Clinical Endocrinology

Wiley Online Library : Clinical Endocrinology
  • Higher IGFB3 is associated with increased incidence of colorectal cancer in older men independently of IGF1
    Objective Insulin-like growth factor 1 (IGF1) has anabolic and growth-promoting effects, raising concerns regarding its potential to promote tumour growth. Circulating IGF1 is bound to binding proteins, which modulate bioavailability of IGF1. This study assessed the associations of IGF1 and its binding proteins 1 (IGFBP1) and 3 (IGFBP3) with cancer risk. Design A prospective cohort study of 4042 men aged ≥70 years. Methods Plasma total IGF1, IGFBP1 and IGFBP3 were measured between 2001-2004. Cancer-related outcomes were assessed until 20th June 2013 using data linkage. Analyses were performed using proportional hazards models with death as a competing risk, and adjustments were made for potential confounders. Results are expressed as subhazard ratios (SHR). Results There were 907 men who were diagnosed with cancer during a median of 9 years follow-up. Of these, there were 359, 139 and 125 prostate, colorectal and lung cancers respectively. After adjustments, total IGF1 was not associated with the incidence of any cancer, prostate, lung or colorectal cancer. In the fully-adjusted model, higher IGFBP3 was associated with increased incidence of colorectal cancer (SHR=1.20, 95% CI 1.01-1.43; p=0.041 for every 1 standard deviation increase in IGFBP3) but not other cancers. This effect was not attenuated by inclusion of total IGF1 into the multivariate model (SHR=1.28, 95% CI 1.03-1.58; p=0.025). Neither total IGF1, IGFBP1 or IGFBP3 were associated with cancer-related deaths. Conclusion Higher IGFBP3 predicted increased incidence of colorectal cancer in older men independent of conventional risk factors and total IGF1. Further studies are warranted to explore potential underlying mechanisms. This article is protected by copyright. All rights reserved.
  • Males with prolactinoma are at increased risk of incident cardiovascular disease
    Objective To investigate whether the risk of incident cardiovascular disease (CVD) is increased in patients with prolactinoma. Design Population-based, retrospective, open-cohort study using The Health Improvement Network (THIN) database. Patients 2,233 patients with prolactinoma and 10,355 matched controls (1:5 ratio) from UK General Practices contributing to THIN were included. Sex, age, body mass index, and smoking status were used as matching parametres. The primary outcome was any incident CVD, defined by Read codes suggesting myocardial infarction, angina pectoris, stroke, transient ischaemic attack or heart failure. Sex-specific adjusted incidence rate ratios (aIRRs) were calculated with Poisson regression, using clinically relevant parameters as model covariates. Sensitivity analyses were performed to check whether a change in the initial assumptions could have an impact on the findings. Results During the 6-year observation period, the composite CVD outcome was recorded in 54 patients with prolactinoma and 180 “non-exposed” individuals. The incidence rate was 1.8 and 14.8 per 1000 person-years for the females and males with prolactinoma, respectively. The aIRRs for CVD were estimated at 0.99 [95% Confidence Interval (CI): 0.61-1.61, p=0.968)] in female patients and 1.94 (95% CI: 1.29-2.91, p-=0.001) in male patients. These findings remained robust in sensitivity analyses restricting to patients with documented record of dopamine agonist treatment and those with newly diagnosed prolactinoma. Conclusions In contrast to females, men with prolactinoma have increased risk for incident CVD; the aetiology of this gender-specific finding remains to be elucidated This article is protected by copyright. All rights reserved.
  • Women with polycystic ovary syndrome demonstrate worsening markers of cardiovascular risk over the short-term despite declining hyperandrogenaemia: Results of a longitudinal study with community controls
    Objective To compare age-associated changes in cardiovascular risk markers in lean and obese reproductive-aged women with polycystic ovary syndrome (PCOS) with community controls Design Longitudinal study at an academic medical centre. Patients Patients diagnosed with PCOS by 2004 Rotterdam criteria in a multi-disciplinary clinic were systematically enrolled from 2006-2014 in a PCOS cohort study and subsequently agreed to participate in a longitudinal study. The comparison controls were from the prospective, longitudinal Ovarian Aging (OVA) study, which consists of healthy women with regular menstrual cycles recruited from 2006 to 2011. Measurements Cardiovascular risk markers and hormone parameters at baseline and follow-up. Results Obese and lean PCOS (n=38) and control women (n=296) completed two study visits. The follow-up time (3.5+1.5 vs 4.0±0.8 years, p=0.06) and magnitude of BMI gain (+0.1 kg/m2/year [-0.11, 0.36] vs +0.26 [-0.18, 0.87] p=0.19) did not differ between obese and lean PCOS and controls. In PCOS subjects, total testosterone decreased in both obese and lean, but the decrease was greater in obese subjects (-0.09nmol/l per year; 95% CI:-0.16,-0.02 versus -0.04 nmol/l per year; 95%CI:-0.11, 0.03). Compared to their respective controls, obese and lean PCOS saw worsening triglyceride (TG) levels (p<0.05) and HOMA-IR (p<0.05) over time, but there was no difference in change in LDL, HDL, fasting glucose, C- reactive protein or ALT. Conclusions In a longitudinal study, reproductive-aged women with PCOS demonstrated declines in biochemical hyperandrogenaemia over time. Despite this, PCOS subjects experienced steeper increases in cardiovascular risk factors associated with insulin resistance, including triglycerides and HOMA-IR. This article is protected by copyright. All rights reserved.
  • The effects of low-dose human chorionic gonadotropin combined with human menopausal gonadotropin protocol on women with hypogonadotropic hypogonadism undergoing ovarian stimulation for in vitro fertilization
    Objectives To investigate the effects of low-dose human chorionic gonadotropin (hCG) combined with human menopausal gonadotropin (HMG) protocol on cycle characteristics and outcomes of infertile women with hypogonadotropic hypogonadism (HH) undergoing ovarian stimulation for in vitro fertilization (IVF). Design A retrospective cohort study. Setting Tertiary-care academic medical centre. Patient(s) Forty-six infertile patients with HH and seventy-one infertile patients with tubal factor (TF) infertility undergoing IVF. Intervention(s) In the study group, all 46 HH patients were given low-dose hCG (50-300IU/d) in combination with HMG daily from cycle day 3. Meanwhile, a control group consisting of 71 patients with tubal factor infertility was set up, where the infertile women were given triptorelin 3.75 mg on cycle day 3 for desensitization and started stimulation with HMG only 5 weeks later. Transvaginal ultrasound and serum sex steroids were used for monitoring the development of follicles. Ovulation was triggered by hCG 5000IU when dominant follicles matured. Viable embryos were transferred on the third day after ovum pickup or cryopreserved for later transfer. Main Outcome Measure(s) The primary outcome measure was the clinical pregnancy rate. Secondary outcomes included hCG day P4, ratio of E2/follicle count, number of oocytes retrieved, number of viable embryos, implantation rate, ongoing pregnancy rate and cumulative pregnancy rate. Result(s) With lower basal FSH, LH and E2, HH patients showed longer HMG stimulation duration (13 (10-22) d vs 12 (8-18) d, P < .001) and higher HMG dose (2960 ± 560 IU vs 2663 ± 538 IU, P = .005). Whilst the antral follicle count (AFC), number of follicles with diameters greater than 10mm on trigger day and oocytes retrieved were less in the HH group, the number of follicles with diameters greater than 14 mm and viable embryos were comparable. The ratio of E2/follicle count (>10 mm) and E2/follicle count (>14 mm) were distinctively higher in the HH group (1056 ± 281 vs 830 ± 245, P < .001; 1545 ± 570 vs 1312 ± 594pmol/L, P = .037; respectively). The clinical pregnancy rate, implantation rate, ongoing pregnancy rate and cumulative pregnancy rate per woman were comparable between the two groups. Comparison among the subgroups with different hCG dosage showed that HMG duration shortened with the increase of daily hCG dose (14.84 ± 2.88 vs 13.96 ± 2.63 vs 12.96 ± 1.30 days, P = .037). No significant differences were detected in outcomes between fresh embryo transfer (ET) group and frozen-thawed embryo transfer (FET) group. Conclusion(s) Low-dose hCG combined with HMG is a feasible protocol for HH women undergoing ovarian stimulation in IVF, providing favourable cycle characteristics and pregnancy rates. Low-dose hCG reduces HMG duration, whilst the hCG dose and embryo quality are not positively correlated. The outcomes of FET are comparable to ET, which provides a greater chance of success from IVF in the low responders with HH.
  • Clinical features and prognosis of thymic neuroendocrine tumours associated with multiple endocrine neoplasia type 1: A single-centre study, systematic review and meta-analysis
    Objective Thymic neuroendocrine tumour (TH-NET) accounts for almost 20% of multiple endocrine neoplasia type 1 (MEN1)-associated mortality. Identifying risk factors for the development of these rare tumours and prognostic factors for clinical outcomes will be helpful in clinical practice. Design and Patients We performed a retrospective analysis of patients treated for TH-NET associated with MEN1 in a single institution and meta-analysis of literature reports. We used a fixed effect model to pool results across studies to evaluate the prevalence, clinical features and prognosis. Results TH-NET was detected in 9 (7.4%) of 121 patients with MEN1 seen in our institution, and 5 (55.6%) were women. Seven additional studies were identified through a systematic review of the literature. The pool estimate of TH-NET prevalence was 3.7% (n = 99) in MEN1 (n = 2710), sex ratio was 79:20 (male vs female), and the median age at diagnosis was 43.0 years (range, 16.0-72.0 years). Forty-three patients died with a median survival time of 8.4 years. Older age at diagnosis (HR = 1.4, 95% CI = 1.0-1.8, P = .03), maximum tumour diameter (HR = 1.5, 95% CI = 1.0-2.3, P = .04) and presence of metastasis (HR = 1.6, 95% CI = 1.0-2.5, P = .04) were associated with worse outcome. A male predominance (91.9% vs 59.5%, P < .001) and history of smoking (59.0% vs 23.5%, P = .015) were more common in American/European series compared to Asian reports. Conclusion TH-NET is a rare but fatal component of MEN1. Earlier detection of TH-NET in patients with MEN1 may be recommended which should theoretically result in better outcomes. Different genetic backgrounds (race) appear to result in clinical difference.
  • The risk of metabolic syndrome in polycystic ovary syndrome: A systematic review and meta-analysis
    Background and Objective Polycystic ovary syndrome (PCOS) is a common heterogeneous endocrine disorder associated with metabolic syndrome (MetS). The aim of this systematic review and meta-analysis was to provide the most reliable estimate risk of MetS in women with PCOS, compared to healthy controls. Methods A comprehensive literature search was performed in PubMed [including Medline], Web of Science and Scopus databases for retrieving articles in English language on the prevalence/incidence and odds of MetS in women with PCOS compared to healthy controls. Mantel-Haenszel methods of meta-analysis were used to present results in terms of the pooled odds ratio (OR) (95% confidence interval [CI]) using fixed/random-effects models with/without the publication bias correction, based on the various subgroups of age and study methods. Newcastle-Ottawa Scaling and The Cochrane Collaboration's risk of bias assessment tool were used to evaluate the quality of studies included. Results The search strategy yielded 2759 potentially relevant articles of which 44 articles were included for meta-analysis. Results of the meta-analysis demonstrated that the patients with PCOS regardless of age, BMI and recruitment sources of samples had higher odds of MetS compared to healthy controls (OR 2.5, 95% CI 2.0-3.2). However, adolescents with PCOS had an increased odds of MetS compared to healthy adolescent controls in population- and nonpopulation-based studies (OR 4.7, 95% CI 1.8-11.9; OR 6.1, 95% CI 6.0- 6.1, respectively). However, the odds of MetS had no differences between adults with PCOS compared to healthy controls in population-based studies. These results were confirmed by the subgroup meta-analysis of some studies using age and BMI adjustment/matching. In addition, subgroup analysis based on diagnostic criteria of PCOS showed that the OR of MetS in PCOS using NIH criteria was higher than AES and Rotterdam criteria (Pooled Overall OR based on NIH criteria = 6.05, 95% CIL: 6.0-6.04). Conclusion These findings provide some information on the real features and a broader view of this syndrome that also helps clarify conflicting results documented in the literature. Accordingly, in prevention strategies, routine screening for metabolic syndrome is suggested for adolescents with PCOS.
  • Gain-of-Function Mutations in G-protein Coupled Receptor Genes Associated with Human Endocrine Disorders
    The human genome encodes more than 700 G-protein coupled receptors (GPCRs), many of which are involved in hormone secretion. To date, more than 100 gain-of-function (activating) mutations in at least ten genes for GPCRs, in addition to several loss-of-function mutations, have been implicated in human endocrine disorders. Previously reported gain-of-function GPCR mutations comprise various missense substitutions, frameshift mutations, intragenic inframe deletions, and copy-number gains. Such mutations appear in both germline and somatic tumour cells, and lead to various hormonal abnormalities reflecting excessive receptor activity. Phenotypic consequences of these mutations include distinctive endocrine syndromes, as well as relatively common hormonal abnormalities. Such mutations encode hyperfunctioning receptors with increased constitutive activity, broadened ligand specificity, increased ligand sensitivity, and/or delayed receptor desensitization. Furthermore, recent studies proposed a paradoxical gain-of-function mechanism caused by inactive GPCR mutants. Molecular diagnosis of GPCR activating mutations serves to improve the clinical management of mutation-positive patients. This review aims to introduce new aspects regarding gain-of-function mutations in GPCR genes associated with endocrine disorders. This article is protected by copyright. All rights reserved.
  • Age-stratified thresholds of anti-Müllerian hormone improve prediction of polycystic ovary syndrome over a population-based threshold
  • Antibiotics, gut microbiome, and obesity
    Antibiotics have been hailed by many as ‘miracle drugs’ that have been effectively treating infectious diseases for over a century, leading to a marked reduction in morbidity and mortality. However, with the increasing use of antibiotics, we are now faced not only with the increasing threat of antibiotic resistance, but also with a rising concern about potential long-term effects of antibiotics on human health, including the development of obesity. The obesity pandemic continues to increase, a problem that affects both adults and children alike. Disruptions to the gut microbiome have been linked to a multitude of adverse conditions, including obesity, type 2 diabetes, inflammatory bowel diseases, anxiety, autism, allergies, and autoimmune diseases. This review focuses on the association between antibiotics and obesity, and the role of the gut microbiome. There is strong evidence supporting the role of antibiotics in the development of obesity in well-controlled animal models. However, evidence for this link in humans is still inconclusive, and we need further well-designed clinical trials to clarify this association. This article is protected by copyright. All rights reserved.
  • Hyperthyroidism in patients with ischemic heart disease after iodine load induced by coronary angiography: long-term follow-up and influence of baseline thyroid functional status
    Objective To study the effect of a iodine load on thyroid function of patients with ischemic heart disease (IHD) and the long-term influence of unknown subclinical hyperthyroidism. Context Subclinical hyperthyroidism is considered an independent risk factors for cardiovascular morbidity of patients with IHD. They routinely undergo coronary angiography with iodine contrast media (ICM) which may induce or even worsen hyperthyroidism. Design A cross-sectional study followed by a longitudinal study on patients with subclinical hyperthyroidism. Patients 810 consecutive IHD outpatients without known thyroid diseases or treatment with drugs influencing thyroid activity undergoing elective coronary angiography. Measurements We evaluated thyroid function either before and 1 month after ICM; patients with thyrotoxicosis at baseline or after ICM were then followed for 1 years. Results 58 patients had hyperthyroidism at baseline (HB, 7.2%), independently associated to FT4 levels, thyroid nodules and family history of thyroid diseases. After ICM, the prevalence of hyperthyroidism was 81 (10%). Hyperthyroidism after ICM was positively predicted by baseline fT4 levels, thyroid nodules, age over 60, male gender, family history of thyroid diseases. Three months after ICM 34 patients (4.2%) still showed hyperthyroidism (22 from HB, 13 treated with methimazole). One year after ICM hyperthyroidism was still present in 20 patients (2.5%, all from HB, 13 treated). Conclusions The prevalence of spontaneous subclinical hyperthyroidism in IHD is surprisingly elevated and is further increased by iodine load, particularly in patients with thyroid nodules and familial history of thyroid diseases, persisting in a not negligible number of them even after one year. This article is protected by copyright. All rights reserved.
  • Weight Gain After Treatment of Graves’ Disease in Children
    Objective The frequency of and risk factors for weight gain in children treated for Graves disease have not been described. We evaluated change in BMI Z score and predictors of weight gain in this population. Design Retrospective review of data from January 2000 to July 2011. Patients 222 children and adolescents with Graves’ disease (ages 2-18 years) evaluated following radioactive iodine administration (RAI) (n=101), thyroidectomy (n=9), and initiation of medical therapy (n=112). Measurements Changes in body mass index Z score over 12 months (ΔBMI-Z0-12). Results All treatment groups in each gender and race increased BMI-Z (median ΔBMI-Z0-12 was positive). T3 levels following RAI (p=.04) and weight lost at time of administration (p=.02) in the RAI group, and free T4 levels in the medical therapy group (p=.03) were positively correlated with ΔBMI-Z0-12. Race was a significant predictor only in the medical therapy group (p=.01). Age negatively correlated with ΔBMI-Z0-12 in both the RAI (p<.001) and medical therapy groups (p=.003). Gender, maximum TSH in the 12 months after RAI, and initial dose of LT4 replacement did not correlate with ΔBMI-Z0-12. The prevalence of overweight and obesity in our cohort was similar to US children. Conclusions Weight gain during treatment for Graves’ disease is common in children, and many children become overweight or obese during treatment. Risk factors include greater degree of hyperthyroidism at presentation and time of RAI and younger age. Weight lost upon presentation may also predict greater weight gain. Control of subsequent hypothyroidism does not appear to affect weight gain. This article is protected by copyright. All rights reserved.
  • Progressive impairment of testicular endocrine function in ageing men: Testosterone and dihydrotestosterone decrease, and luteinizing hormone increases, in men transitioning from the 8th to 9th decades of life
    Context Sex hormone trajectories in ageing men and their health implications remain unclear. We examined longitudinal trajectories and associations of testosterone (T), dihydrotestosterone (DHT), oestradiol (E2), luteinizing hormone (LH) and sex hormone-binding globulin (SHBG) in oldest old men. Design Prospective cohort study. Participants We studied 1025 community-dwelling men median age 75.1 years at baseline with 8.6 years of follow-up. Measurements Baseline and follow-up T, DHT and E2 were assayed using mass spectrometry. Physical performance was assessed at follow-up. Correlations and covariate-adjusted P-values were determined. Results Longitudinal change in T was −2.0%/year, DHT −7.2%/year, LH +7.5%/year, SHBG +5.6%/year while E2 remained stable. Annualized increases in LH correlated with decreases in T and DHT (r = −.20, P < .0001 and r = −.12, P = .0035, respectively). Higher baseline T correlated with better physical performance at follow-up (eg, Step test r = .07, P = .03), as did higher baseline DHT (eg, time to sit–stand [TSS] r = −.07, P = .01). Larger annualized increases in LH predicted poorer physical performance at follow-up (eg, TSS r = .14, P = .001). Higher T at follow-up was associated with better physical performance (eg, TSS r = −.07, P = .04), as were higher DHT and lower LH. At baseline, 24 men (2.4%) had abnormally high LH (>16 IU/L); at follow-up, 175 (17.4%) had high LH of whom 70 had low T (<6.4 nmol/L). Conclusions Annualized increases in LH are associated with declines in T and DHT, and predict poorer subsequent physical performance in oldest old men. Men transitioning from 8th to 9th decades exhibit biochemical evidence of progressively impaired testicular endocrine function, warranting further evaluation.
  • Endocrinopathies with use of cancer immunotherapies
    Background Immunomodulatory therapies, including CTLA-4 and PD-1 inhibitors, provide a directed attack against cancer cells by preventing T cell deactivation. However, these drugs also prevent the downregulation of auto-reactive T cells, resulting in immune-related adverse events (IRAEs). Reports show a varied incidence of endocrine IRAEs, ranging from 0% to 63%. Objective To describe the frequency and clinical characteristics of endocrine IRAEs in patients taking cancer immunomodulatory therapies. Design Retrospective cohort study. Patients A total of 388 patients aged ≥18 years who were prescribed ipilimumab, nivolumab and/or pembrolizumab between 2009 and 2016 at our institution. Measurements Biochemical criteria were used to define endocrine IRAEs, including thyroid, pituitary, pancreas and adrenal dysfunction, following use of immunomodulatory therapies. Results Fifty endocrine IRAEs occurred in our cohort, corresponding to a rate of 12.9%. The most common endocrine IRAEs were thyroid dysfunction (11.1%), with a lower incidence of pituitary dysfunction (1.8% of patients). Conclusions Over 12% of patients receiving ipilimumab, nivolumab and/or pembrolizumab in our study sample developed an endocrine IRAE. Patients who undergo treatment with immunomodulatory therapies should be monitored for the development of endocrine IRAEs.
  • Serum 25-hydroxyvitamin D as a predictor of mortality and cardiovascular events: A 20-year study of a community-based cohort
    Objective Prospective studies, mostly from Europe and North America, suggest that serum 25-hydroxyvitamin D (25(OH)D) is inversely associated with mortality and cardiovascular disease (CVD) risk. Data from other regions are limited, and threshold levels for adverse cardiovascular outcomes are uncertain. We examined serum 25(OH)D as a predictor of total mortality and cardiovascular outcomes in an Australian cohort. Design A 20-year, community-based cohort study. Patients Participants in the 1994/1995 Busselton Health Survey (n = 3946, baseline age 25-84 years). Measurements Baseline serum 25(OH)D and mortality and cardiovascular outcomes to 2014 obtained by record linkage. Results The mean serum 25(OH)D concentration was 60.6 ± 18.0 nmol/L. During 20-year follow-up (excluding the first 2 years), 889 participants died (including 363 from CVD) and 944 experienced a CVD event (including 242 with heart failure). In the full cohort, controlling for Framingham risk score variables, higher baseline 25(OH)D was associated with significantly reduced all-cause mortality (adjusted HR 0.83 per SD increment of 25(OH)D, 95% CI 0.77-0.90), CVD death (HR 0.85, 95% CI 0.74-0.96) and heart failure (HR 0.81, 95% CI 0.69-0.94), but not CVD events (HR 0.99, 0.92-1.07). In restricted cubic spline regression models, serum 25(OH)D below 65 and 55 nmol/L was associated with higher total mortality and higher CVD mortality/heart failure, respectively. In participants without CVD at baseline (n = 3220), results were similar, but hazard ratios were attenuated and associations with CVD mortality no longer significant. Conclusions In an Australian community-based cohort, baseline vitamin D levels below 55-65 nmol/L are predictive of all-cause mortality, CVD death and heart failure.
  • Clinical Case Seminar: Post-menopausal ovarian androgen excess: challenges in diagnostic work-up and management of ovarian thecosis
    A 72 year old female was referred to the Department of Endocrinology with a 20-year history of hirsutes, mostly affecting her face and torso, the initial onset of which dated shortly after menopause age 52 years. There was no history of subfertility, menstrual irregularity, or hyperandrogenism during reproductive life to suggest prior polycystic ovary syndrome (PCOS), with three live births, two miscarriages and one still-birth. This article is protected by copyright. All rights reserved.
  • Disagreement in normative IGF-I levels may lead to different clinical interpretations and GH dose adjustments in GH deficiency
    Introduction and Background Normative data for the iSYS IGF-I assay have been published both in the VARIETE cohort and by Bidlingmaier et al. Aim of the study To investigate whether normative data of the VARIETE cohort lead to differences in Z-Scores for total IGF-I and clinical interpretation compared to normative data of Bidlingmaier et al. Methods We used total IGF-I values previously measured by the IDS-iSYS assay in 102 GH deficient subjects before starting GH treatment and after 12 months of GH treatment. Z-scores were calculated for all samples by using the normative data of the VARIETE cohort and by the normative data reported by Bidlingmaier et al. Results Before GH treatment Z-scores calculated by using the normative data of the VARIETE cohort were significantly lower than those calculated by the normative data of Bidlingmaier et al.: -2.40 (-4.52 to +1.31) (mean (range)) vs. -1.41 (-3.14 to +1.76); p<0.001). After 12 months of GH treatment again the Z-scores based on the normative data of the VARIETE cohort were significantly lower than those based on the normative data of Bidlingmaier et al.: -0.65 (-4.32 to +2.79) vs. 0.21 (-3.00 to +3.28); p<0.001). Conclusions IGF-I Z-scores in 102 GH deficient subjects differed significantly when normative data from two different sources were used. In daily clinical practice this would most likely have led to different clinical interpretations and GH dose adjustments. This article is protected by copyright. All rights reserved.
  • Influence of coexistent Hashimoto's thyroiditis on the extent of cervical lymph node dissection and prognosis in papillary thyroid carcinoma
    Objective Previous studies did not focus on the differences in the extent of cervical lymph node (LN) dissection according to coexistent Hashimoto's thyroiditis (HT) in patients with papillary thyroid carcinoma (PTC) and its clinical impact. We aimed to determine whether extensive cervical LN dissection is responsible for favourable clinical outcomes in PTC patients with HT and whether the coexistence of HT itself has an independent protective effect regardless of LN status. Design Retrospective cohort study. Patients 1369 patients with PTC who underwent total thyroidectomy with central compartment neck dissection. Measurements Metastatic LN ratio, defined as number of metastatic LNs divided by number of removed LNs, was used to evaluate the extent of LN dissection as well as the status of LN metastasis. Disease-free survival and dynamic risk stratification were compared for clinical outcomes. Results Presence of HT did not lower the risk of cervical LN metastasis (61.6% in patients with HT vs 65.1% in patients without HT, P = .292). Patients with HT had significantly larger numbers of removed LNs than patients without HT (11 vs 8, respectively, P < .001). Accordingly, metastatic LN ratio was smaller in patients with HT (P = .002), which was independently associated with structural persistent/recurrent disease (hazard ratio [HR] 2.33, 95% confidence interval [CI] 1.30-4.16, P = .004). HT itself was negatively associated with structural persistent/recurrent disease after adjustment for other clinicopathological factors (HR 0.39, 95% CI 0.18-0.87, P = .020). Conclusions Coexistence of HT itself is an independent factor associated with favourable outcome in PTC patients, regardless of the extent of LN dissection.
  • Decrease of salivary cortisol levels after glucocorticoid dose reduction in patients with adrenal insufficiency: a prospective proof-of-concept study
    Background and aim Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Cortisol measurement in saliva is increasingly being used: we assessed salivary cortisol rhythm in outpatients with AI, in order to provide new insights regarding the management of GC treatment. Materials and methods 19 AI outpatients collected six saliva samples from awakening (Fa, before taking the morning GC therapy), during the day (F1.5h, F6h before the afternoon GC dose, F8.5h, F12h)until bedtime (Fb).We measured daily cortisol exposure by calculating the area under the curve (AUCFaFb).Saliva samples were collected at baseline and one year after GG dose reduction (by at least 5 mg of hydrocortisone) Results Hydrocortisone equivalents decreased from median 25 mg/day (baseline, interquartile range IQR 20-27.5) to 15 mg/day (IQR 15-20, p<0.01). As expected, we observed a reduction of both daily cortisol exposure (AUCFaFb 23982 nmol·h/L, IQR 12635-45369, to 14689 nmol·h/L, IQR 7168-25378, p<0.001) and salivary cortisol levels at F6h (24.8 nmol/l, IQR 20.1-35.7, to 21 nmol/l, IQR 8.7-29.2, p<0.05) and Fb (8.7 nmol/l, IQR 3.4-20.2, to 3.7 nmol/l, IQR 3.0-5.8, p<0.05). None of the patients developed signs or symptoms consistent with AI after GC reduction. Median diastolic blood pressure (DPB) values fell from baseline to the end of follow-up (87.5 mmHg, IQR 80-90, to 80 mmHg, IQR 80-85, p<0.05). The AUCFaFb of patients at baseline was above the reference value (90th percentile of controls) in 12 patients (60%); after the dosage reduction, 30% of patients normalized their daily cortisol exposure (AUCFaFb). Conclusions The reduction of GC treatment in patients with AI resulted in better control of daily cortisol rhythm, measured with salivary cortisol, and in an improvement of DPB. Further studies are needed to ascertain if salivary cortisol could be used as a biomarker to manage GC replacement therapy. This article is protected by copyright. All rights reserved.
  • Prognostic Indicators of Outcomes in Patients with Lung Metastases from Differentiated Thyroid Carcinoma during Long-term Follow-up
    Background Distant metastases, although uncommon, represent maximum disease-related mortality in differentiated thyroid carcinoma (DTC). Lungs are the most frequent sites of metastases. We aimed to evaluate long-term outcomes and identify prognostic factors in metastatic DTC limited to the lungs. Methods This retrospective study included 89 patients with DTC and metastases limited to the lungs, who were treated between 1996 and 2012 at Samsung Medical Center. Progression free survival (PFS) and cancer specific survival (CSS) rates were evaluated according to clinicopathologic factors. Cox regression analysis was used to identify independent factors associated with structural progressive disease (PD) and cancer specific death. Results With a median follow-up of 84 months, the 5- and 10-year CSS rates were 78% and 73%, respectively. Older age at diagnosis (≥ 55 years), radioactive iodine (RAI) non-avidity, pre-operative or late diagnosis of metastasis, and macro-nodular metastasis (≥1 cm) were predictive of decreased PFS and CSS. Multivariate analysis identified older age (p = 0.002), RAI non-avidity (p = 0.045), and pre-operative (p = 0.030) or late diagnosis (p = 0.026) as independent predictors of structural PD. RAI avidity was also independent predictor of cancer specific death (p = 0.025). Conclusion Patients with DTC and metastatic disease limited to the lungs had favorable long-term outcomes. Age, RAI avidity, and timing of metastasis were found to be major factors for predicting prognosis. This article is protected by copyright. All rights reserved.
  • Factitious ACTH-dependent, apparent hypercortisolism: The problem with late-night salivary cortisol measurements collected at home
  • Autoantibodies against the calcium-sensing receptor and cytokines in autoimmune polyglandular syndromes types 2, 3 and 4
    Objective The frequency of autoimmunity against the parathyroid glands in patients with polyglandular autoimmunity that is not due to autoimmune polyendocrine syndrome type 1 (APS1) is unclear. To investigate this, this study aimed to determine the prevalence of autoantibodies against parathyroid autoantigens, calcium-sensing receptor (CaSR) and NACHT leucine-rich-repeat protein 5 (NALP5), in a large group of patients with non-APS1 polyendocrine autoimmunity. Possible occult APS1 was investigated by cytokine autoantibody measurement and AIRE gene analysis. Design, Subjects and Measurements Subjects were 178 patients with APS2, 3 or 4, and 80 healthy blood donors. Autoantibodies against the CaSR, NALP5 and cytokines were measured by immunoprecipitation, radioligand binding assays or ELISA, respectively. Results Four patient samples (2.2%), but none of the controls, were positive for CaSR autoantibodies. NALP5 autoantibodies were not detected in any participant. Eleven patients (6.2%) had cytokine autoantibodies, but none of the control samples was positive. None of the patients with cytokine autoantibodies had any known or novel mutations in the AIRE gene. Conclusions The low prevalence of CaSR autoantibodies indicate a very low level of subclinical parathyroid autoimmunity in APS types 2, 3 and 4. In addition, autoantibodies against cytokines constitute an uncommon feature of non-APS1 polyglandular autoimmunity.
  • Letter to Liu et al.'s “Efficacy of Exenatide on weight loss, metabolic parameters and pregnancy in overweight/obese polycystic ovary syndrome”
  • Primary hyperparathyroidism: Dynamic postoperative metabolic changes
    Objective Little is known about the natural changes in parathyroid function after successful parathyroid surgery for primary hyperparathyroidism. The association of intact parathyroid hormone (iPTH) and calcium (Ca) with “temporary hypoparathyroidism” and “hungry bone syndrome” (HBS) was evaluated. Design Potential risk factors for temporary hypoparathyroidism and HBS were evaluated by taking blood samples before surgery, intra-operatively, at postoperative day (POD) 1, at POD 5 to 7, in postoperative week (POW) 8 and in postoperative month (POM) 6. Patients Of 425 patients, 43 (10.1%) had temporary hypoparathyroidism and 36 (8.5%) had HBS. Measurements The discriminative ability of iPTH and Ca on POD 1 for temporary hypoparathyroidism and HBS. Results Intact parathyroid hormone (IPTH) on POD 1 showed the highest discriminative ability for temporary hypoparathyroidism (C-index = 0.952), but not for HBS. IPTH was helpful in diagnosing HBS between POD 5 and 7 (C-index = 0.708). Extending the model by including Ca resulted in little improvement of the discriminative ability for temporary hypoparathyroidism (C-index = 0.964) and a decreased discriminative ability for HBS (C-index = 0.705). Normal parathyroid metabolism was documented in 139 (32.7%) patients on POD 1 and in 423 (99.5%) 6 months postoperatively, while 2 (0.5%) patients had persistent hyperparathyroidism, one diagnosed between POD 5 and 7 and another at POW 8. No patients suffered from permanent hypoparathyroidism. Conclusions The necessity for Ca and vitamin D3 substitution cannot be predicted with certainty before POD 5 to 7 without serial laboratory measurements. Based on the results, a routine 8-week course of Ca and vitamin D3 treatment seems reasonable and its necessity should be evaluated in a follow-up study.
  • Increased prevalence of fracture and hypoglycaemia in young adults with concomitant type 1 diabetes mellitus and coeliac disease
    Background Both Type 1 diabetes mellitus (T1DM) and coeliac disease (CD) are independently associated with reduced bone mineral density (BMD) and increased fracture risk. Whilst poorer glycaemic control and increased microvascular complications have been described, the literature examining bone health and fractures in adults with concomitant T1DM and CD (T1DM+CD) is limited. Objective To evaluate fracture prevalence and explore associations with glycaemic control, hypoglycaemia and microvascular disease in T1DM+CD compared with T1DM alone. Methods We conducted a retrospective cross-sectional study of young adults with T1DM, who attended diabetes clinics at a large tertiary referral centre between August 2016 and February 2017. Clinical information, radiological and biochemistry results were extracted from medical records. Patients with comorbid chronic kidney disease, glucocorticoid use, hypogonadism and untreated hyperthyroidism were excluded. Results 346 patients with T1DM alone (median age 23 years) and 49 patients with T1DM+CD (median age 24 years) were included. Median age, gender distribution, BMI, haemoglobin A1c, daily insulin dose and serum 25-hydroxyvitamin D levels were similar between groups. Higher adjusted fracture risk was observed in T1DM+CD compared with T1DM (12.2% vs. 3.5%; OR 3.50, 95% CI 1.01–12.12, p=0.01), yet bone mineral density was only measured in 6% of patients. The adjusted risk of hypoglycaemia ≥2/week was greater for T1DM+CD (55% vs. 38%, OR 3.28, 95% CI 1.61–6.69, p=0.001), however this was not independently associated with fractures. Replete vitamin D (≥ 50 nmol/L) was associated with less hypoglycaemia (OR 0.48, 95% CI 0.29-0.80; p=0.005), but not with fractures. Conclusions CD status was independently associated with increased fracture prevalence in young adults with T1DM. Recurrent hypoglycaemia was also increased in T1DM+CD, although hypoglycaemia was not independently associated with fractures. Prospective studies are required to determine the long-term impacts of CD on bone health and on glycemic control in T1DM. This article is protected by copyright. All rights reserved.
  • Multicentre clinical evaluation of the new highly-sensitive Elecsys® thyroglobulin II assay in patients with differentiated thyroid carcinoma
    Objective A highly-sensitive thyroglobulin assay (Elecsys® Tg II, Roche Diagnostics, Penzberg, Germany) has become available for monitoring patients with differentiated thyroid cancer (DTC). Here we evaluated the clinical performance of Elecsys® Tg II assay in a multicentre patients series and compare it with the established Access® Tg assay (Beckman Coulter, Brea, US). Design Retrospective analysis on prospectively selected patients in four thyroid cancer referral centres with uniform DTC management. Participants All DTC cases diagnosed, treated and followed-up in four tertiary referral centres for thyroid cancer since January 2005 (n=1456) were retrieved and predefined selection criteria were applied to prevent relevant enrollment biases. A series of 204 patients was finally selected for the present study. Measurements Samples had been stored at -80° C. Tg was measured by fully automated immunometric Elecsys® Tg II and Access® Tg assays in a centralized laboratory. Results Two hundred and four DTC were finally included. Of these, 10.8% had structural recurrence (sREC) and 81.4% showed no evidence of disease (NED) at the end of follow-up. There was a significant analytical bias between methods that cannot be used interchangeably. Using ROC curve analysis, the best basal and rhTSH-stimulated Tg cutoffs to detect sREC were 0.41 μg/L and 1.82 μg/L for Elecsys® and 0.36 μg/L and 1.62 μg/L for Access® assay, respectively. Using Cox proportional hazard regression, Tg was the only independent predictor of cancer relapse. Conclusions Using appropriate assay-specific cutoffs, the clinical performance of the Elecsys® Tg II assay was comparable to that provided by the well-established Access® Tg assay. This article is protected by copyright. All rights reserved.

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