in PubMed/Embase until March 2018.Study SelectionIncluded studies described prevalence of insomnia or insomnia symptoms and/or its association with metabolic parameters or glycemic control in adults with T2D.Data ExtractionData extraction was performed independently by 2 reviewers, on a standardized, prepiloted form. An adaptation of Quality Assessment Tool for Quantitative Studies was used to assess the methodological quality of the included studies. Data SynthesisWhen possible, results were meta-analyzed using random-effects analysis and rated using Grading of Recommendations Assessment, Development and Evaluation (GRADE).ResultsA total of 11 329 titles/abstracts were screened and 224 were read full text in duplicate, of which 78 studies were included. The pooled prevalence of insomnia (symptoms) in people with T2D was 39% (95% confidence interval, 34–44) with I2 statistic of 100% (P < 0.00001), with a very low GRADE of evidence. Sensitivity analyses identified no clear sources of heterogeneity. Meta-analyses showed that in people with T2D, insomnia (symptoms) were associated with higher hemoglobin A1c levels (mean difference, 0.23% [0.1–0.4]) and higher fasting glucose levels (mean difference, 0.40 mmol/L [0.2–0.7]), with a low GRADE of evidence. The relative low methodological quality and high heterogeneity of the studies included in this meta-analysis complicate the interpretation of our results.ConclusionsThe prevalence of insomnia (symptoms) is 39% (95% confidence interval, 34–44) in the T2D population and may be associated with deleterious glycemic control.
      PubDate: Fri, 11 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz065
      Issue No: Vol. 105, No. 3 (2019)
  • Correlation Between Telomere Attrition of Zona Fasciculata and Adrenal
           Weight Reduction in Older Men
    • Authors: Nonaka K; Aida J, Takubo K, et al.
      Abstract: AbstractContextAlthough numerous theories are reported on sex differences in longevity, the underlying biological mechanisms remain unknown. We previously reported that telomere length in the zona reticularis cells of the human adrenal cortex was significantly longer in older than that in younger subjects. However, we could not evaluate sex differences in the telomere lengths.ObjectiveTo compare the telomere lengths of adrenocortical and adrenal medullar cells between men and women from infancy through older adulthood.MethodsAdrenal glands of 30 male (aged 0 to 100 years) and 25 female (aged 0 to 104 years) autopsied subjects were retrieved from autopsy files. Using quantitative fluorescence in situ hybridization, relative telomere lengths were determined in the parenchymal cells of the 3 adrenocortical zones and medulla. Age-related changes in the weight of adrenal glands were also investigated.Main resultsOlder male subjects (aged 65 years or older) had significantly shorter telomere lengths in zona fasciculata (ZF) cells compared to the corresponding female subjects. In men, older subjects exhibited a significant age-related reduction in adrenal weight; however, no age-related changes in adrenal weight were detected in women.ConclusionTelomere attrition of ZF cells was correlated with adrenal weight reduction in older men but not in older women, suggesting a decreased number of ZF cells in older men. This may help us understand the possible biological mechanisms of sex difference in longevity of humans.
      PubDate: Wed, 09 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz214
      Issue No: Vol. 105, No. 3 (2019)
  • Thyroid Hormone Effects on Glucose Disposal in Patients With Insulin
           Receptor Mutations
    • Authors: Kushchayeva Y; Startzell M, Cochran E, et al.
      Abstract: AbstractContextPatients with mutations of the insulin receptor gene (INSR) have extreme insulin resistance and are at risk for early morbidity and mortality from diabetes complications. A case report suggested that thyroid hormone could improve glycemia in INSR mutation in part by increasing brown adipose tissue (BAT) activity and volume.ObjectiveTo determine if thyroid hormone increases tissue glucose uptake and improves hyperglycemia in INSR mutation.DesignSingle-arm, open-label study of liothyronine.SettingNational Institutes of Health.ParticipantsPatients with homozygous (n = 5) or heterozygous (n = 2) INSR mutation.InterventionLiothyronine every 8 hours for 2 weeks (n = 7); additional 6 months’ treatment in those with hemoglobin A1c (HbA1c) > 7% (n = 4).OutcomesWhole-body glucose uptake by isotopic tracers; tissue glucose uptake in muscle, white adipose tissue (WAT) and BAT by dynamic [18F] fluorodeoxyglucose positron emission tomography/computed tomography; HbA1c.ResultsThere was no change in whole-body, muscle, or WAT glucose uptake from baseline to 2 weeks of liothyronine. After 6 months, there was no change in HbA1c (8.3 ± 1.2 vs 9.1 ± 3.0%, P = 0.27), but there was increased whole-body glucose disposal (22.8 ± 4.9 vs 30.1 ± 10.0 µmol/kg lean body mass/min, P = 0.02), and muscle (0.7 ± 0.1 vs 2.0 ± 0.2 µmol/min/100 mL, P < 0.0001) and WAT glucose uptake (1.2 ± 0.2 vs 2.2 ± 0.3 µmol/min/100 mL, P < 0.0001). BAT glucose uptake could not be quantified because of small volume. There were no signs or symptoms of hyperthyroidism.ConclusionLiothyronine administered at well-tolerated doses did not improve HbA1c. However, the observed increases in muscle and WAT glucose uptake support the proposed mechanism that liothyronine increases tissue glucose uptake. More selective agents may be effective at increasing tissue glucose uptake without thyroid hormone–related systemic toxicity.Clinical Trial Registration Number: NCT02457897;
      PubDate: Mon, 07 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz079
      Issue No: Vol. 105, No. 3 (2019)
  • Associations Between Anti-Mullerian Hormone and Cardiometabolic Health in
           Reproductive Age Women Are Explained by Body Mass Index
    • Authors: Rios J; Greenwood E, Pavone M, et al.
      Abstract: AbstractContextThe relationship between reproductive and cardiometabolic aging is unclear. It is unknown if the relationship differs across different clinical populations.ObjectiveTo determine whether markers of ovarian reserve are associated with cardiometabolic risk in reproductive aged women with unexplained infertility (UI), polycystic ovary syndrome (PCOS), and regularly cycling women (OVA).Design and settingCross-sectional data from 8 US-based academic centers.ParticipantsWomen aged 25–40 from 3 clinical populations: 870 with UI, 640 with PCOS, and 921 community-based OVA.Main Outcome MeasuresMultivariable linear regression models were used to relate anti-mullerian hormone (AMH) and antral follicle count with cardiometabolic parameters including body mass index (BMI), waist circumference (WC), fasting glucose and insulin, homeostasis model assessment-insulin resistance (HOMA-IR), lipids, and C-reactive protein.ResultsIn age and study site-adjusted models, AMH inversely related to BMI in the UI and OVA groups (P = 0.02 and P < 0.001). Among women with PCOS, AMH inversely related to BMI (P < 0.001), and also to WC (P < 0.001), fasting insulin (P < 0.01), HOMA-IR (P < 0.01), triglycerides (P = 0.04), and C-reactive protein (P < 0.001) and directly related to higher total (P = 0.02), low-density lipoprotein (P < 0.01), and high-density lipoprotein cholesterol (P < 0.01). In OVA, AMH also varied inversely with WC (P < 0.001), fasting insulin (P = 0.02), and HOMA-IR (P = 0.02). Adjustment for BMI eliminated associations in the OVA group but in PCOS, the relationship of AMH to total (P = 0.03) and low-density lipoprotein cholesterol (P = 0.003) remained.ConclusionAssociations observed between AMH and cardiometabolic indices are largely explained by BMI in women with and without PCOS. (J Clin Endocrinol Metab XX: 0-0, 2019)
      PubDate: Sat, 05 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz012
      Issue No: Vol. 105, No. 3 (2019)
  • No Association of Antenatal Synthetic Glucocorticoid Exposure and Hair
           Steroid Levels in Children and Adolescents
    • Authors: Ilg L; Kirschbaum C, Li S, et al.
      Abstract: AbstractContextAntenatal synthetic glucocorticoid (sGC) treatment constitutes a potent programming factor of the hypothalamic–pituitary–adrenal (HPA) axis. Previous findings from our group revealed long-term changes in cortisol stress reactivity following antenatal sGC therapy. However, the few prior studies exclusively relied on spot measurements of phasic HPA axis activity, which may not adequately capture cortisol output over prolonged periods of time.ObjectiveTo address this gap, the current study utilized hair steroid concentrations, a valid marker of integrated long-term HPA-axis activity, to investigate endocrine changes in individuals treated with antenatal sGC.Design, Setting, and ParticipantsThis cross-sectional study comprised 76 term-born children (7–12 years) and 58 adolescents (14–18 years). Cumulated hormonal secretion in scalp hair over a 3-month period was determined for different biomarkers of tonic HPA axis activity by liquid chromatography coupled with tandem mass spectrometry. Hair steroid levels were compared between participants with antenatal sGC therapy (dexamethasone or betamethasone) and different control groups.ResultsFindings from this study provide no evidence for a significant effect of antenatal sGCs on long-term hair steroid concentrations. Participants treated with antenatal sGC exhibited comparable levels of hair cortisol, cortisone, dehydroepiandrosterone, and cortisol/dehydroepiandrosterone ratios compared to those of mothers who had been admitted to hospital for pregnancy complications but had never received sGC therapy and controls from physiological pregnancies.ConclusionIn conjunction with data from previous studies, it is thus tempting to speculate that sGC may affect the capacity of dynamic changes and flexible adaption of an individual’s HPA axis rather than changes in tonic steroid output.
      PubDate: Sat, 05 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz064
      Issue No: Vol. 105, No. 3 (2019)
  • Impulse Control Disorders in Dopamine Agonist-Treated Hyperprolactinemia:
           Prevalence and Risk Factors
    • Authors: De Sousa S; Baranoff J, Rushworth R, et al.
      Abstract: AbstractContextThere are growing reports of dopamine agonist (DA)-induced impulse control disorders (ICDs) in hyperprolactinemic patients. However, the magnitude of this risk and predictive factors remain uncertain.ObjectiveTo determine ICD prevalence and risk factors in DA-treated hyperprolactinemic patients compared to community controls.Design, Setting and ParticipantsMulticenter cross-sectional analysis of 113 patients and 99 healthy controls.Main Outcome MeasuresParticipants completed a neuropsychological questionnaire consisting of the Depression Anxiety Stress Scale (DASS21), Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP-S), Hypersexual Behavior Inventory (HBI), Hypersexual Behavior Consequences Scale and Social Desirability Response Set Scale. Demographic and clinical data were collated to determine ICD risk factors. Patients testing positive for an ICD were offered a semistructured psychological interview.ResultsPatients were more likely than controls to test positive by QUIP-S for any ICD (61.1 vs 42.4%, P = .01), hypersexuality (22.1 vs 8.1%, P = .009), compulsive buying (15.9 vs 6.1%, P = .041) and punding (18.6 vs 6.1%, P = 0.012), and by HBI for hypersexuality (8.0 vs 0.0%, P = 0.004). Independent risk factors were male sex (odds ratio [OR] 13.85), eugonadism (OR 7.85), Hardy’s tumor score and psychiatric comorbidity (OR 6.86) for hypersexuality, and age (OR 0.95) for compulsive buying. DASS21 subset scores were higher in patients vs controls and in patients with vs without different ICDs. Only 19/51 (37.3%) interviewed patients were aware of the relationship between DAs and ICDs before the study.ConclusionsDA therapy poses a high, previously underestimated risk of ICDs, especially in the form of hypersexuality in eugonadal men.
      PubDate: Thu, 03 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz076
      Issue No: Vol. 105, No. 3 (2019)
  • Body Composition and Markers of Cardiometabolic Health in Transgender
           Youth Compared With Cisgender Youth
    • Authors: Nokoff N; Scarbro S, Moreau K, et al.
      Abstract: AbstractContextAs many as 1.8% of adolescents identify as transgender and many more seek care, yet the impact of gender-affirming hormone therapy (GAHT) on cardiometabolic health is unknown.ObjectiveTo determine insulin sensitivity and body composition among transgender females (TF) and males (TM) on estradiol or testosterone, compared with cisgender females (CF) and males (CM).DesignPilot, cross-sectional study conducted from 2016–2018.SettingAcademic regional transgender referral center.ParticipantsTransgender adolescents on either testosterone or estradiol for at least 3 months were recruited. Nineteen TM were matched to 19 CM and 42 CF on pubertal stage and body mass index (BMI). Eleven TF were matched to 23 CF and 13 TF to 24 CM on age and BMI.Main Outcome Measures1/[fasting insulin] and body composition (dual-energy x-ray absorptiometry).ResultsTotal body fat was lower in TM than CF mean ± SD: (29% ± 7% vs 33% ± 7%; P = 0.002) and higher than in CM (28% ± 7% vs 24% ± 9%; P = 0.047). TM had higher lean mass than CF (68% ± 7% vs 64% ± 7%, P = 0.002) and lower than CM (69% ± 7% vs 73% ± 8%; P = 0.029). Insulin sensitivity was not different between the groups.TF had lower body fat than CF (31% ± 7% vs 35% ± 8%; P = 0.033) and higher than CM (28% ± 6% vs 20% ± 10%; P = 0.001). TF had higher lean mass than CF (66% ± 6% vs 62% ± 7%; P = 0.032) and lower than CM (69% ± 5% vs 77% ± 9%; P = 0.001). TF were more insulin resistant than CM (0.078 ± 0.025 vs 0.142 ± 0.064 mL/μU; P = 0.011).ConclusionsTransgender adolescents on GAHT have significant differences in body composition compared with cisgender controls, with a body composition intermediate between BMI-matched CMs and CFs. These changes in body composition may have consequences for the cardiometabolic health of transgender adolescents.ClinicalTrials.govNCT02550431
      PubDate: Mon, 23 Sep 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz029
      Issue No: Vol. 105, No. 3 (2019)
  • Weight Change and Development of Subclinical Carotid Atherosclerosis Among
           Metabolically Healthy Adults: A Cohort Study
    • Authors: Sinn D; Kang D, Cho S, et al.
      Abstract: AbstractBackgroundThe benefit of weight loss for reducing cardiovascular disease (CVD) risk in metabolically healthy obese people is unknown.ObjectivesWe evaluated the association between weight change and incident subclinical carotid atherosclerosis (SCA) in metabolically healthy but overweight or obese subjects.MethodsCohort study of 3117 metabolically healthy overweight or obese adults who did not have any metabolic syndrome components or insulin resistance at baseline. SCA was assessed using carotid artery ultrasonography. The study outcome was the development of incident SCA among participants free of the disease at baseline.ResultsDuring 12 248 person-years of follow-up (median 3.42 years), 747 participants developed SCA. The proportions of participants with no reduction or increased weight, reduction in weight from 0.1% to 4.9%, and reduction in weight ≥ 5% during follow-up were 47.0%, 44.4%, and 8.6%, respectively. The fully-adjusted hazard ratios (HRs) for incident SCA in participants with a reduction in weight of 0.1% to 4.9% and ≥ 5% compared with those with no reduction or increased weight were 0.84 (95% CI, 0.72–0.98) and 0.66 (95% CI, 0.50–0.87), respectively.ConclusionsIn a large cohort study of metabolically healthy but overweight or obese adult men and women, weight reduction was associated with a lower incidence of SCA. Our findings suggest that metabolically healthy overweight or obese subjects may benefit from weight reduction in terms of CVD risk.
      PubDate: Mon, 23 Sep 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz040
      Issue No: Vol. 105, No. 3 (2019)
  • Pioglitazone Exposure Reduced the Risk of All-Cause Mortality in
           Insulin-Treated Patients with Type 2 Diabetes Mellitus
    • Authors: Yen F; Wang H, Pan C, et al.
      Abstract: AbstractContextThe long-term safety and benefit of pioglitazone use in combination with insulin are still uncertain.ObjectiveThis study compared the risks of all-cause mortality and major cardiovascular (CV) events between pioglitazone users and nonusers receiving insulin therapy.Design, Setting and PatientsWe conducted a 13-year retrospective cohort study by using data from the population-based National Health Insurance Research Database in Taiwan. A total of 20 376 patients with type 2 diabetes mellitus (T2DM) receiving insulin therapy were enrolled during 2000 to 2012. Overall, the incidence rates of all-cause mortality and CV events were compared between 2579 pioglitazone users and 2579 matched nonusers.ResultsAfter adjustment for age, sex, comorbidities, Diabetes Complications Severity Index scores, and drugs used, mortality rates were 30.26 and 15.02 per 1000 person-years for pioglitazone nonusers and users, respectively. The adjusted hazard ratio (aHR) of mortality was 0.47 (95% confidence interval [CI]: 0.38–0.58, P < 0.001) for pioglitazone users compared with nonusers. The aHRs of CV and non-CV deaths were 0.78 (95% CI: 0.51–1.19) and 0.50 (95% CI: 0.38–0.66), respectively. The aHRs of hospitalized coronary artery disease, hospitalized stroke, and incident heart failure were not significantly different between pioglitazone users and nonusers.ConclusionsThis nationwide cohort study demonstrated that pioglitazone use reduced the risks of all-cause mortality and non-CV death for patients with T2DM undergoing insulin therapy.
      PubDate: Mon, 23 Sep 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz026
      Issue No: Vol. 105, No. 3 (2019)
  • Efficacy and Safety of First- and Second-Line Drugs to Prevent
           Glucocorticoid-Induced FracturesNetwork Meta-Analysis
    • Authors: Ding L; Hu J, Wang D, et al.
      Abstract: AbstractContextThe evidence about benefits and harms of drugs for glucocorticoid (GC)-induced osteoporosis (GIOP) is limited, and the comparative efficacy and safety of first-line and second-line agents to prevent GC-induced (GI) fractures remains unclear.ObjectiveTo assess the comparative clinical efficacy, safety, and tolerability of first-line and second-line agents in preventing GI fractures.Data SourcesWe searched 3 different databases through March 5, 2019.Study SelectionWe included randomized controlled trials enrolling patients receiving long-term GCs and compared a first-line and second-line agent with one another and with placebo.Data ExtractionTwo reviewers independently extracted study and participant characteristics and outcome data.Data SynthesisWe performed multivariate random-effects network meta-analyses including base, 3 subgroups, and 12 sensitivity analyses. We included 22 papers from 19 unique trials involving 4328 patients receiving GCs. Teriparatide (risk ratio [RR] 0.11, 95% confidence interval [CI] 0.03–0.47), denosumab (RR 0.21, 95% CI 0.09–0.49), and risedronate (RR 0.33, 95% CI 0.19–0.58) reduced the risk of GI vertebral fractures, and the former 2 were the most efficacious according to violin plots including the surface under the cumulative ranking curve values calculated by base and sensitivity analyses. Oral alendronate (RR 0.33, 95% CI 0.12–0.93) reduced this risk in patients receiving GCs with at least 7.5 mg/day, while intravenous ibandronate (RR 0.25, 95% CI 0.06–0.99) was efficacious for the primary prevention of GIOP. Six drugs were similar in terms of the 5 other outcomes.ConclusionsIn terms of clinical efficacy and safety, second-line teriparatide and denosumab pose a challenge to first-line oral bisphosphonates for prevention of GI fractures.
      PubDate: Thu, 12 Sep 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz023
      Issue No: Vol. 105, No. 3 (2019)
  • A Novel Anti-CD40 Monoclonal Antibody, Iscalimab, for Control of Graves
           Hyperthyroidism—A Proof-of-Concept Trial
    • Authors: Kahaly G; Stan M, Frommer L, et al.
      Abstract: AbstractContextThe CD40-CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves disease (GD) by promoting autoreactive B-cell activation.ObjectiveEvaluate efficacy and safety of a human, blocking, nondepleting anti-CD40 monoclonal antibody, iscalimab, in hyperthyroid patients with GD.DesignOpen-label, phase II proof-of-concept study.SettingMulticenter.PatientsFifteen with GD.InterventionPatients received 5 doses of iscalimab at 10 mg/kg intravenously over 12 weeks.Main outcome measuresThyroid-related hormones and autoantibodies, plasma soluble CD40, free CD40 on B cells, soluble CXCL13, pharmacokinetics, and safety were assessed.ResultsThe iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks. A clinical response and biochemical euthyroidism was observed in 7 of 15 (47%) patients. Free and total triiodothyronine and thyroxine normalized in 7 patients who did not receive any rescue medication with antithyroid drugs (ATD), and 2/15 (13.3%) showed normal thyrotropin. Six (40%) patients required ATD. Four of 7 responders relapsed after treatment completion. Serum concentrations of thyrotropin receptor autoantibodies (TSH-R-Ab) significantly declined in all patients (mean 15.3 IU/L vs 4.0 IU/L, 66% reduction; P < 0.001) and TSH-R-Ab levels normalized in 4 (27%). Thyroperoxidase and thyroglobulin autoantibodies significantly decreased in responders. Iscalimab rapidly reduced serum CXCL13 concentrations (P < 0.001). Twelve (80.0%) patients reported at least 1 adverse event (AE). All treatment-related AE were mild or moderate and resolved by end of the study.ConclusionIscalimab was generally safe and clinically effective in a subgroup of hyperthyroid GD patients. The potential therapeutic benefit of iscalimab should be further tested.
      PubDate: Thu, 12 Sep 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz013
      Issue No: Vol. 105, No. 3 (2019)
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