Primary glucocorticoid resistance (OMIM 615962) is a rare endocrinologic condition caused by resistance of the human glucocorticoid receptor (hGR) to glucocorticoids (GR) and characterised by general or partial insensitivity of target organs to GK. Compensatory activation of hypothalamic-pituitary-andrenal axis results in development of a various pathological conditions caused by overstimulation of adrenal glands. Clinical spectrum may range from asymptomatic cases to severe cases of mineralocorticoid and/or androgen excess. At present time, primary generalized glucocorticoid resistance has been exclusively associated with defects in the NR3C1 gene. Here, we present a case report of an adolescent patient with clinical presentation of glucocorticoid resistance confirmed by detailed endocrinologic evaluation but no confirmed mutations in the NR3C1 gene.

Academic pressure is a prevalent stressor among Chinese adolescents and is often linked to anxiety symptoms, although the underlying mechanism remains unclear. This study aimed to investigate the association between NR3C1 gene methylation, academic pressure, and anxiety symptoms among Chinese adolescents.
This nested-case control study included 150 adolescents (boys: 38.7%; baseline age: 12-17 years) from a school-based longitudinal study of Chinese adolescents. Cases (n = 50) were defined as those with anxiety symptoms at both baseline and follow-up, while controls (n = 100) were randomly selected from those without anxiety symptoms at both timepoints. The cases and controls were 1:2 matched by age. Academic pressure, anxiety symptoms, and potential covariates were measured using a self-report questionnaire. Peripheral whole blood samples were collected from each participant for the detection of cortisol level (i.e., morning serum cortisol level) and DNA methylation. The methylation analysis included a total of 27 CpG units at the NR3C1 promoter region.
The final adjusted models showed that students with heavy academic pressure at baseline were at a higher risk of anxiety symptoms at follow-up compared to those with mild academic pressure (β estimate: 6.24 [95% CI: 3.48 ~ 9.01]). After adjusting for covariates, the methylation level of one CpG unit (NR3C1-16 CpG10) in NR3C1 differed significantly between cases and controls (F = 6.188, P = 0.014), and the difference remained significant after correction for multiple testing (P < 0.025). The adjusted regression models showed that moderate (β estimate = 0.010 [95% CI: 0.000 ~ 0.020], P = 0.046) and heavy (β estimate = 0.011 [95% CI: 0.001 ~ 0.020], P = 0.030) academic pressure were significantly associated with the methylation level of NR3C1-16 CpG 10. Further mediation analysis demonstrated that the association of academic pressure and anxiety symptoms was significantly mediated by the methylation of NR3C1-16 CpG 10 (β estimate for indirect effect = 0.11 [95% CI: 0.005 ~ 0.32]; indirect/total effect = 8.3%).
The present study suggests that NR3C1-16 CpG 10 DNA methylation might be a potential mechanism that partially explains the lasting effects of academic pressure on subsequent anxiety symptoms among adolescents. Further studies with larger sample sizes are recommended to replicate this finding.

暂无摘要。

The effectiveness of steroid rotation from dexamethasone to prednisolone for hiccups caused by dexamethasone for antiemetic chemotherapy has been reported overseas, but has not been reported in Japan. The effectiveness of steroid rotation in Japanese individuals is unclear because ethnic differences and variations in glucocorticoid receptors affect sensitivity to dexamethasone. We report a case of the effectiveness of steroid rotation in a Japanese patient with hiccups caused by dexamethasone for antiemetic chemotherapy. A 74-year-old man was diagnosed as having stage IV gastric cancer. Chemotherapy was initiated using S-1 (80 mg/d on Days 1-21) and cisplatin (80 mg on Day 8), with dexamethasone (8 mg/d on Day 8 intravenously and on Days 9-11 orally) as antiemetic. Severe hiccups developed on Day 10 and resolved on Day 11 by the 1st cycle of chemotherapy. Subcutaneous injection of atropine by the 5th cycle and ingestion of Syakuyakukanzouto (Glycyrrhiza extract) by the 6th cycle did not effectively relieve the hiccups. By the 7th cycle, the hiccups resolved after the dose of dexamethasone was decreased from 8 mg/d to 4 mg/d but recurred by the 8th cycle. We then changed to prednisolone 30 mg/d from dexamethasone 4 mg/d by the 9th cycle; the hiccups completely resolved thereafter. Steroid rotation from dexamethasone to prednisolone completely controlled the hiccups, with no further recurrence. No emetic episodes occurred during chemotherapy. Therefore, this demonstrates the effectiveness of steroid rotation in a Japanese patient with hiccups caused by dexamethasone for antiemetic chemotherapy.

To explore the associations between stress response genes and attention deficit hyperactivity disorder (ADHD) in children, we conducted a case-control study consisting of 406 newly diagnosed ADHD cases and 432 controls in Wuhan, China. We genotyped the candidate genes, nuclear receptor subfamily 3 group C member 1(NR3C1) and solute carrier family 6 member 4(SLC6A4), using the Sequenom MassARRAY technology. After correction by Bonferroni (α\' = 0.05/6 = 0.008), the rs6191 SNP was found to be associated with a reduced risk of ADHD in the dominant model (OR = 0.564, 95% CI = 0.389-0.819, P = 0.003) while the rs25531 SNP was associated with an increased risk of ADHD in the multiplicative model (OR = 1.380, 95% CI = 1.111-1.714, P = 0.004). Additionally, both the rs6191 and rs25531 SNPs were significantly associated with the attention deficit factor (P = 0.006, P = 0.003, respectively) but not with the hyperactivity/impulsivity factor in the Swanson, Nolan and Pelham-IV Questionnaire (SNAP-IV) scale. Furthermore, we found that these two SNPs were significantly associated with pure ADHD, and not affected by the comorbidities (P =  0.001, P =  0.007, respectively). Besides, there was an interaction between these two SNPs. This study demonstrated the role of NR3C1 and SLC6A4 polymorphisms in ADHD, yet independent replication of the findings of this study in multi-center and multi-stage studies with large samples is warranted in the future.

Glucocorticoid resistance is a rare, sporadic or familial condition caused by mutation of the gene encoding the glucocorticoid receptor (GR). Clinically it is characterized by symptoms developed due to local, tissue-specific, or generalized partial insensitivity to glucocorticoids.
A 31-year-old woman was evaluated because of infertility at the Endocrine Unit of the 2nd Department of Medicine, Semmelweis University. During her laboratory investigations, elevated serum and salivary cortisol were observed which failed to be suppressed after administration of 1 mg dexamethasone. 24 h urinary cortisol was increased, but a normal midnight serum cortisol was detected suggesting a maintained circadian rhythm. Plasma dehydroepiandrosterone-sulfate and androstendione levels were also elevated. Repeated plasma ACTH measurements indicated slightly elevated or normal values. Bone mineral density was normal. All laboratory results confirmed the diagnosis of glucocorticoid resistance. Genetic counseling followed by Sanger sequencing of the coding region of the gene encoding human glucocorticoid receptor was performed and a missense mutation (Arg714Gln, R714Q) in a heterozygous form was detected. Following family screening, the same mutation was found in her clinically-healthy 35-year-old sister who had no fertility problems.This variant was not detected in more than 60 patients and controls tested either for glucocorticoid resistance or Cushing\'s syndrome in our Laboratory and it was absent in Exome Variant Server, HumanGene Mutation Database and ExAC databases.
Our case fulfils the diagnostic criteria of glucocorticoid resistance, also named Chrousos syndrome. The glucocorticoid receptor gene mutation detected in our patient has been already reported in a 2-year-old child with hypoglycaemia, hypokalaemia, hypertension and premature puberty. These distinct phenotypes may suggest that other factors may modify the functional consequences of the R714Q variant of GR.

BACKGROUND: Depression during pregnancy or after childbirth is the most frequent perinatal illness affecting women of reproductive age. It could result in unfavourable outcomes for both women and their newborns. The incidence of perinatal depression is higher for those with family history of depression and other mental illness, suggesting the contribution of genetic factors. There is postulation that disruption or fluctuation of reproductive hormones could play a part in women who are sensitive to such changes.
METHODS: This is a case-control study comparing the frequencies of candidate gene variants in patients with perinatal depression with controls. Patients of Chinese descent (N = 725) were recruited from the outpatient clinics of the hospital between 2010 and 2013. Controls were patients who came for postnatal consultations at the obstetrics clinics and scored ≤ 7 on the Edinburgh Postnatal Depression Scale (EPDS) at the postnatal screening programme of the hospital. Cases with confirmed diagnosis of clinical (major) depression related to pregnancy/postpartum were recruited from the hospital\'s outpatient clinic. Genomic DNA was extracted from saliva samples and genotyped for the polymorphisms of interest. Differences between groups were assessed by chi-square analysis.
RESULTS: CRHR1 rs242939 and rs1876828 were not polymorphic in the study population. There was no statistically significant association of perinatal depression for CRHR1 rs242941 and GR rs41423247 (BclI). When all subjects were grouped based on family history of mental illness, there was a statistically significant association of CRHR1 rs242941 with family history regardless of depression status (P = 0.043). There was also a statistically significant difference for GR rs41423247 and regularity of menstrual periods (P < 0.000). Although not statistically significant, women with perinatal depression showed a trend towards higher frequency of self-reported menstrual irregularity.
CONCLUSIONS: No evidence was found for the association of any of the genetic markers with perinatal depression in this study cohort. Instead, the possible genetic links were found in women with positive family history of mental illness and menstrual irregularity, suggesting these could be identifying risk markers for women.

OBJECTIVE: Several mutations of the glucocorticoid receptor (GR) gene cause malfunction of the protein, resulting in steroid resistance. In diseases other than asthma, the GR variants I559N, D641V, and V729I have been linked to steroid resistance. The aim of this study was to evaluate the link of these GR variants in steroid-resistant (SR) asthma in the Chinese Han population.
METHODS: GR polymorphisms were determined in 64 SR asthma patients, 217 steroid-sensitive (SS) asthma patients and 221 healthy control (CTR) individuals. The analysis of the GR variants was performed using PCR-sequence specific primers according to the European Molecular Biology Laboratory database (NC_000005.8). In addition, ligand binding and serum cortisol levels were determined.
RESULTS: Compared with SS asthma patients and CTRs, a significant lower frequency of the GR D641V variant AA genotype (P=0.003, 0.014, respectively) and the A allele (P=0.001, 0.009, respectively) was found in SR asthma patients. Furthermore, the equilibrium dissociation constant (Kd) of GR ligand binding in SR asthma patients with the GR D641V variant AA genotype was significantly lower compared with the AT or the TT genotype carriers (P=0.006, 0.016, respectively). There was no significant difference between the I559N and V729I GR variants on comparing SR asthma patients with SS asthma patients or CTRs.
CONCLUSIONS: This study suggests that the D641V variant of the GR is probably associated with SR asthma in the Chinese Han population.

Hormone receptors are a necessary (although not sufficient) part of the process through which hormones like corticosterone create physiological responses. However, it is currently unknown to what extent receptor concentrations across different target tissues may be correlated within individual animals. In this study, we examined this question using a large dataset of radioligand binding data for glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in 13 different tissues in the house sparrow (Passer domesticus) (n=72). Our data revealed that individual house sparrows tended to exhibit higher or lower receptor binding across all tissues, which could be part of what creates the physiological and behavioral syndromes associated with different hormonal profiles. However, although statistically significant, the correlations between tissues were very weak. Thus, when each tissue was independently regressed on receptor concentrations in the other tissues, multivariate analysis revealed significant relationships only for sc fat (for GR) and whole brain, hippocampus, kidney, omental fat, and sc fat (for MR). We also found significant pairwise correlations only between receptor concentrations in brain and hippocampus, and brain and kidney (both for MR). This research reveals that although there are generalized individual consistencies in GR and MR concentrations, possibly due to such factors as hormonal regulation and genetic effects, the ability of 2 different tissues to respond to the same hormonal signal appears to be affected by additional factors that remain to be identified.

BACKGROUND: Glucocorticoids are an important component of treatment for childhood acute lymphoblastic leukemia (ALL). To induce antileukemic effects, glucocorticoids have to bind their intracellular receptors. Little is known about probable mechanisms of glucocorticoid resistance in ALL.
OBJECTIVE: The aim of this study was to evaluate the possible association between 3 prominent glucocorticoid receptor gene polymorphisms-BclI, N363S, and ER22/23EK-and the risk of relapse in children with ALL.
METHODS: We conducted a case-control study on 100 children with ALL, aged 0 to 15 years, including 50 nonrelapsed (control) and 50 relapsed (case) subjects. Required patient information such as demographic characteristics; relevant clinical and paraclinical findings at diagnosis; chemotherapy protocols used at diagnosis; and relapse properties, including time interval from date of initial diagnosis to relapse and number, type, and site of relapse, were gathered from patients\' medical files. Genotyping of BclI, N363S, and ER22/23EK polymorphisms was carried out by polymerase chain reaction restriction fragment-length polymorphism (PCR-RFLP). Statistical analysis was performed. The distribution of BclI, N363S, and ER22/23EK polymorphism genotypes in our population and in populations examined in similar studies was compared using the χ(2) test or Fischer exact test.
RESULTS: One hundred children with ALL, consisting of 65 males and 35 females, were recruited into this study. Their mean (SD) age was 5.39 (3.02) years. No relapsed or nonrelapsed individuals were homozygous for N363S and ER22/23EK polymorphisms. The allelic frequencies of mutant alleles of BclI, N363S, and ER22/23EK polymorphisms in all patients were 0.195, 0.02, and 0.005, respectively. No statistically significant association between BclI, N363S, and ER22/23EK polymorphisms and risk of relapse in children with ALL was observed (P = 0.104 [BclI], not calculated for the last 2 polymorphisms [N363S and ER22/23EK]). The incidence of BclI polymorphism in our population (35/100) differed significantly from that in a Canadian population with European descent (135/219) and a Dutch population (29/53) (P < 0.001 and P = 0.007, respectively).
CONCLUSIONS: Our data suggest that there did not appear to be any prognostic value of BclI, ER22/23EK, and N363S polymorphisms for predicting relapse in this population of 100 Iranian children with ALL.