Clinical Endocrinology

Wiley Online Library : Clinical Endocrinology
  • Is Doppler ultrasonography of value for the differentiation between noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and invasive encapsulated follicular variant of papillary thyroid carcinoma?
  • Hormone therapy and patient satisfaction with treatment, in a large cohort of diverse disorders of sex development
    Objectives To describe and investigate the hormone treatments in individuals with different forms of disorders of sex development (DSD) and the patients’ own views on their treatment. Design Multicentre cross-sectional clinical evaluation, dsd-LIFE in 6 European countries from February 2014 to September 2015. Participants A total of 1040 adolescents and adults (≥16 years) with different DSD conditions. Main outcomes measures Hormone replacement, information received and patient satisfaction. Results Included were women with Turner syndrome (301), 46,XX GD (n = 20), and women with 45,X/46XY (n = 24). Individuals with Klinefelter syndrome (n = 218), 46,XX males (n = 6), individuals with different forms of 46,XY DSD (n = 243): 46,XY DSD conditions (n = 222), men with 45,X/46XY (n = 21) 46,XX CAH, (n = 226). Oestrogen ± progestin was used by 306 (81%) individuals, 72 (19%) received ethinylestradiol and 198 had testosterone treatment. The overall adherence was good, with 10% of women with oestrogen and 5% of those on testosterone had stopped the medication despite 20% reporting dissatisfaction with the treatment, mostly because of psychological side effects. Glucocorticoid replacement in patients with CAH was very seldom stopped. More than 75% were satisfied with the information about the treatment, but the satisfaction with information about treatment options and side effects was lower. Conclusions More than 50% in the total cohort had hormone replacement. Although adherence was generally good, this study shows that hormone replacement therapy may be improved. This may be achieved by better individualization of the treatment and by providing specific information to patients regarding both long-term and short-term hormonal effects and side effects.
  • Translational evidence of prothrombotic and inflammatory endothelial damage in Cushing syndrome after remission
    Objective Sustained evidence from observational studies indicates that after remission of Cushing syndrome (CS) a cardiovascular risk phenotype persists. Here, we performed a translational study in active CS and CS in remission (RCS) to evaluate the subclinical cardiometabolic burden and to explore the direct pro-inflammatory and prothrombotic potential of their sera on the endothelium in an in vitro translational atherothrombotic cell model. Patients Cross sectional study. The groups were (n = 9/group): I. RCS; II. Active CS (ACS) and III. Controls (CTR), all matched for age, body mass index, sex, without other hormonal deficits. Design We evaluated in vivo: cardiometabolic profile; endothelial markers (sVCAM-1, NO); endothelial dysfunction (FMD); intima-media thickness and body composition (DEXA). In vitro endothelial cells (EC) were exposed to sera taken from the different subjects to evaluate inflammatory EC response (tisVCAM) and thrombogenicity of the generated extracellular matrix (ECM): von Willebrand factor (VWF) and platelet reactivity. Results Three of the 9 RCS subjects were on glucocorticoid replacement therapy (GC-RT). Patients on GC-RT had a shorter period of time in stable remission. In vivo analysis ACS showed typically metabolic features, while cardiometabolic markers reached statistical significance for RCS only for Hs-CRP (P < .01). In vitro:EC exposed to ACS and RCS sera displayed increased tisVCAM-1 (P < .01 for ACS and P < .05 for RCS vs CTR), VWF (P < .01 for ACS and P < .05 for RCS vs CTR) and platelet adhesion on ECM (P < .01 for ACC and P < .05 for RCS vs CTR). No statistically significant differences were observed between GC-RT RSC and RCS without GC-RT. Conclusions The sera of premenopausal women with CS in remission, without atherothrombotic disease, contain circulatory endothelial deleterious factors with a direct thrombogenic and pro-inflammatory endothelial effect that could increase cardiovascular risk.
  • Progestin-primed ovarian stimulation with or without clomiphene citrate supplementation in normal ovulatory women undergoing IVF/ICSI: a prospective randomized controlled trial
    Objective To compare the endocrinological profiles, cycle characteristics and pregnancy outcomes of progestin-primed ovarian stimulation (PPOS) with or without clomiphene citrate (CC) supplementation in normal ovulatory women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). Design Prospective randomized controlled study. Patient(s) A total of 320 infertile women undergoing IVF/ICSI. Medroxyprogesterone acetate (MPA) and human menopausal gonadotropin (hMG) were simultaneously administered on menstrual cycle day 3. The women were randomized into two equal groups with or without CC supplementation. Measures The primary outcome measure was the percentage of women with profound pituitary suppression (luteinizing hormone (LH) < 1.0 IU/L on the trigger day). The secondary outcomes were endocrinological profiles, cycle characteristics and pregnancy outcomes. Results The percentage of women with profound pituitary suppression was significantly lower in the study group (hMG + MPA + CC) than in the control group (hMG + MPA) (1.9% vs. 33.1%, P < 0.001). The mean LH level during controlled ovarian stimulation (COS) was higher in the study group than in the control group (P < 0.001), but none of the patients in either group exhibited a premature LH surge. The doses of Gn in the study group were significantly lower than those in the control group (1334.06 ± 212.53 IU vs. 1488.28 ± 325.08 IU, P < 0.001). The number of oocytes retrieved was similar between the two groups (10.03 ± 5.97 vs. 10.34 ± 7.52, P > 0.05). No significant differences were observed in either the number of viable embryos or the pregnancy outcomes between the two groups. Conclusion(s) CC is an effective adjuvant to alleviate pituitary suppression in the PPOS protocol; however, it has no impact on clinical outcomes. This article is protected by copyright. All rights reserved.
  • High risk of hypogonadism in young male cancer survivors
    Objective Cancer and its treatment in childhood and young adulthood can cause hypogonadism, leading to increased risk of long term morbidity and mortality. The aim of this study was to evaluate the risk of presenting with biochemical signs of hypogonadism in testicular cancer survivors (TCS) and male childhood cancer survivors (CCS) in relation to the type of treatment given. Design Case-control study. Patients Ninety-two TCS, 125 CCS (mean age 40 and median age 34 years, respectively; mean follow-up time 9.2 and 24 years, respectively) and a corresponding number of age-matched controls. Measurements Fasting morning blood samples were analyzed for total testosterone (TT), follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The odds ratios (OR) for hypogonadism, defined as either primary, secondary, compensated or ongoing androgen replacement, were calculated for TCS and CCS, and for subgroups defined by diagnosis and treatment. Results Hypogonadism was found in 26% of CCS and 36% of TCS, respectively (OR: 2.1, p=0.025 and OR=2.3, p=0.021). Among CCS, the OR was further increased in those given testicular irradiation (OR=28, p=0.004). Radiotherapy other than cranial or testicular irradiation plus chemotherapy, or cranial irradiation without chemotherapy, associated also with increased ORs (OR=3.7, p=0.013, and OR=4.4, p=0.038, respectively). Among TCS, those receiving >4 cycles of cisplatin-based chemotherapy had OR=17, p=0.015. Conclusions Biochemical signs of testosterone deficiency are recognized as markers of decreased life expectancy. Thus, the risk of hypogonadism in TCS and CCS should be recognized and emphasizes the need of long-term follow-up for these men. This article is protected by copyright. All rights reserved.
  • Twin models of environmental and genetic influences on pubertal development, salivary testosterone, and estradiol in adolescence
    Objective Research on sources of variation in adolescent's gonadal hormone levels is limited. We sought to decompose individual differences in adolescent testosterone, estradiol, and pubertal status, into genetic and environmental components. Design A sample of male and female adolescent twins from the greater Austin and Houston areas provided salivary samples, with a subset of participants providing longitudinal data at 2 waves. Participants The sample included 902 adolescent twins, 49% female, aged 13-20 years (M = 15.91) from the Texas Twin Project. Thirty-seven per cent of twin pairs were monozygotic; 30% were same-sex dizygotic (DZ) pairs; and 33% were opposite-sex DZ pairs. Measurements Saliva samples were assayed for testosterone and estradiol using chemiluminescence immunoassays. Pubertal status was assessed using self-report. Biometric decompositions were performed using multivariate quantitative genetic models. Results Genetic factors contributed substantially to variation in testosterone in males and females in the follicular phase of their menstrual cycle (h2 = 60% and 51%, respectively). Estradiol was also genetically influenced in both sexes, but was predominately influenced by nonshared environmental factors. The correlation between testosterone and estradiol was mediated by a combination of genetic and environmental influences for males and females. Genetic and environmental influences on hormonal concentrations were only weakly correlated with self-reported pubertal status, particularly for females. Conclusions Between-person variability in adolescent gonadal hormones and their interrelationship reflects both genetic and environmental processes, with both testosterone and estradiol containing sizeable heritable components.
  • Central and peripheral leptin and agouti-related protein during and after pregnancy in relation to weight change
    Objective To study changes of neuropeptides and adipokines in cerebrospinal fluid (CSF) and serum from pregnancy to postpregnancy in relation to weight changes, fat mass and glucose metabolism. Context With high postpartum weight retention being a risk factor in future pregnancies and of lifelong obesity, we evaluated neuropeptide and adipokine changes in women who either gained weight or were weight stable. Design Women were followed for 5 ± 1 years after pregnancy and divided into two groups, weight stable and weight gain, by weight change from start of pregnancy. Patients Twenty-five women (BMI 27 ± 5 kg/m2) recruited at admission for elective caesarean section. Measurements CSF and serum levels of agouti-related protein (AgRP), leptin and insulin, and serum levels of adiponectin and soluble leptin receptor were measured during and after pregnancy. These measurements were further related to fat mass and insulin sensitivity (HOMA-IR). Results S-AgRP levels during pregnancy were lower in the weight stable group and a 1 unit increase in s-AgRP was associated with 24% higher odds of pertaining to the weight gain group. After pregnancy, s-AgRP increased in the weight stable group but decreased in the weight gain group. Decreased transport of leptin into CSF during pregnancy was reversed by an increased CSF:serum leptin ratio after pregnancy. In women who returned to their prepregnancy weight, serum adiponectin increased after pregnancy and correlated negatively with HOMA-IR. Conclusion S-AgRP concentration in late pregnancy may be one factor predicting weight change after pregnancy, and circulating AgRP may be physiologically important in the long-term regulation of body weight.
  • Long-term cardiovascular morbidity and mortality in patients treated for differentiated thyroid cancer
    Objectives Thyroid hormone suppression therapy has been widely used in the treatment of thyroid cancer, but concerns have been raised about the cardiovascular risks of this treatment. The objective of this study was to evaluate long-term cardiovascular morbidity and mortality in patients treated for differentiated thyroid cancer (DTC) and to assess the effect of TSH suppression and radioiodine (RAI) treatment on the cardiovascular outcome. Design Retrospective cohort study. Patients and measurements Patients (n = 901) treated for DTC between 1981 and 2002 at 2 Finnish University hospitals were compared with a randomly chosen reference group (n = 4485) matched for age, gender and the place of residence. Kaplan-Meier and Cox regression analyses were used to estimate the risk of morbidity or death due to different cardiovascular diseases (CVD) after the diagnosis of DTC. Results Morbidity due to any CVD (hazard ratio [HR] 1.16, 95% confidence interval [CI] 1.05-1.28) and due to all arrhythmias (HR 1.25, CI 1.06-1.48) and atrial fibrillation (AF) (HR 1.29, CI 1.06-1.57) was more frequent in the DTC patients than in the controls. The increased cardiovascular morbidity was confined to patients with a mean TSH level below 0.1 mU/L (HR 1.27, CI 1.03-1.58) and to those treated with RAI (HR 1.18, CI 1.05-1.31). Cardiovascular mortality, however, was lower among the patients than the controls (HR 0.73, CI 0.58-0.92), due to a lower mortality from coronary artery disease. Conclusions Differentiated thyroid cancer patients have an increased CVD morbidity, which is mostly accountable to AF and to TSH suppression below 0.1 mU/L.
  • Clinical and genetic characteristics of Pseudohypoparathyroidism in the Chinese population
    Background Pseudohypoparathyroidism (PHP) is caused by mutations and epimutations in the GNAS locus, and characterized by the possibility of resistance to multiple hormones and Albright's hereditary osteodystrophy. PHP can be classified into the forms 1A/C, sporadic 1B and familial 1B. Objectives To obtain an overall view of the clinical and genetic characteristics of the Chinese PHP patient population. Methods From 2000 to 2016, 120 patients were recruited and studied using Sanger sequencing, methylation-specific multiple ligation-dependent probe amplification (MS-MLPA) and combined bisulfite restriction analysis (COBRA). Of these patients, 104 had positive molecular alterations indicative of certain forms of PHP and were included in data analysis. Clinical and laboratory features were compared between PHP1A/C and PHP1B patients. Results Ten PHP1A/C, 21 familial PHP1B and 73 sporadic PHP1B patients were identified. Four novel GNAS mutations were discovered in these patients, including c.1038+1G>T, c.530+2T>C, c.880_883delCAAG and c.311_312delAAG, insT. The most common symptoms in this series were recurrent tetany (89.4%) and epilepsy (47.1%). The prevalence of weight excess increased with age for PHP1B (10%-35%) and PHP1A/C (50%-75%). Intracranial calcification had a prevalence of 94.6% and correlated with seizures (r = .227, P = .029). Cataracts occurred in 56.2% PHP patients, and there was a trend towards longer disease duration in patients with cataracts (P = .051). Statistically significant differences (P < .05) were observed when comparing certain clinical characteristics between PHP1B and PHP1A/C patients, including age of onset (10 vs 7 year), short stature (21.3% vs 70%), rounded face (60.6% vs 100%), brachydactyly (25.5% vs 100%), ectopic ossification (1.1% vs 40%) and TSH resistance (44.6% vs 90%), respectively. Conclusions This study is the largest single-centre series of PHP patients and summarizes the clinical and genetic features of the Chinese PHP population. While there was substantial clinical overlap between PHP1A/C and PHP1B, differences in disease progression were observed.
  • Relationships of serum 25-hydroxyvitamin D, ionized calcium and parathyroid hormone after obesity surgery
    Objective The high prevalence of secondary hyperparathyroidism (SHPT) after obesity surgery is a concern for long-term bone health. Limited knowledge exists about optimal vitamin D and suppression of parathyroid hormone (PTH) after these procedures. The aim of this study was to investigate the prevalence of SHPT and its relation to vitamin D status. Design A cross-sectional study at Oslo University Hospital, Norway. Patients 502 consecutive patients, age 22-64 years, attending 2-year follow-up after Roux-en-Y gastric bypass. Measurements A serum intact PTH >7.0 pmol/l in the absence of elevated serum ionized calcium (iCa) was considered as SHPT. Vitamin D status was defined by serum concentrations of 25-hydroxyvitamin D (S-25(OH)D). Results Altogether, 171 patients (34%) had SHPT. The prevalence of SHPT varied across the range of S-25(OH)D (P<0.001), being highest (71%) with S-25(OH)D <25 nmol/l. Compared with S-25(OH)D <50 nmol/l, the prevalence of SHPT was lower with S-25(OH)D ≥50 nmol/l (29.0%; RR=0.64 (95%-CI:0.50-0.81)) and S-25(OH)D ≥75 nmol/l (27.7%; RR=0.61 (95%-CI:0.44-0.84)). S-25(OH)D ≥100 nmol/l was associated with the lowest PTH and the lowest prevalence of SHPT (16.0%; RR=0.35 (95%-CI:0.14-0.88) compared with S-25(OH)D <50 nmol/l), and the most normal calcium distribution. These associations were most pronounced with iCa in the lower range. A synergistic association was found for S-25(OH)D and iCa on SHPT. Conclusions Vitamin D deficient patients had the highest prevalence of SHPT two years after gastric bypass. PTH and the prevalence of SHPT were notably lower with S-25(OH)D ≥100 nmol/l, compared with lower target levels. This article is protected by copyright. All rights reserved.
  • Sex hormone binding globulin is associated with androgen deficiency features independently of total testosterone
    Objective It is recognized that total testosterone (TT) does not sufficiently describe androgen status when sex hormone binding globulin (SHBG) is altered. However, in humans, evidence supporting the existence of a hypogonadism due to low T bioactivity is scanty. The aim of the study was to assess whether changes in SHBG levels, independently of TT, are associated with subjective and objective androgen dependent parameters. Design Cross-sectional observation. Patients 2622 men (aged 51.1±13.5 years) attending a Sexual Medicine and Andrology Outpatient Clinic for sexual dysfunctions. Measurements All patients underwent a standardized diagnostic protocol before starting any treatment. Clinical and biochemical parameters have been collected. Higher ANDROTEST score has been used as a comprehensive marker of more severe hypogonadal symptoms. Prostate specific antigen (PSA) and hematocrit have been used as objective surrogate markers of T bioactivity. Results After adjusting for TT and lifestyle, SHBG showed a significant positive association with ANDROTEST score (B=0.79 [0.61;0.96], p<0.0001). Conversely, higher SHBG, independently of TT, was negatively related to PSA (B=-0.86 [-0.83;-0.89]; p<0.0001) and hematocrit (B=-0.64 [-0.88;-0.40]; p<0.0001), after adjustment for the aforementioned confounders along with age and body mass index. Furthermore, a relationship between SHBG and lipids or blood pressure was found, with lower SHBG levels associated with a worse metabolic profile, independently of TT. Conclusions Higher SHBG, independently of TT, is associated with either subjective or objective androgen deficiency features. This indicates that besides a hypogonadism due to an impaired T production, a hypogonadism due to a lower biological activity of T does exist. This article is protected by copyright. All rights reserved.
  • Cardiac function in pediatric patients with congenital adrenal hyperplasia due to 21 hydroxylase deficiency
    Background Hyperandrogenism and exogenous glucocorticoid excess may cause unfavorable changes in the cardiovascular risk profile of patients with congenital adrenal hyperplasia (CAH). Objective To evaluate the cardiac function in pediatric patients with CAH. Patients and methods 27 pediatric patients with CAH, aged 8-16 years, were evaluated by physical examination, electrocardiogram (ECG), conventional echocardiography, tissue Doppler imaging and two-dimensional (2D) myocardial strain (rate) imaging. Results were compared to 27 age and gender matched healthy controls. Results No signs of left ventricular hypertrophy or dilatation were detected on ECG and echocardiography. ECG revealed a high prevalence (25.9%) of incomplete right bundle branch block. Left ventricular posterior wall thickness in diastole (LVPWd) was significantly lower in patients with CAH compared to controls (5.55 vs 6.53 mm; p=0.009). The LVPWd Z-score was significantly lower in patients with CAH yet within the normal range (-1.12 vs -0.35; p=0.002). Isovolumetric relaxation time was significantly lower in patients with CAH (49 vs 62 ms; p=0.003). Global longitudinal, radial and circumferential strain were not significantly different compared to controls. Global radial strain rate was significantly higher compared to healthy controls (2.58 vs 2.06 1/s; p=0.046). Global longitudinal strain was negatively correlated with 24 hour blood pressure parameters. Conclusion Cardiac evaluation of pediatric patients with CAH showed no signs of left ventricular hypertrophy or ventricular dilatation. LVPWd was lower in patients with CAH than in controls, but within the normal range. A shorter isovolumetric relaxation time in patients with CAH may be a sign of mild left ventricular diastolic dysfunction. This article is protected by copyright. All rights reserved.
  • Anti-Müllerian hormone measurement for the diagnosis of polycystic ovary syndrome
    Objective Anti-Müllerian hormone (AMH) is derived from the small antral follicles, and an elevated level has been suggested to add value to the Rotterdam criteria for the diagnosis of PCOS in cases of diagnostic uncertainty. Therefore, the role of AMH in the classical phenotype of PCOS was defined within a Caucasian population. Design This was a cross-sectional study. Patients Sixty Five women without PCOS and 110 women with PCOS fulfilling all 3 diagnostic Rotterdam criteria. Measurements The main outcomes were the utility of serum AMH for the diagnosis of PCOS and its relationship to the metabolic parameters. Results Anti-Müllerian hormone was increased in PCOS compared to controls (P < .001). Areas under the receiver operator curve showed AMH to be predictive of PCOS (0.76) using a cut-off AMH of 46 pmol/L, which is derived from the 95th percentile of the controls that gave a 41% sensitivity and 86% specificity; an AMH cut-off of 35 pmol/L gave a 55% sensitivity and 79% specificity. Age- and BMI-adjusted multiple logistic regression showed that AMH was more predictive of PCOS independently of either serum testosterone (T) (OR = 4.04; 95% CI 1.42-11.11; P = .007) or free androgen index (FAI) (OR = 3.90; 95% CI 1.40-10.83; P = .009). Conclusion Whilst an elevated AMH has poor sensitivity, it is fourfold more likely to be associated with a diagnosis of PCOS, and supplementary to biochemical parameters will make a positive diagnosis of PCOS in 22% of patients when neither serum testosterone nor FAI is elevated.
  • Multi-disciplinary management of refractory insulinomas
    Insulinomas are predominantly benign (~90%), pancreatic neuroendocrine tumours characterised by hyperinsulinaemic hypoglycaemia. They usually present as a small (<2cm), well demarcated, solitary nodule that can arise in any part of the organ. Treatment of sporadic insulinomas is generally aimed at curative surgical resection with special consideration in genetic syndromes. Patients with significant hypoglycaemia can pose a difficult management challenge. In isolated cases where the patient is not medically fit for surgery or with metastatic spread, other treatment options are employed. Medical therapy with diazoxide or somatostatin analogues are commonly used first-line for symptom control, albeit with variable efficacy. Other medical options are emerging including newer targeted biological therapies, including everolimus (an mTOR inhibitor), sunitinib (a tyrosine kinase inhibitor) and pasireotide, a multi-somatostatin receptor ligand. Pasireotide and everolimus both cause hyperglycaemia by physiological mechanisms synergistic with its anti-tumour/anti-proliferative effects. Minimally invasive treatment modalities such as ethanol ablation are available in selected cases (particularly in patients unfit for surgery), peptide receptor radionuclide therapy (PRRT) can effectively control tumour growth or provide symptomatic benefit in metastatic disease while cytotoxic chemotherapy can be used in patients with higher grade tumours. This review considers the developments in the medical and other non-surgical management options for cases refractory to standard medical management. Early referral to a dedicated neuroendocrine multidisciplinary team is critical considering the array of medical, oncological, interventional radiological and nuclear medical options. We discuss the evolving armamentarium for insulinomas when standard medical therapy fails. This article is protected by copyright. All rights reserved.
  • The association between irisin and muscle metabolism in different thyroid disorders
    Background Irisin is a new adipo-myokine, encoded by the FNDC5 gene. Currently, there is a discussion regarding the relation between thyroid function and irisin concentration. This prospective study assesses the influence of thyrometabolic changes on serum irisin concentration in association with altered muscle metabolism. This is performed on a large cohort of patients affected by severe hypo- or hyperthyroidism, as well as by the expression of the FNDC5 gene in thyroid tissue affected by different pathologies. Methods The study group comprised 119 patients with newly diagnosed severe hyperthyroidism or hypothyroidism, and a control group of 45 healthy subjects. Body composition, serum irisin concentrations, and thyroid-related hormones, creatine kinase, dystrophin and titin concentrations were evaluated. FNDC5 expression was also analyzed in tissue samples from 80 patients with non-toxic multinodular goiter, toxic goiter, Graves’ disease and papillary thyroid cancer. Results Irisin concentration was lower in patients with prolonged hypothyroidism. There was a tendency toward lower dystrophin and titin concentrations in patients with hypothyroidism and hyperthyroidism. Restoration of euthyroidism in patients with hypothyroidism resulted in a decreased muscle mass with an increase in irisin concentrations, while the hyperthyroid group showed an increase in fat mass. Statistically significant overexpression of FNDC5 gene was found in patients with toxic goiter as compared to Graves’ disease, papillary thyroid cancer and controls. Conclusions The presented data support the theory that irisin concentration changes are associated with prolonged hypothyroidism and might primarily constitute the result of prolonged myopathy. These changes are most likely not related to the expression of the FNDC5 gene in the thyroid gland. This article is protected by copyright. All rights reserved.
  • Which patients with gynaecomastia require more detailed investigation?
    Gynaecomastia may be due to medication, chronic liver or kidney disease, hypogonadism (primary or secondary to pituitary disease) or hyperthyroidism. Having excluded these aetiologies, it is imperative to be vigilant for underlying malignancy causing gynaecomastia. These include human chorionic gonadotrophin-secreting testicular and extratesticular tumours, and oestrogen-secreting testicular tumours and feminising adrenal tumours. This article is protected by copyright. All rights reserved.
  • Impact of hypercortisolism on skeletal muscle mass and adipose tissue mass in patients with adrenal adenomas
    Context Abdominal visceral adiposity and central sarcopenia are markers of increased cardiovascular risk and mortality. Objective To assess whether central sarcopenia and adiposity can serve as a marker of disease severity in patients with adrenal adenomas and glucocorticoid secretory autonomy. Design Retrospective cohort study. Patients Twenty-five patients with overt Cushing's syndrome (CS), 48 patients with mild autonomous cortisol excess (MACE) and 32 patients with a nonfunctioning adrenal tumour (NFAT) were included. Methods Medical records were reviewed, and body composition measurements (visceral fat [VAT], subcutaneous fat [SAT], visceral/total fat [V/T], visceral/subcutaneous [V/S] and total abdominal muscle mass) were calculated based on abdominal computed tomography (CT). Results In patients with overt CS, when compared to patients with NFAT, the V/T fat and the V/S ratio were increased by 0.08 (P < .001) and by 0.3 (P < .001); however, these measurements were decreased by 0.04 (P = .007) and 0.2 (P = .01), respectively, in patients with MACE. Total muscle mass was decreased by −10 cm2 (P = .02) in patients with overt CS compared to patients with NFAT. Correlation with morning serum cortisol concentrations after dexamethasone suppression testing revealed that for every 28 nmol/L cortisol increase there was a 0.008 increase in V/T (P < .001), 0.02 increase in the V/S fat ratio (P < .001) and a 1.2 cm2 decrease in mean total muscle mass (P = .002). Conclusions The severity of hypercortisolism was correlated with lower muscle mass and higher visceral adiposity. These CT-based markers may allow for a more reliable and objective assessment of glucocorticoid-related disease severity in patients with adrenal adenomas.
  • Use of salivary cortisol and cortisone in the high- and low-dose synacthen test
    Context Salivary cortisone reflects serum cortisol levels, is more sensitive than salivary cortisol at lower values of serum cortisol and is noninvasive. Objective To investigate the relationship between serum cortisol and salivary cortisol and cortisone following low- and high-dose synacthen. Design and setting Prospective pharmacodynamic studies in clinical research facilities. Participants and intervention Thirty-five dexamethasone-suppressed, healthy adult males underwent an intravenous synacthen test: N = 23 low-dose (1 mcg), N = 12 high-dose (250 mcg). Paired serum and salivary samples were taken at 15 sampling points over 120 minutes. Main outcome measure Serum cortisol and salivary cortisol and cortisone were analysed for correlations and by a mixed-effects model. Results At baseline, the correlation between serum cortisol and salivary cortisol was weak with many samples undetectable (r = .45, NS), but there was a strong correlation with salivary cortisone (r = .94, P < .001). Up to 50 minutes following synacthen, the correlation coefficient between serum cortisol and salivary cortisol and cortisone was <0.8, but both had a stronger correlation at 60 minutes (salivary cortisol r = .89, P < .001, salivary cortisone r = .85, P < .001). The relationship was examined excluding samples in the dynamic phase (baseline to 60 minutes). Salivary cortisol and cortisone showed a close relationship to serum cortisol. Salivary cortisone showed the stronger correlation: salivary cortisol r = .82, P < .001, salivary cortisone r = .96, P < .001. Conclusion Following synacthen, both salivary cortisol and cortisone reflect serum cortisol levels, but there is a lag in their rise up to 60 minutes. The results support further research for possible future use of a 60-minute salivary cortisone measurement during the synacthen test.
  • Associations of lifestyle factors with serum dehydroepiandrosterone sulphate and insulin-like growth factor-1 concentration in prepubertal children
    Objective Little is known about the relationships of dietary factors, physical activity and sedentary behaviour to dehydroepiandrosterone sulphate (DHEAS) and insulin-like growth factor-1 (IGF-1) concentrations among prepubertal children. Therefore, we studied the associations of these lifestyle factors with serum DHEAS and IGF-1 in children. Design and subjects Cross-sectional analysis of a population sample of 431 prepubertal children aged 6-9 years. Measurements Assessment of dietary factors by food records and physical activity and sedentary behaviour by a combined heart rate and movement monitor and a questionnaire. Measurement of serum DHEAS and IGF-1. Results Consumption of low-fibre grain products (standardized regression coefficient β = .118, P = .017) and intake of vegetable protein (β = .100, P = .045) was positively and consumption of sugar-sweetened beverages (β = −.117, P = .018) was inversely associated with DHEAS after adjustment for sex, age and body fat percentage. Energy intake (β = .160, P = .001) was positively associated with IGF-1 adjusting for sex, age and body fat percentage. Vigorous physical activity was inversely associated with DHEAS after adjustment for sex and age (β = −.120, P = .027), and total (β = −.137, P = .007), moderate (β = −.130, P = .012), vigorous (β = −.136, P = .011) and moderate to vigorous physical activity (β = −.160, P = .003) were inversely and total sedentary behaviour (β = .151, P = .003) was positively associated with IGF-1 adjusting for sex and age. None of physical activity measures was associated with DHEAS or IGF-1 after additional adjustment for body fat percentage. Conclusions Lifestyle factors have weak and moderate associations with biochemical markers of adrenarche in prepubertal children. These associations indicate body fat independent and dependent influences of diet and physical activity, respectively.
  • Elevated Luteinising Hormone despite Normal Testosterone Levels in older Men – Natural History, Risk Factors, and Clinical Features
    Objective Elevated LH with normal testosterone (T) suggests compensated dysregulation of the gonadal axis. We describe the natural history, risk factors and clinical parameters associated with the development of high LH (HLH, LH>9.4 U/L) in ageing men with normal T (T≥10.5 nmol/L). Design, Patients and Measurements We conducted a 4.3 year prospective observational study of 3,369 community-dwelling European men aged 40-79 years. Participants were classified as: incident (i) HLH (n=101, 5.2%); persistent (p) HLH (n=128, 6.6%); reverted (r) HLH (n=46, 2.4%); or persistent normal LH (pNLH, n=1667, 85.8%). Potential predictors and changes in clinical features associated with iHLH and rHLH were analysed using regression models. Results Age >70 years (OR=4.12[2.07–8.20]), diabetes (OR=2.86[1.42–5.77]), chronic pain (OR=2.53[1.34–4.77]), pre-degree education (OR=1.79[1.01–3.20]) and low physical activity (PASE≤78, OR=2.37[1.24–4.50]) predicted development of HLH. Younger age (40-49 years, OR=8.14[1.35-49.13]) and non-smoking (OR=5.39[1.48–19.65]) predicted recovery from HLH. Men with iHLH developed erectile dysfunction, poor health, cardiovascular disease (CVD) and cancer more frequently than pNLH men. In pHLH men, co-morbidities, including CVD, developed more frequently, and cognitive and physical function deteriorated more, than in pNLH men. Men with HLH developed primary hypogonadism more frequently (OR=15.97[5.85–43.60]) than NLH men. Men with rHLH experienced a small rise in BMI. Conclusions Elevation of LH with normal T is predicted by multiple factors, reverts frequently and is not associated with unequivocal evidence of androgen deficiency. High LH is a biomarker for deteriorating health in aged men who tend to develop primary hypogonadism. This article is protected by copyright. All rights reserved.
  • Telomerase reverse transcriptase promoter hypermethylation is associated with metastatic disease in abdominal paraganglioma
  • Circulating B-type natriuretic peptide in women with and without recent gestational diabetes: The impact of current glucose intolerance
    Context Circulating B-type natriuretic peptide, as measured by the N-terminal fragment of its prohormone (NT-proBNP), is inversely associated with incident type 2 diabetes (T2DM) but positively related to future cardiovascular disease (CVD). Recognizing that gestational diabetes (GDM) identifies women at future risk for both T2DM and CVD, we sought to determine whether gestational glucose tolerance relates to NT-proBNP in the years after delivery. Design/Patients/Measurements Three hundred and forty women underwent a glucose challenge test (GCT) and an oral glucose tolerance test (OGTT) in pregnancy, yielding 4 gestational glucose tolerance groups: GDM (n = 105); gestational impaired glucose tolerance (n = 59); abnormal GCT with a normal OGTT (n = 98); and normal GCT with normal OGTT (n = 75). At 3-year postpartum, they underwent cardiometabolic characterization (including measurement of estimated glomerular filtration rate (eGFR), adiponectin and NT-proBNP) and repeated the OGTT, revealing 69 women with glucose intolerance (prediabetes/diabetes). Results At 3-year postpartum, serum NT-proBNP did not differ between the 4 original gestational glucose tolerance groups (P = .44), but instead progressively decreased across current glucose tolerance strata, from normal to prediabetes to diabetes (P = .006). Indeed, on logistic regression analysis, NT-proBNP emerged as a negative predictor of prediabetes/diabetes (OR = 0.903, 95% CI 0.825-0.988, P = .026). On multiple linear regression analyses of NT-proBNP, the significant association with current glucose intolerance was ultimately attenuated in a fully adjusted model, revealing two independent determinants of NT-proBNP: eGFR (t = −2.71, P = .007) and adiponectin (t = 2.44, P = .015). Conclusion Serum NT-proBNP relates to current glucose intolerance, rather than preceding gestational dysglycaemia. Thus, the diabetic (rather than vascular) risk implications of NT-proBNP predominate in young women.
  • Tumour lateralization in Cushing's disease by inferior petrosal sinus sampling with desmopressin
    Background Bilateral inferior petrosal sinus sampling (IPSS) with corticotropin-releasing hormone (CRH) is currently the gold standard in the diagnosis of Cushing's disease (CD) and has also been used in tumour lateralization. Our objective was to determine the diagnostic value and lateralization accuracy of IPSS with desmopressin. Methods We retrospectively analysed 91 patients with Cushing's syndrome who had either negative findings on pituitary dynamic enhanced magnetic resonance imaging (MRI) or nonsuppressed high-dose dexamethasone suppression tests (HDDST). Thin-slice thoracoabdominal computed tomography (CT) and octreotide receptor imaging of whole body were also negative to rule out ectopic adrenocorticotropin hormone (ACTH) syndrome. All patients went through IPSS with desmopressin. Afterwards, transsphenoidal pituitary surgery, light microscope pathology and immunohistological staining for ACTH were performed in all patients. Results Diagnosis of CD. Among the 91 patients included, 90 were confirmed with CD, of whom 89 had positive IPSS findings, therefore the sensitivity was 98.9%. The one patient who was negative for CD also had negative IPSS findings, therefore the specificity was 100%. Tumour lateralization. Among the 51 patients who were ultimately diagnosed with CD and whose lateralization by IPSS and surgery was either left or right, 37 had IPSS lateralization in concordance with surgery, therefore the concordance rate was 72.5%. Patients in the concordant group had a higher frequency of right lateralization by surgery. Conclusions IPSS with desmopressin is a sensitive approach in the diagnosis of CD and has moderate accuracy in tumour lateralization, making it an alternative choice to IPSS with CRH.
  • Clinical guidance for radioiodine refractory differentiated thyroid cancer
    Prognosis from differentiated thyroid cancer is worse when the disease becomes refractory to radioiodine. Until recently, treatment options have been limited to local therapies such as surgery and radiotherapy, but the recent availability of systemic therapies now provides some potential for disease control. Multitargeted kinase inhibitors (TKIs) including lenvatinib and sorafenib have been shown to improve progression-free survival in phase III clinical trials, but are also associated with a spectrum of adverse effects. Other TKIs have been utilized as “redifferentiation” agents, increasing sodium iodide symporter expression in metastases and thus restoring radioiodine avidity. Some patients whose disease progresses on initial TKI therapy will still respond to a different TKI and clinical trials currently in progress will clarify the best options for such patients. As these drugs are not inexpensive, care needs to be taken to minimize not only biological but also financial toxicity. In this review, we examine the basic biology of radioiodine refractory disease and discuss optimal treatment approaches, with specific focus on choice and timing of TKI treatment. This clinical field remains fluid, and directions for future research include exploring biomarkers and considering adjuvant TKI use in certain patient groups.
  • Vitamin D and calcium supplementation, skeletal muscle strength and serum testosterone in young healthy adult males: Randomized control trial
    Background Cholecalciferol and/or calcium supplementation might increase skeletal muscle strength and serum testosterone in young adult males. Objective We performed a randomized control trial assessing the effect of cholecalciferol/calcium on skeletal muscle strength and serum testosterone in vitamin D deficient young males. Design Two-by-two factorial RCT. Subject and Intervention Two-hundred and twenty-eight young males were block-randomized to (i) double-placebo, (ii) calcium/placebo, (iii) cholecalciferol/placebo and (iv) cholecalciferol/calcium. Doses for cholecalciferol were 60 000 IU/wk for 8 weeks followed by 60 000 IU/fortnightly, and doses for elemental calcium were 500 mg/twice daily for 6 months. A total of 180 subjects completed the study protocol. Their  ean age, body mass index and baseline 25(OH)D were 20.2 ± 2.2 years, 23.0 ± 3.6 kg/m2 and 21.5 ± 9.5 nmol/L, respectively. Measurements Handgrip (primary outcome), pinch-grip strength, distance walked in 6 minutes, dyspnoea-score, quality of life by Short Form 36, serum 25(OH)D, 1,25(OH)2D, iPTH, total testosterone and free androgen index (FAI). Results After intervention, mean serum 25(OH)D was >75.0 nmol/L in cholecalciferol groups. However, the handgrip strength (29.7 ± 4.4, 29.3 ± 4.6, 30.6 ± 5.0 and 28.8 ± 4.3 kg, P = .28) was comparable in the 4 groups. Subgroups analysis among subjects with baseline serum 25OH)D < 25.0 and <12.0 nmol/L showed similar results. The mean serum testosterone decreased significantly at 6 months; however, delta change was similar in 4 groups. Change in handgrip strength and other outcomes was similar in 4 groups with and without adjustment for delta testosterone and FAI. Conclusions Six months of cholecalciferol/calcium supplementation had no significant effect on skeletal muscle strength and serum testosterone in young adult males.

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