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Journal of Clinical Endocrinology & Metabolism
Journal Prestige (SJR): 2.941
Citation Impact (citeScore): 5
Number of Followers: 189  
  Full-text available via subscription Subscription journal
ISSN (Print) 0021-972X - ISSN (Online) 1945-7197
Published by Endocrine Society, The Homepage  [3 journals]
  • Does Hormone Therapy Protect the Heart' It Is a Stressful Question
    • Authors: Santoro N.
      Abstract: The notion that menopausal hormone therapy provides cardioprotection for women is one of the most contentious controversies in menopausal medicine. It is a vexing problem because it forces us to confront an apparent discrepancy between observational cohort studies and randomized, clinical trials. The Nurses’ Health Study, one of the most comprehensive and longstanding cohort studies of women, reported an overall, age-adjusted relative risk (RR) of coronary disease of 0.5 for ever users of hormone therapy, and 0.3 for current users (1). Ten-year follow-up confirmed this reduction in risk (age-adjusted RR 0.72, 95% CI 0.55-0.95, P = .02), but at a lesser magnitude (2). In the same 1985 issue of the New England Journal of Medicine, the Framingham Heart Study reported an increased RR of heart disease of 1.76 in association with menopausal hormone therapy (3). The Women’s Health Initiative (WHI), which was largely conceptualized to resolve this discrepancy, did not find any cardiovascular benefit of estrogen-alone therapy and found harm with use of estrogen plus progestin in the initial publication (4), which became nonsignificant with further follow-up (5). Controversy has raged ever since about the presence of cardioprotection, the possible relationship to age or timing within the menopause transition of the intervention, and the mechanisms by which menopausal hormone therapy might attenuate cardiovascular risk.
      PubDate: Wed, 25 Mar 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa011
      Issue No: Vol. 105, No. 5 (2020)
  • Hypercortisolism in the Brain, a Highly Dynamic Process With Stable and
           Detrimental Consequences
    • Authors: Meszaros K; Patocs A.
      Abstract: hypercortisolismbrain manifestationsfollow-up
      PubDate: Mon, 23 Mar 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa101
      Issue No: Vol. 105, No. 5 (2020)
  • Neonatal Hypocalcemic Seizures in Offspring of a Mother With Familial
           Hypocalciuric Hypercalcemia Type 1 (FHH1)
    • Authors: Dharmaraj P; Gorvin C, Soni A, et al.
      Abstract: AbstractContextFamilial hypocalciuric hypercalcemia type 1 (FHH1) is caused by loss-of-function mutations of the calcium-sensing receptor (CaSR) and is considered a benign condition associated with mild-to-moderate hypercalcemia. However, the children of parents with FHH1 can develop a variety of disorders of calcium homeostasis in infancy.ObjectiveThe objective of this work is to characterize the range of calcitropic phenotypes in the children of a mother with FHH1.MethodsA 3-generation FHH kindred was assessed by clinical, biochemical, and mutational analysis following informed consent.ResultsThe FHH kindred comprised a hypercalcemic man and his daughter who had hypercalcemia and hypocalciuria, and her 4 children, 2 of whom had asymptomatic hypercalcemia, 1 was normocalcemic, and 1 suffered from transient neonatal hypocalcemia and seizures. The hypocalcemic infant had a serum calcium of 1.57 mmol/L (6.28 mg/dL); normal, 2.0 to 2.8 mmol/L (8.0-11.2 mg/dL) and parathyroid hormone of 2.2 pmol/L; normal 1.0 to 9.3 pmol/L, and required treatment with intravenous calcium gluconate infusions. A novel heterozygous p.Ser448Pro CaSR variant was identified in the hypercalcemic individuals, but not the children with hypocalcemia or normocalcemia. Three-dimensional modeling predicted the p.Ser448Pro variant to disrupt a hydrogen bond interaction within the CaSR extracellular domain. The variant Pro448 CaSR, when expressed in HEK293 cells, significantly impaired CaSR-mediated intracellular calcium mobilization and mitogen-activated protein kinase responses following stimulation with extracellular calcium, thereby demonstrating it to represent a loss-of-function mutation.ConclusionsThus, children of a mother with FHH1 can develop hypercalcemia or transient neonatal hypocalcemia, depending on the underlying inherited CaSR mutation, and require investigations for serum calcium and CaSR mutations in early childhood.
      PubDate: Mon, 09 Mar 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa111
      Issue No: Vol. 105, No. 5 (2020)
  • References for Ultrasound Staging of Breast Maturation, Tanner Breast
           Staging, Pubic Hair, and Menarche in Norwegian Girls
    • Authors: Bruserud I; Roelants M, Oehme N, et al.
      Abstract: AbstractContextDiscriminating adipose and glandular tissue is challenging when clinically assessing breast development. Ultrasound facilitates staging of pubertal breast maturation (US B), but has not been systematically compared to Tanner breast (Tanner B) staging, and no normative data have been reported.ObjectiveTo present normative references for US B along with references for Tanner B, pubic hair (PH), and menarche.Design, Setting, and ParticipantsA cross-sectional sample of 703 healthy girls aged 6 to 16 years were examined.Main Outcome MeasuresBreast development was determined with US B and Tanner B staging. Tanner PH and menarcheal status were recorded. The age distributions of entry in US B, Tanner B, and PH stages and menarche were estimated with generalized linear and generalized additive models with a probit link. Method agreement was tested with weighted Cohen’s kappa.ResultsThe median (±2SD) ages for thelarche, US B2 and Tanner B2, were 10.2 (7.7, 12.8) and 10.4 (8.0, 12.7) years. The median (±2SD) ages at Tanner PH2 and menarche were 10.9 (8.5, 13.3) and 12.7 (11.0, 16.2) years. Cohen’s kappa of agreement (95% confidence interval) between US B and Tanner B was 0.87 (0.85–0.88). When the methods disagreed, US B was usually more advanced.ConclusionThelarche occurred at a slightly younger age when assessed with ultrasound compared to clinical Tanner staging, although the 2 methods had a very good agreement when determining pubertal breast maturation. A significant decrease of 2.8 months in age at menarche was observed during the past decade in Norwegian girls.
      PubDate: Fri, 06 Mar 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa107
      Issue No: Vol. 105, No. 5 (2020)
  • Serum Angiopoietin-like Protein 6, Risk of Type 2 Diabetes, and Response
           to Hyperglycemia: A Prospective Cohort Study
    • Authors: Fan K; Wu H, Wei J, et al.
      Abstract: AbstractContextAngiopoietin-like protein 6 (ANGPTL6) is a hepatokine that improves insulin sensitivity in animals. However, serum ANGPTL6 concentration was found to be higher in human participants with diabetes or metabolic syndrome in cross-sectional studies, implying that ANGPTL6 may be induced to counteract hyperglycemia.ObjectiveTo investigate whether serum ANGPTL6 can predict incident diabetes and explore whether glucose or insulin can regulate ANGPTL6 expression and secretion.DesignThis cohort study included adults without diabetes at baseline who were followed every 2 years for incident diabetes. Serum ANGPTL6 concentrations were measured at baseline and during oral glucose tolerance tests (OGTTs). A hepatic cell line, HepG2, and diet-induced obesity mouse model were used to evaluate the response of ANGPTL6 expression and secretion to hyperglycemia and the metabolic syndrome.ResultsWe recruited 1103 participants without diabetes at baseline. During the 4.22-year follow-up, 113 (10.2%) participants developed incident diabetes. Serum ANGPTL6 was negatively associated with the incidence of diabetes (adjusted hazard ratio, 0.77; P = 0.042). However, serum ANGPTL6 level was higher in participants with prediabetes (P = 0.018) and was elevated during OGTT. In HepG2 cells, treatment with glucose, but not insulin, induced ANGPTL6 expression. Hepatic ANGPTL6 expression and serum ANGPTL6 concentrations were significantly higher in mice fed with a high-fat diet than in those fed with a standard chow (both P < 0.05).ConclusionA high serum ANGPTL6 level is associated with a low incidence of diabetes in humans. ANGPTL6 is expressed and secreted in response to hyperglycemia to maintain glucose homeostasis.
      PubDate: Tue, 03 Mar 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa103
      Issue No: Vol. 105, No. 5 (2020)
  • Serum Androgens Are Independent Predictors of Insulin Clearance but Not of
           Insulin Secretion in Women With PCOS
    • Authors: Tosi F; Dal Molin F, Zamboni F, et al.
      Abstract: AbstractContext/ObjectiveIn insulin-resistant individuals, hyperinsulinemia is a key compensatory mechanism, aimed at maintaining glucose homeostasis. Increased secretion and reduced clearance of insulin may both potentially contribute to this phenomenon. Insulin resistance and hyperinsulinemia are common findings in women with polycystic ovary syndrome (PCOS). While there is some information on insulin secretion, very few studies have investigated metabolic clearance rate of insulin (MCRI) in these women. Moreover, there is paucity of data on the relationships between MCRI and the pathophysiological characteristics of PCOS. The aim of the study was to explore these issues.PatientsOne hundred ninety women with PCOS, diagnosed according to the Rotterdam criteria, with normal glucose tolerance.DesignAssessment of MCRI and clinical, hormonal, and metabolic characteristics of subjects. MCRI and insulin sensitivity were measured by the hyperinsulinemic euglycemic clamp. Serum androgens were assessed by liquid chromatography-mass spectrometry and equilibrium dialysis. A historical sample of healthy women was used to define the corresponding reference intervals.ResultsMCRI was impaired in about two-thirds of women with PCOS. Subjects with low MCRI differed from those with normal MCRI for a number of anthropometric, metabolic, and endocrine features. In multivariate analysis, the degree of adiposity, estimates of insulin secretion, and serum androgen concentrations were independent predictors of MCRI. Conversely, age, adiposity, MCRI, and insulin sensitivity, but not serum androgens, were independent predictors of insulin secretion.ConclusionsIn women with PCOS, metabolic clearance of insulin is reduced, contributing to generating hyperinsulinemia. Serum androgens are independent predictors of this phenomenon.
      PubDate: Mon, 02 Mar 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa095
      Issue No: Vol. 105, No. 5 (2020)
  • Interleukin-6 (IL-6) Activates the NOTCH1 Signaling Pathway Through
           E-Proteins in Endometriotic Lesions
    • Authors: Song Y; Su R, Joshi N, et al.
      Abstract: AbstractContextNOTCH signaling is activated in endometriotic lesions, but the exact mechanisms remains unclear. IL-6, which is increased in the peritoneal fluid of women with endometriosis, induces NOTCH1 through E-proteins including E2A and HEB in cancer.ObjectiveTo study the role of E-proteins in inducing NOTCH1 expression under the regulation of IL-6 in endometriosis.Setting and DesignThe expression of E-proteins and NOTCH1 was first investigated in endometrium of women with endometriosis and the baboon model of endometriosis. Regulation of E-proteins and NOTCH1 expression was examined after IL-6 stimulation and siRNA mediated inhibition of E2A or/and HEB in human endometriotic epithelial cells (12Z) in vitro, and subsequently following IL-6 treatment in the mouse model of endometriosis in vivo.ResultsE2A, HEB, and NOTCH1 were significantly upregulated in glandular epithelium (GE) of ectopic endometrium compared to eutopic endometrium in both women and the baboon model. IL-6 treatment upregulated the expression of NOTCH1 together with E2A and HEB in 12Z cells. Small interfering RNA inhibition of E2A and HEB or HEB alone decreased NOTCH1 expression. Binding efficiency of both E2A and HEB was significantly higher at the binding sites on the human NOTCH1 promoter after IL-6 treatment. Finally, IL-6 treatment resulted in a significantly increased number of endometriotic lesions along with increased expression of E2A, HEB, and NOTCH1 in GE of the lesions compared with the vehicle group in an endometriosis mouse model.ConclusionsIL-6 induced NOTCH1 expression is mediated by E-proteins in the ectopic GE cells, which may promote endometriotic lesion development.
      PubDate: Mon, 02 Mar 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa096
      Issue No: Vol. 105, No. 5 (2020)
  • Recharacterizing the Metabolic State of Energy Balance in Thrifty and
           Spendthrift Phenotypes
    • Authors: Hollstein T; Basolo A, Ando T, et al.
      Abstract: AbstractPurposeThe human thrifty phenotype hypothesis presupposes that lower 24-hour (24h) energy expenditure (24EE) during famine preserves body mass and promotes survival. The prevailing view defines thrifty individuals as having a lower 24EE during fasting. However, it is also plausible that the greater decline in 24EE during fasting in thrifty individuals is due to higher 24EE during energy balance conditions (ENBAL). Herein, we provide evidence that this is indeed the case.MethodsIn 108 healthy subjects, 24EE was measured in a whole-room indirect calorimeter both during ENBAL and 24h fasting conditions. Subjects were categorized as thrifty or spendthrift based on the median value (−162 kcal/day) of the difference in 24EE (adjusted for body composition) between fasting and ENBAL conditions. Concomitant 24h urinary catecholamines were assessed by liquid chromatography–mass spectrometry.ResultsCompared to ENBAL, 24EE decreased during 24h fasting by 172 kcal/day (standard deviation = 93; range, −470 to 122). A greater-than-median decrease in 24EE (“thriftier” phenotype) was due to higher 24EE during ENBAL (+124 kcal/day; P < 0.0001) but not to lower 24EE during fasting (P = 0.35). Greater fasting-induced increase in epinephrine was associated with concomitant lower decrease in 24EE (r = 0.27; P = 0.006).Main ConclusionThe greater decrease in 24EE during acute fasting (which characterizes the thrifty phenotype) is not due to reduced metabolic rate during fasting but to a relatively higher 24EE during feeding conditions, and this decrease in 24EE during fasting is accompanied by a smaller increase in epinephrine. These results recharacterize the prevailing view of the short-term 24EE responses that define the human metabolic phenotypes.Clinical Trials: NCT00523627, NCT00687115, NCT02939404
      PubDate: Mon, 02 Mar 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa098
      Issue No: Vol. 105, No. 5 (2020)
  • Differential Frequency of CYP2R1 Variants Across Populations Reveals
           Pathway Selection for Vitamin D Homeostasis
    • Authors: Casella A; Long C, Zhou J, et al.
      Abstract: AbstractContextNormal vitamin D homeostasis is necessary to ensure optimal mineral metabolism. Dietary insufficiency of vitamin D and the lack of sunlight each have well understood roles in vitamin D deficiency; however, the extent to which common genetic variations in vitamin D metabolizing enzymes contribute to alterations in vitamin D homeostasis remains uncertain.ObjectiveTo examine the possibility that common coding variation in vitamin D metabolizing enzymes alters vitamin D homeostasis we determined the effect of 44 nonsynonymous polymorphisms in CYP2R1, the vitamin D 25-hydroxylase, on enzyme function.ResultsTwenty-one of these polymorphisms decreased activity, while 2 variants increased activity. The frequency of CYP2R1 alleles with decreased 25-hydroxylase activity is 3 in every 1000 Caucasians and 7 in every 1000 African Americans. In populations where exposure to sunlight is high, alleles with decreased function occur at a frequency as high as 8%. The pattern of selected variation as compared to nonselected variation is consistent with it being the result of positive selection for nonfunctional alleles closer to the equator. To examine this possibility, we examined the variation pattern in another protein in the vitamin D pathway, the vitamin D binding protein (GC protein). The pattern of selected variation in the GC protein as compared to nonselected variation is also consistent with it being the result of positive selection for nonfunctional alleles closer to the equator.ConclusionsCYP2R1 polymorphisms have important effects on vitamin D homeostasis, and the geographic variability of CYP2R1 alleles represents an adaptation to differential exposures to UVB irradiation from sunlight.
      PubDate: Mon, 02 Mar 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa056
      Issue No: Vol. 105, No. 5 (2020)
  • Hormonal Profiles of Menstrual Bleeding Patterns During the
           Luteal-Follicular Transition
    • Authors: Jacobson M; Howards P, Kesner J, et al.
      Abstract: AbstractContextMenstrual cycle function is determined by a complex endocrine axis that controls the ovaries and endometrium. While the late luteal phase is characterized by declining progesterone and estrogen, how these hormonal profiles relate to menstrual bleeding patterns is not well understood.ObjectiveCharacterize associations between luteal phase hormonal profiles and subsequent menstrual bleeding patterns, specifically spotting before bleeding.Design, Setting, and ParticipantsWe examined creatinine-adjusted urinary estrone 3-glucuronide (E13G) and pregnanediol 3-glucuronide (Pd3G) levels in relation to spotting in 116 premenopausal women (ages 20–47) who kept daily menstrual diaries and collected first morning urine samples for ≥ 2 consecutive cycles or 1 luteal-follicular transition (n = 283 transitions). We used linear mixed models to estimate associations between luteal phase hormone levels and spotting before bleeding.Main Outcome Measure(s) and ResultsTransitions with ≥ 1 days of spotting before menstrual bleeding (n = 118) had greater luteal phase Pd3G levels vs nonspotting transitions (n = 165). Differences in Pd3G between spotting and nonspotting transitions were largest at menses onset (34.8%, 95% confidence interval, 18.9%, 52.7%). Pd3G levels for spotting transitions dropped to similar levels as nonspotting transitions an average of 1 day later, which aligned with the first day of bleeding for transitions with contiguous spotting. Spotting transitions were preceded by slower rates of Pd3G decline than nonspotting transitions, whereas E13G declines were similar.ConclusionsSelf-reported bleeding patterns may provide insight into luteal phase Pd3G levels. First bleed appears to be the best choice for defining the end of the luteal phase and achieving hormonal consistency across transitions.
      PubDate: Mon, 02 Mar 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa099
      Issue No: Vol. 105, No. 5 (2020)
  • Activating Antibodies to The Calcium-sensing Receptor in
           Immunotherapy-induced Hypoparathyroidism
    • Authors: Lupi I; Brancatella A, Cetani F, et al.
      Abstract: AbstractContextImmune checkpoint inhibitors (ICIs), such as programmed cell death protein-1 (PD-1), programmed cell death protein-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibodies, are approved for the treatment of some types of advanced cancer. Their main treatment-related side-effects are immune-related adverse events (irAEs), especially thyroid dysfunction and hypophysitis. Hypoparathyroidism, on the contrary, is an extremely rare irAE.ObjectivesThe aim of the study was to investigate the etiology of autoimmune hypoparathyroidism in a lung cancer patient treated with pembrolizumab, an anti-PD-1.MethodsCalcium-sensing receptor (CaSR) autoantibodies, their functional activity, immunoglobulin (Ig) subclasses and epitopes involved in the pathogenesis of autoimmune hypoparathyroidism were tested.ResultsThe patient developed hypocalcemia after 15 cycles of pembrolizumab. Calcium levels normalized with oral calcium carbonate and calcitriol and no remission of hypocalcemia was demonstrated during a 9-month follow-up. The patient was found to be positive for CaSR-stimulating antibodies, of IgG1 and IgG3 subclasses, that were able to recognize functional epitopes on the receptor, thus causing hypocalcemia.ConclusionThe finding confirms that ICI therapy can trigger, among other endocrinopathies, hypoparathyroidism, which can be caused by pathogenic autoantibodies.
      PubDate: Sat, 29 Feb 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa092
      Issue No: Vol. 105, No. 5 (2020)
  • Perioperative Glucocorticoid Therapy in Adrenal Insufficiency: What Is the
           Correct Dose'
    • Authors: Salvatori R.
      Abstract: Few endocrinology topics are more controversial and approached more empirically than the perioperative glucocorticoid (GC) treatment of patients with adrenal insufficiency (AI). Since very early reports of adrenal crisis precipitated by surgery in patients with AI (1), treatment with “stress-dose steroids” has been used routinely for surgical procedures in AI patients, despite the paucity of rigorous studies that would address the proper dosing and time frame of GC administration in the perioperative period. Additionally, despite obvious differences between primary and secondary AI (in which an intact renin-angiotensin-aldosterone system is likely to make the disease less dangerous), often the 2 diseases are approached with the same protocols. The Endocrine Society guidelines on treatment of primary AI acknowledged the lack of controlled studies, and noted that adults produce 75 to 100 mg/day of cortisol in response to major surgery and 50 mg/day in response to minor surgery, and that cortisol secretion in the first 24 hours after surgery rarely exceeded 200 mg (2). They note that although lower doses of hydrocortisone (HC) (25-75 mg/24 h) for surgical stress have been advocated in secondary AI, this has not been studied in patients with primary AI. The Society Hypopituitarism Guidelines recommend 25 to 75 mg HC per 24 hours for minor or moderate surgeries, and 100 mg followed by an infusion of 200 mg/24 hours (or 50 mg every 6 hours) for major surgeries, without specifying the exact definition of “major” (3).
      PubDate: Tue, 18 Feb 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa102
      Issue No: Vol. 105, No. 5 (2020)
  • Serum Anti-Müllerian Hormone in the Prediction of Response to hCG
           Stimulation in Children With DSD
    • Authors: Lucas-Herald A; Kyriakou A, Alimussina M, et al.
      Abstract: AbstractIntroductionThe relationship between serum anti-Müllerian hormone (AMH) and the testosterone response to human chorionic gonadotropin (hCG) stimulation test is unclear.MethodsChildren who had hCG stimulation tests in one tertiary centre from 2001 to 2018 were included (n = 138). Serum testosterone was measured before (day 1 [D1]) and after 3 days (D4) of hCG stimulation. Sixty-one of these children also had prolonged hCG stimulation for 2 more weeks and serum testosterone measured after 21 days (D22). All children had a serum AMH measured on D1.ResultsOf the 138 children, D4 testosterone was normal in 104 (75%). AMH was low in 24/138 (17%) children, and 16 (67%) of these had a low D4 testosterone. Median AMH in those who had a normal vs low D4 testosterone was 850 pmol/L (24, 2280) and 54 pmol/L (0.4, 1664), respectively (P < 0.0001). An AMH > 5th centile was associated with a low D4 testosterone in 18/118 (13%; P < 0.0001). Of the 61 children who had prolonged hCG stimulation, D22 testosterone was normal in 39 (64%). AMH was low in 10/61(16%) children and 9 (90%) of these had a low D22 testosterone. Median AMH in children who responded and did not respond by D22 was 639 pmol/L (107, 2280) and 261 pmol/L (15, 1034) (P < 0.0001).ConclusionA normal AMH may provide valuable information on overall testicular function. However, a low AMH does not necessarily predict a suboptimal testosterone response to hCG stimulation.
      PubDate: Tue, 04 Feb 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa052
      Issue No: Vol. 105, No. 5 (2020)
  • Risk Factors for Cardiovascular Disease (CVD) in Adults with Type 1
           Diabetes: Findings from Prospective Real-life T1D Exchange Registry
    • Authors: Shah V; , Bailey R, et al.
      Abstract: ContextCardiovascular disease (CVD) is a major cause of mortality in adults with type 1 diabetes.ObjectiveWe prospectively evaluated CVD risk factors in a large, contemporary cohort of adults with type 1 diabetes living in the United States.DesignObservational study of CVD and CVD risk factors over a median of 5.3 years.SettingThe T1D Exchange clinic network.PatientsAdults (age ≥ 18 years) with type 1 diabetes and without known CVD diagnosed before or at enrollment.Main Outcome MeasureAssociations between CVD risk factors and incident CVD were assessed by multivariable logistic regression.ResultsThe study included 8,727 participants (53% female, 88% non-Hispanic white, median age 33 years [interquartile ratio {IQR} = 21, 48], type 1 diabetes duration 16 years [IQR = 9, 26]). At enrollment, median HbA1c was 7.6% (66 mmol/mol) (IQR = 6.9 [52], 8.6 [70]), 33% used a statin, and 37% used blood pressure medication. Over a mean follow-up of 4.6 years, 325 (3.7%) participants developed incident CVD. Ischemic heart disease was the most common CVD event. Increasing age, body mass index, HbA1c, presence of hypertension and dyslipidemia, increasing duration of diabetes, and diabetic nephropathy were associated with increased risk for CVD. There were no significant gender differences in CVD risk.ConclusionHbA1c, hypertension, dyslipidemia and diabetic nephropathy are important risk factors for CVD in adults with type 1 diabetes. A longer follow-up is likely required to assess the impact of other traditional CVD risk factors on incident CVD in the current era.
      PubDate: Sun, 19 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgaa015
      Issue No: Vol. 105, No. 5 (2020)
  • Thigh Muscle Fat Infiltration Is Associated With Impaired Physical
           Performance Despite Remission in Cushing’s Syndrome
    • Authors: Martel-Duguech L; Alonso-Jiménez A, Bascuñana H, et al.
      Abstract: ContextMuscle weakness is common in patients with Cushing’s syndrome (CS) and may persist after the resolution of hypercortisolism. Intramuscular fatty infiltration has been associated with the deterioration of muscle performance in several conditions.ObjectivesTo quantify the degree of fatty infiltration in the thigh muscles of “cured” CS patients and evaluate the relationship between intramuscular fatty infiltration and physical performance.DesignThis was a cross-sectional study.SettingTertiary referral center.PatientsThirty-six women with CS in remission, and 36 controls matched for age, BMI, menopausal status, and level of physical activity.Main Outcome MeasuresWe analyzed the percentage fat fraction (FF) of the thigh muscles in the anterior, posterior, and combined anterior and posterior compartments using MRI and 2-point Dixon sequence. We assessed muscle function and strength using the following tests: gait speed (GS), timed up and go (TUG), 30-second chair stand, and hand grip strength.ResultsFat fraction in all the compartments analyzed was increased in patients as compared with controls. The performance on TUG, 30-second chair stand, and GS was more impaired in CS patients versus controls. In patients, greater FF was negatively associated with performance on functional tests. Fat fraction in the combined anterior and posterior compartments predicted performance on TUG (ß 0.626, P < 0.000) and GS (ß -0.461, P = 0.007), after adjusting for age, BMI, menopausal status, and muscle mass.ConclusionsThigh muscle fatty infiltration is increased in “cured” CS patients and is associated with poorer muscle performance. Future studies are needed to establish therapeutic strategies to improve muscle weakness in these patients.
      PubDate: Wed, 08 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgz329
      Issue No: Vol. 105, No. 5 (2020)
  • Objective Response and Prolonged Disease Control of Advanced
           Adrenocortical Carcinoma with Cabozantinib
    • Authors: Kroiss M; Megerle F, Kurlbaum M, et al.
      Abstract: BackgroundObjective response of advanced adrenocortical carcinoma (ACC) to mitotane and cytotoxic chemotherapy regimen is only ~20% and early tumor progression is frequent. Previous clinical trials with oral multikinase inhibitors were negative, which has been attributed in part to inadvertent drug interaction with mitotane. Cabozantinib (CABO) is an inhibitor of c-MET, vascular endothelial growth factor receptor 2, AXL, and RET and approved for advanced kidney cancer, liver carcinoma after previous sorafenib, and medullary thyroid carcinoma.ObjectiveTo investigate the clinical efficacy and safety of CABO monotherapy in ACC patients.DesignRetrospective cohort study.SettingThree referral centers for ACC (Germany, United States).ResultsSixteen patients (13 female) with progressive ACC received CABO after previous mitotane in 15/16 and 3 (median, range 0-8) further systemic treatments. Prior CABO therapy, mitotane was discontinued in all patients. Mitotane plasma concentration was <2 mg/L in 7/16 patients and discontinued >12 months in 6 additional patients before CABO use. In 4/5 cases with available plasma samples, CABO concentration was in the expected steady-state range. Adverse events of grade 1/2 and 3 were observed in 13 and 3 patients, respectively, and consistent with the known safety profile of CABO. Best response was partial response in 3, stable disease in 5, and progressive disease in 8 patients. Median progression-free and overall survival was 16 and 58 weeks, respectively.ConclusionCABO monotherapy appears to be safe and effective as a monotherapy in advanced ACC after failing prior treatments. Therefore, prospective investigation of CABO in ACC patients is warranted.
      PubDate: Sat, 04 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgz318
      Issue No: Vol. 105, No. 5 (2020)
  • Postmenopausal Dense Breasts Maintain Premenopausal Levels of GH and
           Insulin-like Growth Factor Binding Proteins in Vivo
    • Authors: Dabrosin N; Dabrosin C.
      Abstract: ContextDense breast tissue is associated with 4 to 6 times higher risk of breast cancer by poorly understood mechanisms. No preventive therapy for this high-risk group is available. After menopause, breast density decreases due to involution of the mammary gland. In dense breast tissue, this process is haltered by undetermined biological actions. Growth hormone (GH) and insulin-like binding proteins (IGFBPs) play major roles in normal mammary gland development, but their roles in maintaining breast density are unknown.ObjectiveTo reveal in vivo levels of GH, IGFBPs, and other pro-tumorigenic proteins in the extracellular microenvironment in breast cancer, in normal breast tissue with various breast density in postmenopausal women, and premenopausal breasts. We also sought to determine possible correlations between these determinants.Setting and DesignMicrodialysis was used to collect extracellular in vivo proteins intratumorally from breast cancers before surgery and from normal human breast tissue from premenopausal women and postmenopausal women with mammographic dense or nondense breasts.ResultsEstrogen receptor positive breast cancers exhibited increased extracellular GH (P < .01). Dense breasts of postmenopausal women exhibited similar levels of GH as premenopausal breasts and significantly higher levels than in nondense breasts (P < .001). Similar results were found for IGFBP-1, -2, -3, and -7 (P < .01) and for IGFBP-6 (P <.05). Strong positive correlations were revealed between GH and IGFBPs and pro-tumorigenic matrix metalloproteinases, urokinase-type plasminogen activator, Interleukin 6, Interleukin 8, and vascular endothelial growth factor in normal breast tissue.ConclusionsGH pathways may be targetable for cancer prevention therapeutics in postmenopausal women with dense breast tissue.
      PubDate: Sat, 04 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgz323
      Issue No: Vol. 105, No. 5 (2020)
  • Delayed Denosumab Injections and Bone Mineral Density Response: An
           Electronic Health Record-based Study
    • Authors: Lyu H; Zhao S, Yoshida K, et al.
      Abstract: ContextDiscontinuation of denosumab leads to a rapid reversal of its therapeutic effect. However, there are no data regarding how unintended delays or missed injections of denosumab impact bone mineral density (BMD) response.ObjectiveWe examined the association of delays in injections of denosumab with BMD change.DesignWe used electronic medical records from two academic hospitals from 2010 to 2017.ParticipantsPatients older than 45 years of age and used at least 2 doses of 60 mg denosumab. Denosumab adherence was evaluated by the medication coverage ratio (MCR). Good adherence corresponds to a dosing interval ≤7 months (defined by MCR ≥93%), moderate adherence corresponds to an interval of 7 to 10 months (MCR 75%–93%), and poor adherence corresponds to an interval ≥10 months (MCR ≤75%).Outcome MeasuresAnnualized percent BMD change from baseline at the lumbar spine, total hip, and femoral neck.ResultsWe identified 938 denosumab injections among 151 patients; the mean (SD) age was 69 (10) years, and 95% were female. Patients with good adherence had an annualized BMD increase of 3.9% at the lumbar spine, compared with patients with moderate (3.0%) or poor adherence (1.4%, P for trend .002). Patients with good adherence had an annualized BMD increase of 2.1% at the total hip, compared with patients with moderate (1.3%) or poor adherence (0.6%, P for trend .002).ConclusionsA longer interval between denosumab injections is associated with suboptimal BMD response at both spine and total hip. Strategies to improve the timely administration of denosumab in real-world settings are needed.
      PubDate: Thu, 02 Jan 2020 00:00:00 GMT
      DOI: 10.1210/clinem/dgz321
      Issue No: Vol. 105, No. 5 (2020)
  • Computerized Analysis of Brain MRI Parameter Dynamics in Young Patients
           With Cushing Syndrome—A Case-Control Study
    • Authors: Tirosh A; RaviPrakash H, Papadakis G, et al.
      Abstract: BackgroundYoung patients with Cushing Syndrome (CS) may develop cognitive and behavioral alterations during disease course.MethodsTo investigate the effects of CS on the brain, we analyzed consecutive MRI scans of patients with (n = 29) versus without CS (n = 8). Multiple brain compartments were processed for total and gray/white matter (GM/WM) volumes and intensities, and cortical volume, thickness, and surface area. Dynamics (last/baseline scans ratio per parameter) were analyzed versus cortisol levels and CS status (persistent, resolved, and non-CS).ResultsTwenty-four-hour urinary free cortisol (24hUFC) measurements had inverse correlation with the intensity of subcortical GM structures and of the corpus callosum, and with the cerebral WM intensity. 24hUFC dynamics had negative correlation with volume dynamics of multiple cerebral and cerebellar structures. Patients with persistent CS had less of an increase in cortical thickness and WM intensity, and less of a decrease in WM volume compared with patients with resolution of CS. Patients with resolution of their CS had less of an increase in subcortical GM and cerebral WM volumes, but a greater increase in cortical thickness of frontal lobe versus controls.ConclusionChanges in WM/GM consistency, intensity, and homogeneity in patients with CS may correlate with CS clinical consequences better than volume dynamics alone.
      PubDate: Thu, 26 Dec 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz303
      Issue No: Vol. 105, No. 5 (2019)
  • Circulating miR-181c-5p and miR-497-5p Are Potential Biomarkers for
           Prognosis and Diagnosis of Osteoporosis
    • Authors: Ma J; Lin X, Chen C, et al.
      Abstract: ContextOsteoporosis is a degenerative bone disease in aging men and women. MiRNAs associated with progressive bone loss in osteoporosis had not been clearly demonstrated.ObjectiveThe evaluation of the differentially expressed miRNAs in the bone tissue and serum of osteoporotic women with aging.MethodsMiRNAs GeneChip and real-time PCR were used to screen differently expressed miRNAs in bone tissues of 21 osteoporotic women ages 60–69 years and 80–89 years. Identified miRNAs were detected in the serum of the validation cohort, which consisted of 14 healthy premenopausal women and 86 postmenopausal women with osteopenia or osteoporosis. MiR-181c-5p and miR-497-5p expression were validated in aging and OVX mice models, and osteoblasts. Their role in osteogenesis was validated in vitro.ResultsTwenty-four miRNAs showed the highest differential expression in bone tissues of osteoporotic women in initial screening. Among them, four miRNAs were identified both in the bone tissue and serum in the validation cohort. The levels of miR-181c-5p and miR-497-5p were decreased in the serum of postmenopausal women with osteopenia or osteoporosis, but increased in subjects treated with bisphosphonate plus calcitriol. MiR-181c-5p and miR-497-5p were significantly downregulated in the bone tissue of aging and OVX mice models, and upregulated during the osteogenic differentiation of hFOB1.19 and MC3T3-E1 cells. Overexpression of miR-181c-5p and miR-497-5p promoted the differentiation and mineralization of osteoblasts.ConclusionsMiR-181c-5p and miR-497-5p are involved in bone metabolism and associated with progressive bone loss of due to osteoporosis, suggesting that circulating miR-181c-5p and miR-497-5p might act as potential biomarkers for monitoring the effects of antiosteoporotic therapies or the diagnostic approach.
      PubDate: Tue, 24 Dec 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz300
      Issue No: Vol. 105, No. 5 (2019)
  • Increased Prevalence of TG and TPO Mutations in Sudanese Children With
           Congenital Hypothyroidism
    • Authors: Bruellman R; Watanabe Y, Ebrhim R, et al.
      Abstract: AbstractContextCongenital hypothyroidism (CH) is due to dyshormonogenesis in 10% to 15% of subjects worldwide but accounts for 60% of CH cases in the Sudan.ObjectiveTo investigate the molecular basis of CH in Sudanese families.DesignClinical phenotype reporting and serum thyroid hormone measurements. Deoxyribonucelic acid extraction for whole-exome sequencing and Sanger sequencing.SettingUniversity research center.PatientsTwenty-six Sudanese families with CH.InterventionClinical evaluation, thyroid function tests, genetic sequencing, and analysis. Our samples and information regarding samples from the literature were used to compare TG (thyroglobulin) and TPO (thyroid peroxidase) mutation rates in the Sudanese population with all populations.ResultsMutations were found in dual-oxidase 1 (DUOX1), dual-oxidase 2 (DUOX2), iodotyrosine deiodinase (IYD), solute-carrier (SLC) 26A4, SLC26A7, SLC5A5, TG, and TPO genes. The molecular basis of the CH in 7 families remains unknown. TG mutations were significantly higher on average in the Sudanese population compared with the average number of TG mutations in other populations (P < 0.05).ConclusionsAll described mutations occur in domains important for protein structure and function, predicting the CH phenotype. Genotype prediction based on phenotype includes low or undetectable thyroglobulin levels for TG gene mutations and markedly higher thyroglobulin levels for TPO mutations. The reasons for higher incidence of TG gene mutations include gene length and possible positive genetic selection due to endemic iodine deficiency.
      PubDate: Mon, 23 Dec 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz297
      Issue No: Vol. 105, No. 5 (2019)
  • Single Islet Autoantibody at Diagnosis of Clinical Type 1 Diabetes is
           Associated With Older Age and Insulin Resistance
    • Authors: Redondo M; Sosenko J, Libman I, et al.
      Abstract: ContextMultiple islet autoantibody positivity usually precedes clinical (stage 3) type 1 diabetes (T1D).ObjectiveTo test the hypothesis that individuals who develop stage 3 T1D with only a single autoantibody have unique metabolic differences.DesignCross-sectional analysis of participants in the T1D TrialNet study.SettingAutoantibody-positive relatives of individuals with stage 3 T1D.ParticipantsAutoantibody-positive relatives who developed stage 3 T1D (at median age 12.4 years, range = 1.4–58.6) and had autoantibody data close to clinical diagnosis (n = 786, 47.4% male, 79.9% non-Hispanic white).Main Outcome MeasuresLogistic regression modeling was used to assess relationships between autoantibody status and demographic, clinical, and metabolic characteristics, adjusting for potential confounders and correcting for multiple comparisons.ResultsAt diagnosis of stage 3 T1D, single autoantibody positivity, observed in 119 (15.1%) participants (72% GAD65, 13% microinsulin antibody assay, 11% insulinoma-associated antigen 2, 1% islet cell antibody, 3% autoantibodies to zinc transporter 8 [ZnT8]), was significantly associated with older age, higher C-peptide measures (fasting, area under the curve, 2-hour, and early response in oral glucose tolerance test), higher homeostatic model assessment of insulin resistance, and lower T1D Index60 (all P < 0.03). While with adjustment for age, 2-hour C-peptide remained statistically different, controlling for body mass index (BMI) attenuated the differences. Sex, race, ethnicity, human leukocyte antigen DR3-DQ2, and/or DR4-DQ8, BMI category, and glucose measures were not significantly associated with single autoantibody positivity.ConclusionsCompared with multiple autoantibody positivity, single autoantibody at diagnosis of stage 3 T1D was associated with older age and insulin resistance possibly mediated by elevated BMI, suggesting heterogeneous disease pathogenesis. These differences are potentially relevant for T1D prevention and treatment.
      PubDate: Mon, 23 Dec 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz296
      Issue No: Vol. 105, No. 5 (2019)
  • The Effect of Perimenopausal Transdermal Estradiol and Micronized
           Progesterone on Markers of Risk for Arterial Disease
    • Authors: Gordon J; Rubinow D, Watkins L, et al.
      Abstract: AbstractBackgroundThe arterial effects of hormone therapy remain controversial. This study tested the effects of transdermal estradiol plus intermittent micronized progesterone (TE + IMP) in healthy perimenopausal and early postmenopausal women on several mechanisms involved in the pathophysiology of arterial disease.MethodsHealthy perimenopausal and early postmenopausal women, ages 45 to 60 years, were enrolled in this randomized, double-blind, placebo-controlled trial. Women were randomized to receive TE (0.1 mg/day) + IMP (200 mg/day for 12 days) or identical placebo patches and pills for 12 months. Outcomes included: change in stress reactivity composite z-score (combining inflammatory, cortisol, and hemodynamic responses to a standardized psychological laboratory stressor); flow-mediated dilation (FMD) of the brachial artery (an index of vascular endothelial function); baroreflex sensitivity; and metabolic risk (presence of the metabolic syndrome or insulin resistance), all assessed at baseline and at months 6 and 12.ResultsOf 172 women enrolled, those assigned to TE + IMP tended to have higher resting baroreflex sensitivity than those assigned to placebo across the 6- and 12-month visits. Although treatment groups did not differ in terms of the other prespecified outcomes, a significant treatment-by-age interaction was found for FMD and stress reactivity such that an age-related decrease in FMD and increase in stress reactivity were seen among women assigned to placebo but not those assigned to TE + IMP. Women on TE + IMP also had lower resting diastolic blood pressure, lower levels of low-density lipoprotein cholesterol, and higher baroreflex sensitivity during stress testing.ConclusionsTE + IMP tended to improve cardiac autonomic control and prevented age-related changes in stress reactivity and endothelial function among healthy perimenopausal and early postmenopausal women.
      PubDate: Sun, 15 Dec 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz262
      Issue No: Vol. 105, No. 5 (2019)
  • Associations Between Maternal Thyroid Function in Pregnancy and Obstetric
           and Perinatal Outcomes
    • Authors: Lee S; Cabral H, Aschengrau A, et al.
      Abstract: ContextThe effects of maternal subclinical hypothyroidism on pregnancy outcomes are not clear.ObjectiveWe aimed to assess potential associations between maternal thyrotropin (thyroid-stimulating hormone [TSH]) levels in pregnancy and obstetric and perinatal outcomes.DesignRetrospective cohort study.SettingTertiary academic medical center.PatientsWomen aged ≥18 years with a singleton gestation and no known thyroid disease seen for prenatal care at Boston Medical Center from January 1, 2003 through May 22, 2014, and their fetuses and infants were included.Main Outcome MeasuresRisk ratios of adverse obstetric and perinatal outcomes.ResultsA total of 8,413 pregnant women (mean age 29.1 years, 15% white, 60% black, 13% Hispanic) and their fetuses and infants (mean gestational age at birth 38.5 weeks, 52% male, mean birth weight 3.2 kg) were included in the analyses. The median (interquartile range) TSH level was 1.06(0.62–1.60) mIU/L, and 130 women (1.6%) had TSH > 4 mIU/L. Maternal TSH levels > 4 mIU/L were associated with increased risks of prematurity (risk ratio [RR] 2.17 [95% confidence interval 1.15–4.07] P = .016) and neonatal respiratory distress syndrome (RDS) (RR 2.83 [95% confidence interval 1.02–7.86] P = .046) compared to TSH levels ≤ 4 mIU/L. Although not statistically significant, TSH levels > 4 mIU/L were also associated with increased RRs for fetal loss, preeclampsia/eclampsia, and low birth weight. TSH levels > 4 mIU/L were not associated with preterm labor, placental abruption, cesarean section, gestational hypertension or diabetes, or neonatal intensive care unit admission.ConclusionMaternal serum TSH concentration > 4 mIU/L in pregnancy was associated with approximately 2-fold increased risks of prematurity and RDS in offspring. Elevated TSH was also associated with statistically non-significant increases in the risk of fetal loss, preeclampsia/eclampsia, and low birth weight.
      PubDate: Sun, 15 Dec 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz275
      Issue No: Vol. 105, No. 5 (2019)
  • Pioglitazone for the Primary and Secondary Prevention of Cardiovascular
           and Renal Outcomes in Patients with or at High Risk of Type 2 Diabetes
           Mellitus: A Meta-Analysis
    • Authors: Zhou Y; Huang Y, Ji X, et al.
      Abstract: ContextThe goal of the meta-analysis was to evaluate the effect of pioglitazone on the primary and secondary prevention of cardiovascular diseases (CVDs) and renal adverse events in patients with or at high risk of type 2 diabetes mellitus (T2DM).DesignRandomized controlled trials (RCTs) comparing pioglitazone with any control were identified through PubMed, Embase, and the Cochrane Library. Cardiovascular outcomes included major adverse cardiovascular events (MACEs, defined as the composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death), hospitalization for heart failure, and all-cause mortality. Renal outcomes included change in urinary albumin to creatinine ratio and 24-hour urinary protein excretion. Weighted mean difference (WMD) and risk ratio (RR) with 95% confidence intervals (CIs) were pooled.ResultsA total of 26 studies with 19 645 participants were enrolled. Pioglitazone reduced the risk of MACE (RR, 0.8 [95% CI, 0.7–0.9]), with benefit only seen in patients with a history of established CVDs (0.8 [0.7–0.9]) and not in those without (1.0 [0.7–1.3]). Regarding the individual components, pioglitazone reduced the risk of nonfatal myocardial infarction (0.8 [0.6–1.0]) and nonfatal stroke (0.8 [0.7–0.9]), which was confined to patients with a history of established CVDs, whereas no treatment effect was found on cardiovascular death (1.0 [0.7–1.2]) regardless of the presence of established CVDs. Pioglitazone increased the risk of hospitalization for heart failure (1.3 [1.1–1.6]) and had no treatment effect on all-cause mortality (1.0 [0.8–1.1]). Pioglitazone reduced albuminuria by 18.5% (WMD 18.5% [95% CI, 21.1-16.0]), with a similar benefit in patients with different renal function categories.ConclusionsPioglitazone should be considered in patients with or at high risk of T2DM for the prevention of cardiovascular endpoints, especially in those with a history of established CVD who might benefit the most. Robust reductions in progression of renal disease are seen regardless of baseline renal function degree.
      PubDate: Tue, 10 Dec 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz252
      Issue No: Vol. 105, No. 5 (2019)
  • Metrics of Diabetes Risk Are Only Minimally Improved by Exercise Training
           in Postmenopausal Breast Cancer Survivors
    • Authors: Viskochil R; Blankenship J, Makari-Judson G, et al.
      Abstract: ContextInsulin resistance is a risk factor for breast cancer recurrence. How exercise training changes fasting and postglucose insulin resistance in breast cancer survivors is unknown.ObjectiveTo evaluate exercise-induced changes in postglucose ingestion insulin concentrations, insulin resistance, and their associations with cancer-relevant biomarkers in breast cancer survivors.SettingThe University of Massachusetts Kinesiology Department.Participants15 postmenopausal breast cancer survivors not meeting the physical activity guidelines (150 min/week of exercise).InterventionA supervised 12-week aerobic exercise program (60 min/day, 3–4 days/week).Main outcome measuresPostglucose ingestion insulin was determined by peak insulin and area under the insulin curve (iAUC) during a 5-sample oral glucose tolerance test. Insulin sensitivity was estimated from the Matsuda composite insulin sensitivity index (C-ISI). Changes in fitness and body composition were determined from submaximal VO2peak and dual energy X-ray absorptiometry.ResultsParticipants averaged 156.8 ± 16.6 min/week of supervised exercise. Estimated VO2peak significantly increased (+2.8 ± 1.4 mL/kg/min, P < .05) and body weight significantly decreased (–1.1 ± 0.8 kg, P < .05) following the intervention. There were no differences in fasting insulin, iAUC, C-ISI, or peak insulin following the intervention. Insulin was only significantly lower 120 min following glucose consumption (68.8 ± 34.5 vs 56.2 ± 31.9 uU/mL, P < .05), and there was a significant interaction with past/present aromatase inhibitor (AI) use for peak insulin (–11.99 non-AI vs +13.91 AI uU/mL) and iAUC (-24.03 non-AI vs +32.73 AI uU/mL).ConclusionsExercise training had limited overall benefits on insulin concentrations following glucose ingestion in breast cancer survivors but was strongly influenced by AI use.
      PubDate: Wed, 20 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz213
      Issue No: Vol. 105, No. 5 (2019)
  • Dynamic Pituitary–Adrenal Interactions in the Critically Ill after
           Cardiac Surgery
    • Authors: Gibbison B; Keenan D, Roelfsema F, et al.
      Abstract: ContextPatients with critical illness are thought to be at risk of adrenal insufficiency. There are no models of dynamic hypothalamic–pituitary–adrenal (HPA) axis function in this group of patients and thus current methods of diagnosis are based on aggregated, static models.ObjectiveTo characterize the secretory dynamics of the HPA axis in the critically ill (CI) after cardiac surgery.DesignMathematical modeling of cohorts.SettingCardiac critical care unit.Patients20 male patients CI at least 48 hours after cardiac surgery and 19 healthy (H) male volunteers.InterventionsNone.Main Outcome MeasuresMeasures of hormone secretory dynamics were generated from serum adrenocorticotrophic hormone (ACTH) sampled every hour and total cortisol every 10 min for 24 h.ResultsAll CI patients had pulsatile ACTH and cortisol profiles. CI patients had similar ACTH secretion (1036.4 [737.6] pg/mL/24 h) compared to the H volunteers (1502.3 [1152.2] pg/mL/24 h; P = .20), but increased cortisol secretion (CI: 14 447.0 [5709.3] vs H: 5915.5 [1686.7)] nmol/L/24 h; P < .0001). This increase in cortisol was due to nonpulsatile (CI: 9253.4 [3348.8] vs H: 960 [589.0] nmol/L/24 h, P < .0001), rather than pulsatile cortisol secretion (CI: 5193.1 [3018.5] vs H: 4955.1 [1753.6] nmol/L/24 h; P = .43). Seven (35%) of the 20 CI patients had cortisol pulse nadirs below the current international guideline threshold for critical illness-related corticosteroid insufficiency, but an overall secretion that would not be considered deficient.ConclusionsThis study supports the premise that current tests of HPA axis function are unhelpful in the diagnosis of adrenal insufficiency in the CI. The reduced ACTH and increase in nonpulsatile cortisol secretion imply that the secretion of cortisol is driven by factors outside the HPA axis in critical illness.
      PubDate: Mon, 18 Nov 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz206
      Issue No: Vol. 105, No. 5 (2019)
  • Letter to the Editor: “Adrenalectomy Completely Cured Hypertension in
           Familial Hyperaldosteronism Type I Patients with Somatic KCNJ5 Mutation”
    • Authors: Almeida M.
      Abstract: In this very interesting case report, Lin et al (1) described two siblings with primary aldosteronism (PA) due to glucocorticoid-remediable aldosteronism (GRA) and an unilateral aldosteronoma harboring a KCNJ5 somatic mutation (p.G151R). Adrenal venous sampling lateralized for the adenoma side in both cases. This is the first report of an aldosteronoma with KCNJ5 somatic mutation in GRA patients. Surprisingly, the 2 siblings presented hypertension (HT) remission after unilateral adrenalectomy. Besides clinical outcome, it would be interesting to show biochemical reevaluation (aldosterone and renin levels) after adrenalectomy, but these data were not included in the article. These findings suggest that GRA patients whose blood pressure control have become resistant to glucocorticoids can potentially benefit from a lateralization test.
      PubDate: Mon, 21 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz107
      Issue No: Vol. 105, No. 5 (2019)
  • Response to Letter to the Editor: “Adrenalectomy Completely Cured
           Hypertension in Familial Hyperaldosteronism Type I Patients with Somatic
           KCNJ5 Mutation”
    • Authors: Lin Y; Peng K, Chang C, et al.
      Abstract: We would like to thank Dr. Madson Q. Almeida for his interest in our paper and for taking the time to express his concerns and emphasis of the unique impact of the KCNJ5 mutation on primary aldosteronism (PA), which is also a highlighting spot of our article (1).
      PubDate: Mon, 21 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz110
      Issue No: Vol. 105, No. 5 (2019)
  • Genetic Modifiers of Cystic Fibrosis-Related Diabetes Have Extensive
           Overlap With Type 2 Diabetes and Related Traits
    • Authors: Aksit M; Pace R, Vecchio-Pagán B, et al.
      Abstract: AbstractContextIndividuals with cystic fibrosis (CF) develop a distinct form of diabetes characterized by β-cell dysfunction and islet amyloid accumulation similar to type 2 diabetes (T2D), but generally have normal insulin sensitivity. CF-related diabetes (CFRD) risk is determined by both CFTR, the gene responsible for CF, and other genetic variants.ObjectiveTo identify genetic modifiers of CFRD and determine the genetic overlap with other types of diabetes.Design and PatientsA genome-wide association study was conducted for CFRD onset on 5740 individuals with CF. Weighted polygenic risk scores (PRSs) for type 1 diabetes (T1D), T2D, and diabetes endophenotypes were tested for association with CFRD.ResultsGenome-wide significance was obtained for variants at a novel locus (PTMA) and 2 known CFRD genetic modifiers (TCF7L2 and SLC26A9). PTMA and SLC26A9 variants were CF-specific; TCF7L2 variants also associated with T2D. CFRD was strongly associated with PRSs for T2D, insulin secretion, postchallenge glucose concentration, and fasting plasma glucose, and less strongly with T1D PRSs. CFRD was inconsistently associated with PRSs for insulin sensitivity and was not associated with a PRS for islet autoimmunity. A CFRD PRS comprising variants selected from these PRSs (with a false discovery rate < 0.1) and the genome-wide significant variants was associated with CFRD in a replication population.ConclusionsCFRD and T2D have more etiologic and mechanistic overlap than previously known, aligning along pathways involving β-cell function rather than insulin sensitivity. Two CFRD risk loci are unrelated to T2D and may affect multiple aspects of CF. An 18-variant PRS stratifies risk of CFRD in an independent population.
      PubDate: Sat, 19 Oct 2019 00:00:00 GMT
      DOI: 10.1210/clinem/dgz102
      Issue No: Vol. 105, No. 5 (2019)
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Edinburgh, EH14 4AS, UK
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