Biomedical subjects

Jan W Koper

Publications and source records attributed to Jan W Koper.

At least 19 recordsLinked to original sources

PubMed2006

Glucocorticoid receptor variant and risk of dementia and white matter lesions.

OBJECTIVE: Elevated glucocorticoid levels are associated with dementia. A glucocorticoid receptor gene variant (ER22/23EK) is related to relative glucocorticoid resistance. We investigated whether the ER22/23EK allele is associated with dementia and structural brain abnormalities. METHODS: This study was performed in two prospective population-based cohort studies among elderly. The first study included 6034 participants who were screened for dementia (mean follow-up 5.8 years). The second study included 1011 elderly subjects with an MRI at baseline and follow-up. The ER22/23EK allele was assessed for association with dementia, cognitive function and white matter lesions. RESULTS: The ER22/23EK allele was associated with a decreased risk of dementia. Among non-demented participants, ER22/23EK-carriers had a better performance on psychomotor speed tests than non-carriers. No differences were found in memory function between genotypes. In addition, both presence and progression of white matter lesions was lower in ER22/23EK-carriers. No association was found with brain atrophy on MRI. CONCLUSIONS: Our findings suggest a protective effect of the ER22/23EK allele on the risk of dementia and white matter lesions.

Aged↗

PubMed2006

Lack of Association of the 11beta-hydroxysteroid dehydrogenase type 1 gene 83,557insA and hexose-6-phosphate dehydrogenase gene R453Q polymorphisms with body composition, adrenal androgen production, blood pressure, glucose metabolism, and dementia.

CONTEXT: Recently, it was proposed that a combination of the 83,557insA polymorphism in the 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) gene and the R453Q polymorphism in the hexose-6-phosphate dehydrogenase (H6PD) gene interacts to cause cortisone reductase deficiency (CRD) when at least three alleles are affected. OBJECTIVE: The aim was to study the separate and combined effects of these polymorphisms on body composition, adrenal androgen production, blood pressure, glucose metabolism, and the incidence of dementia in the healthy elderly population. DESIGN/SETTING/PARTICIPANTS: The Rotterdam study (n = 6105) and the Frail Old Men study (n = 347) are population-based cohort studies in the elderly. MAIN OUTCOME MEASURES: Genotype distributions and influences of (combined) genotypes on body mass index, adrenal androgen production, waist to hip ratio, systolic and diastolic blood pressure, fasting glucose levels, glucose tolerance test, and incidence of dementia were measured. RESULTS: No influence of the HSD11B1 83,557insA (allele frequencies 22.0 and 21.5%) and H6PD R453Q (allele frequencies 22.9 and 20.2%) variants was found for the different outcome measures that were investigated, either separately or when at least three alleles were affected. CONCLUSIONS: Two population-based studies among Caucasian elderly showed no evidence for (combined) effects of two polymorphisms in the HSD11B1 and H6PD genes on body composition, adrenal androgen production, blood pressure, glucose metabolism, and incidence of dementia. Moreover, the high frequencies observed for these two polymorphisms do not correspond to the low incidence of CRD observed in the general population. Altogether, it is unlikely that these polymorphisms cause CRD.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed2006

Prediction of treatment response by HPA-axis and glucocorticoid receptor polymorphisms in major depression.

OBJECTIVE: We investigated whether treatment response is predicted by hypothalamus-pituitary-adrenal (HPA) axis parameters, or by genetic polymorphisms in the glucocorticoid receptor (GR), that regulates its feedback. METHODS: Ninety-eight outpatients completed 8 weeks of paroxetine treatment. Treatment response was defined as a 50% decrease in Hamilton Rating Scale for depression (HRSD) ratings. At baseline, 24h urinary cortisol excretion, and cortisol and ACTH concentrations in a DEX/CRH test were measured. The presence of polymorphisms in the GR DNA sequence (BclI, ER22/23EK, N363S) was determined. Prediction of treatment response was analysed by calculating response rates per tertile of an HPA-axis parameter and per GR genotype. RESULTS: The response rate in the high ACTH tertile was significantly lower as compared to the intermediate tertile, but not compared to the low tertile (response rates from high to low tertile: 33%, 67% and 42%). Carriers of the BclI polymorphism had higher ACTH values than non-carriers (baseline ACTH: 3 versus 5ng/l, p=0.02) and showed a trend towards lower decrease of HRSD rates than non-carriers (HRSD decrease: 8 versus 11, respectively, p=0.07). In a subgroup of BclI carriers, patients in the high ACTH tertile had a lower decrease in HRSD and lower response rates than patients in the low ACTH tertiles (HRSD decrease from high to low tertile: 5, 9 and 11, p<0.01). CONCLUSION: The results suggest that hyperactivity of the HPA-axis predict worse treatment outcome. The BclI polymorphism explains, in part, DEX/CRH test results and tends to be associated with worse treatment outcome.

Adolescent↗

PubMed2006

Staphylococcus aureus nasal carriage is associated with glucocorticoid receptor gene polymorphisms.

The aim of this study was to determine whether polymorphisms of the glucocorticoid receptor gene, influencing glucocorticoid sensitivity, are associated with persistent nasal carriage of Staphylococcus aureus. Two nasal swab cultures were obtained from each of 2,929 participants. Subjects were classified as persistent carriers (n=563) if both cultures were positive. GG homozygotes of the exon 9beta polymorphism were associated with a 68% reduced risk of persistent S. aureus nasal carriage, whereas carriers of the codon 23 lysine allele displayed an 80% increased risk. Thus, genotype-dependent variation in the sensitivity to glucocorticoids is associated with tolerance toward staphylococcal nasal colonization.

Aged↗

PubMed2006

Glucocorticoid receptor polymorphism affects transrepression but not transactivation.

CONTEXT: Glucocorticoids (GCs) are extensively used in the treatment of inflammatory and autoimmune diseases. Their beneficial effects are thought to be mediated by GC transrepression on gene expression. However, their use is limited by serious adverse effects, presumably mediated by GC transactivation of gene expression. OBJECTIVE: The objective of the study was to investigate the effect of the GC receptor haplotype, characterized by the GR-9beta polymorphism, on GC transactivation and transrepression. DESIGN AND METHODS: This was a cross-sectional study in 216 persons randomly selected from participants in The Rotterdam Study, a population-based cohort study in the elderly. Clinical and biochemical parameters of GC sensitivity were measured: weight, height, waist to hip ratio, glucose, insulin, total cholesterol, high-density lipoprotein, and C-reactive protein. In a dexamethasone suppression test, the response of serum cortisol concentrations was studied. Genotyping for four GC receptor polymorphisms was performed. In addition, ex vivo experiments were performed with leukocytes of 10 healthy controls and two persons homozygous for the GR-9beta polymorphism, in which the expression of two GC-sensitive genes, GC-induced leucine zipper and IL-2, was measured. RESULTS: Persons carrying the GR-9beta haplotype without 22/23EK (n = 53) revealed no significant differences in their body mass index, waist to hip ratio, fat spectrum, and insulin sensitivity or in their cortisol response to dexamethasone and levels of C-reactive protein, compared with noncarriers (n = 113). Ex vivo, GC-induced up-regulation of GC-induced leucine zipper mRNA via transactivation did not significantly differ in GR-9beta homozygotes, whereas the down-regulation of IL-2 expression via transrepression was decreased. CONCLUSION: Persons carrying the GR-9beta haplotype seem to have a decreased GC transrepression with normal transactivation.

Aged↗

PubMed2006

Polymorphisms of the glucocorticoid receptor gene and major depression.

BACKGROUND: The most consistent biological finding in patients with depression is a hyperactivity of the hypothalamic-pituitary-adrenal (HPA)-axis, which might be caused by impaired glucocorticoid signaling. Glucocorticoids act through the glucocorticoid receptor (GR) for which several polymorphisms have been described. The N363S and BclI polymorphisms have been associated with hypersensitivity to glucocorticoids, whereas the ER22/23EK polymorphism is related to glucocorticoid resistance. METHODS: We studied whether the susceptibility to develop a depression is related to these polymorphisms by comparing depressive inpatients (n = 490) and healthy control subjects (n = 496). Among depressed patients, we also investigated the relation between GR variants and dysregulation of the HPA-axis, as measured by the combined dexamethasone suppression/corticotropin-releasing hormone (CRH)-stimulation test, clinical response to antidepressive treatment, and cognitive functioning. RESULTS: Homozygous carriers of the BclI polymorphism and ER22/23EK-carriers had an increased risk of developing a major depressive episode. We found no genetic associations with functional HPA-axis measures in depressed patients. The ER22/23EK-carriers, however, showed a significantly faster clinical response to antidepressant therapy as well as a trend toward better cognitive functioning during depression. CONCLUSIONS: The BclI and ER22/23EK polymorphisms were associated with susceptibility to develop major depression. In addition, the ER22/23EK polymorphism is associated with a faster clinical response to antidepressant treatment. These findings support the notion that variants of the GR gene might play a role in the pathophysiology of a major depression and can contribute to the variability of antidepressant response.

Adult↗

PubMed2006

Association between an IGF-I gene polymorphism and body fatness: differences between generations.

OBJECTIVE: A polymorphism near the promoter region of the IGF-I gene has been associated with serum IGF-I levels, body height and birth weight. In this study, we investigated whether this polymorphism is associated with body composition in young healthy subjects in two cohorts of different generations. DESIGN: Observational study with repeated measurements. METHODS: The study group consisted of two comparable young Dutch cohorts with a generational difference of around 20 years. The older cohort consisted of 359 subjects born between 1961 and 1965. Measurements were performed from 13 until 36 years of age. The younger cohort consisted of 258 subjects born between 1981 and 1989. Measurements were performed from 8 until 14 years of age. Height, body mass index (BMI), fat mass, fat-free mass, waist and hip circumference were compared between wild-type carriers and variant type carriers of the IGF-I polymorphism. RESULTS: In the younger cohort, body weight, BMI, fat mass and waist circumference were significantly higher in female variant carriers of the IGF-I polymorphism. A similar trend was observed in male variant carriers. In contrast, these differences were not observed in the older cohort. Irrespective of genotype, the younger cohort showed a significantly higher total fat mass, body weight and BMI compared with the older cohort. CONCLUSIONS: Because the differences between both genotypes were small, it seems likely that the genetic variability due to this IGF-I polymorphism impacts only slightly on body composition. Importantly, our study suggested that associations between this IGF-I promoter polymorphism and body composition possibly reflect a gene-environmental interaction of this polymorphism and that an environment that promotes obesity leads to a slightly more pronounced fat accumulation in variant carriers of this IGF-I polymorphism.

Adolescent↗

PubMed2005

Strategies for the characterization of disorders in cortisol sensitivity.

CONTEXT: The clinical presentation of abnormalities in glucocorticoid (GC) sensitivity is diverse, and therefore it is difficult to diagnose this condition. OBJECTIVE AND DESIGN: The objective of the study was to develop strategies for the characterization of GC sensitivity disorders. SETTING: The study was conducted in an outpatient clinic. PATIENTS: Nine patients with GC sensitivity disorders participated. INTERVENTIONS: Sequence analysis of the GC receptor (GR), determination of GR number per cell, GR ligand-binding affinity, and GR splice regulation were performed in freshly prepared peripheral blood mononuclear lymphocytes and Epstein-Barr virus-transformed lymphoblasts. Cellular GC sensitivity was determined ex vivo by measuring the effect of dexamethasone on GC-induced leucine-zipper and IL-2 mRNA levels and on cell proliferation. RESULTS: Differences in GR number per cell, GR affinity, GR splice variants, and effects on transactivation or transrepression of GC-sensitive genes were observed between patients and controls. Epstein-Barr virus transformation of lymphoblasts had no influence on GR affinity but increased the GR number 5-fold in healthy controls. In patients diagnosed as cortisol resistant, however, GR number after transformation was increased significantly less than 5-fold, whereas a higher GR number was observed in a patient suspected of cortisol hypersensitivity. CONCLUSION: This study illustrates several strategies to define abnormalities in GC sensitivity by describing nine patients with affected GC sensitivity, all with a unique clinical course and background.

Adolescent↗

PubMed2005

Expression of the human glucocorticoid receptor splice variants alpha, beta, and P in peripheral blood mononuclear leukocytes in healthy controls and in patients with hyper- and hypocortisolism.

CONTEXT: The effects of cortisol are mediated by the alpha-isoform of the glucocorticoid receptor (GR). GR-alpha levels and activity are modulated by alternative splicing of the common pre-mRNA into mRNAs for the GR-beta and GR-P isoforms. OBJECTIVE: The objective of this study was to investigate whether chronic hypercortisolism, chronic hypocortisolism, or acute, relative hypocortisolism influences the expression levels of the GR splice variants in mononuclear leukocytes. DESIGN: This was a case-control study. SETTING: The study was performed at a university hospital. PARTICIPANTS: Eighteen patients with Cushing's syndrome, five patients with hypocortisolemia, seven patients undergoing metyrapone testing, and 14 controls were studied. MAIN OUTCOME MEASURES: The main outcome measures were mRNA levels, GR affinity, and number per cell. RESULTS: All three GR mRNA isoforms were detected in participants from all groups at relative levels of alpha/P/beta = 1:0.25:0.001. There was a significant correlation between the expression levels of the three splice variants and between the mRNA levels and the number of receptors per cell. The GR in Cushing patients had an increased Kd (P < 0.05) preoperatively. GR number was not significantly different. Postoperatively, the Kd decreased. GR-beta mRNA expression was increased compared with controls (P < 0.05) and was decreased after surgery (P < 0.05). In patients with chronic hypocortisolism, GR-alpha mRNA expression was increased, and receptor numbers were increased (P < 0.05), whereas GR affinity was normal. No changes were observed in patients undergoing a metyrapone test. CONCLUSIONS: Cushing's syndrome is accompanied by a reversible decrease in GR affinity, possibly related to an increased GR-beta expression, which may be a compensatory mechanism to GC excess. In chronic hypocortisolism, adaptive changes in GR status seem to occur at the level of GR number.

Adult↗

PubMed2005

Genetic variations in the glucocorticoid receptor gene are not related to glucocorticoid resistance in childhood acute lymphoblastic leukemia.

UNLABELLED: Glucocorticoid sensitivity is an important prognostic factor in pediatric acute lymphoblastic leukemia (ALL). For its antileukemic effect, glucocorticoid binds the intracellular glucocorticoid receptor (GR) subsequently regulating transcription of downstream genes. We analyzed whether genetic variations within the GR gene are related to differences in the cellular response to glucocorticoids. METHODS: In leukemic samples of 57 children, the GR gene was screened for nucleotide variations using a PCR/single-strand conformational polymorphism sequencing strategy. Data were linked to in vivo and in vitro glucocorticoid resistance. RESULTS: No somatic mutations were detected in the GR gene coding region, but six polymorphisms (i.e., ER22/23EK, N363S, BclI, intron mutation 16 bp upstream of exon 5, H588H, and N766N) were identified. In 67% of ALL cases, at least one minor allele of these polymorphisms was detected. Although only borderline significant, the incidence for the N363S polymorphism minor allele was higher (12% versus 6%, P = 0.06) and for the ER22/23EK minor allele lower (4% versus 7.6%, P = 0.1) than in a healthy, comparable population. The different genotypes of the polymorphisms were not related to prednisone resistance. In conclusion, polymorphisms but not somatic mutations in the GR gene coding region occur in leukemic blasts of children with ALL. Our data suggest that these genetic variations are not a major contributor for differences in cellular response to glucocorticoids in childhood ALL. The higher incidence of the N363S minor allele and the lower incidence of the ER22/23EK minor allele in our ALL population as compared with a normal population warrants further research.

Base Sequence↗

PubMed2005

Two polymorphisms in the glucocorticoid receptor gene directly affect glucocorticoid-regulated gene expression.

CONTEXT: Interindividual variation in glucocorticoid (GC)-sensitivity can be partly explained by polymorphisms in the GC receptor (GR) gene. The ER22/23EK and N363S polymorphisms have been described to be associated with lower and higher GC sensitivity, respectively. OBJECTIVE AND DESIGN: We examined the basis of this altered GC sensitivity by expressing GR(N363S) and GR(ER22/23EK) in COS-1 cells and investigating their transactivating and transrepressing capacities using a GC response element-luciferase reporter and a p65-activated nuclear factor kappaB-luciferase reporter, respectively. Furthermore, we evaluated the transactivating and transrepressing capacities of the GR in peripheral blood mononuclear lymphocytes of homozygous and heterozygous carriers of these polymorphisms by determining the maximum effect of dexamethasone on transactivation of the GC-induced leucine-zipper and transinhibition of the IL-2 gene by means of real-time RT-PCR. RESULTS: The effects of the polymorphisms in the GR gene previously observed in population studies were also detected at the level of gene expression. The ER22/23EK polymorphism resulted in a significant reduction of transactivating capacity, in both transfection experiments (-14 +/- 5%, P < 0.05) and peripheral blood mononuclear lymphocytes of carriers of this polymorphism (homozygous: -48 +/- 6%, P < 0.01, n = 1; heterozygous: -21 +/- 4%, P = 0.08, n = 3). The N363S polymorphism, associated with increased GC sensitivity, resulted in a significantly increased transactivating capacity, both in vitro (8 +/- 3%; P < 0.02) and ex vivo (homozygous: 204 +/- 19%, P < 0.0001, n = 1; heterozygous: 124 +/- 8%, P = 0.05, n = 3). Neither the ER22/23EK nor the N363S polymorphism seemed to influence the transrepressing capacity of the GR. CONCLUSION: The presence of these and other GC sensitivity-modulating polymorphisms may have consequences for the use of GCs in a clinical setting.

Animals↗

PubMed2005

A common polymorphism in the CYP3A7 gene is associated with a nearly 50% reduction in serum dehydroepiandrosterone sulfate levels.

CONTEXT: CYP3A7, expressed in the human fetal liver and normally silenced after birth, plays a major role in the 16alpha-hydroxylation of dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and estrone. Due to a replacement of part of the CYP3A7 promoter with a sequence identical with the same region in the CYP3A4 promoter (referred to as CYP3A7*1C), some individuals still express a variant of the CYP3A7 gene later in life. OBJECTIVE: The objective of this study was to examine the effect of the CYP3A7*1C polymorphism on serum steroid hormone levels. DESIGN, SETTING, PARTICIPANTS: Two population-based cohort studies were performed. Study group 1 consisted of 208 subjects randomly selected from the Rotterdam Study, and study group 2 consisted of 345 elderly independently living men. MAIN OUTCOME MEASURES: Serum DHEA(S), androstenedione, estradiol, estrone, and testosterone levels were the main outcome measures. RESULTS: In study groups 1 and 2, heterozygous CYP3A7*1C carriers had almost 50% lower DHEAS levels compared with homozygous carriers of the reference allele [study group 1, 1.74 +/- 0.25 vs. 3.33 +/- 0.15 micromol/liter (P = 0.02); study group 2, 2.09 +/- 0.08 vs. 1.08 +/- 0.12 micromol/liter (P < 0.001)]. No differences in circulating DHEA, androstenedione, estradiol, or testosterone levels were found. However, in study group 2, serum estrone levels were lower in heterozygous CYP3A7*1C carriers compared with homozygous carriers of the reference allele (0.11 +/- 0.002 vs. 0.08 +/- 0.006 nmol/liter; P < 0.001). CONCLUSION: The CYP3A7*1C polymorphism causes the persistence of enzymatic activity of CYP3A7 during adult life, resulting in lower circulating DHEAS and estrone levels.

Aged↗

PubMed2005

Increased expression of the glucocorticoid receptor-A translational isoform as a result of the ER22/23EK polymorphism.

One of the most intriguing polymorphisms in the GR [glucocorticoid (GC) receptor] gene is in codons 22 and 23 [GAGAGG(GluArg) --> GAAAAG (GluLys)]. This polymorphism is associated with a reduced GC sensitivity, a better metabolic and cardiovascular health profile, and an increased survival rate. Recently, Yudt and Cidlowski reported that two different methionine codons in the GR mRNA may be used as initiation codon: AUG-1 and AUG-27, resulting in two isoforms, the GR-A and the GR-B proteins, respectively. They also showed that the GR-B protein had a stronger transactivating effect in transient transfection experiments. In this study, we elucidated the molecular basis for the reduced GC sensitivity by investigating the influence of the ER22/23EK polymorphism on synthesis of GR-A and GR-B by expressing them independently from constructs with and without the polymorphic site. Binding studies with [(3)H]-dexamethasone and transactivation studies showed that, when the ER22/23EK polymorphism is present, approximately 15% more GR-A protein was expressed, whereas total GR levels (GR-A + GR-B) were not affected. These results show that the transcriptional activity in GR(ER22/23EK) carriers is decreased because more of the less transcriptionally active GR-A isoform is formed. This is probably caused by altered secondary mRNA structure.

Alternative Splicing↗

PubMed2005

Differential regulation of synthetic glucocorticoids on gene expression levels of glucocorticoid-induced leucine zipper and interleukin-2.

Individual glucocorticoid (GC) sensitivity was determined by measuring the effects of several clinically used GCs on transactivation of the GC-induced leucine zipper (GILZ) gene and on transrepression of the IL-2 gene using quantitative real-time PCR. A clear difference in relative potencies for transactivation and transrepression of the various GCs was observed, suggesting differential effects. To determine whether the in vitro outcomes could predict in vivo effects of GCs, 15 individuals underwent a 0.25-mg dexamethasone (DEX) suppression test (DST) while determining GILZ and IL-2 mRNA levels in their peripheral blood mononuclear cells incubated with hydrocortisone, DEX, budesonide, and prednisolone. No correlations were found between the DST and the two expression assays. However, significant correlations existed between hydrocortisone and DEX (r = 0.52; P = 0.046), hydrocortisone and budesonide (r = 0.48; P = 0.069), and hydrocortisone and prednisolone (r = 0.86; P = 0.007) regarding GILZ mRNA levels, and between hydrocortisone and DEX (r = 0.62; P = 0.014), hydrocortisone and budesonide (r = 0.71; P = 0.003), and hydrocortisone and prednisolone (r = 0.71; P = 0.047) regarding IL-2 mRNA levels. In conclusion, intra- and inter-individual variations in GC sensitivity were observed using two expression assays representing GC-mediated transactivation and transrepression. The two expression assays did not correlate with each other or with the results of the DST. This suggests that regulation of the hypothalamic-pituitary-adrenal axis is more complex. However, within an individual person, these two tests combined might predict what type and dosage of GC will be preferable in individual patients for its inhibitory clinical effects, together with relatively fewer transactivating effects related to adverse effects.

Dexamethasone↗

PubMed2005

The impact of glucocorticoid receptor gene polymorphisms on glucocorticoid sensitivity is outweighted in patients with multiple sclerosis.

Glucocorticoid (GC) sensitivity varies considerably in healthy controls as well as in patients with chronic inflammatory diseases like multiple sclerosis (MS). We investigated whether polymorphisms in the glucocorticoid receptor (N363S, ER22/23EK, and the BclI) were responsible for altered GC sensitivity. In healthy controls we found an association between the N363S allele of the GR and a reduced peripheral GC sensitivity. In MS patients neither the variant N363S, the BclI RFLP nor the ER22/23EK allele were found to be associated with GC sensitivity. GC sensitivity is probably in part genetically influenced in healthy controls, but in MS patients other factors seem to have more impact on GC sensitivity.

Analysis of Variance↗

PubMed2005

Habituation of cortisol responses to repeated psychosocial stress-further characterization and impact of genetic factors.

Although a rapid response habituation to repeated stress exposure is a key characteristic of the hypothalamus-pituitary-adrenal (HPA) axis, several studies document a substantial inter-individual variability of such HPA response patterns. In order to further investigate the individual differences in the habituation of this important neuroendocrine system to psychosocial stress, 54 male twin pairs were exposed to moderate psychosocial stress on three occasions, each exposure separated by a 1-week interval. Additionally, an ACTH(1-24) stimulation test (1 microg) and a dexamethasone suppression test (0.5mg) were performed. Although on average the expected decrease of mean cortisol and ACTH responses across stress exposures was observed, only 52% of the subjects showed this well-documented general decline and almost 16% of the participants even showed a response sensitization across sessions. Furthermore, a weak habituation was related to low cortisol responses to both the first stress exposure as well as the ACTH challenge. Moreover, genetic analyses did not reveal any evidence for a substantial heritability of the individual cortisol response habituation or an association between this habituation and two common polymorphisms in the glucocorticoid receptor gene.

Adaptation, Physiological↗

PubMed2004

Association of the ER22/23EK polymorphism in the glucocorticoid receptor gene with survival and C-reactive protein levels in elderly men.

PURPOSE: We recently demonstrated that a polymorphism in codons 22 and 23 of the glucocorticoid receptor gene is associated with relative glucocorticoid resistance, greater insulin sensitivity, and lower total and low-density lipoprotein cholesterol levels. In the present study, we investigated whether the ER22/23EK polymorphism is associated with survival, cholesterol levels, and two predictors of mortality: serum C-reactive protein and interleukin 6 levels. METHODS: We studied 402 men (mean [+/- SD] age, 77.8 +/- 3.6 years). C-reactive protein was measured by a highly sensitive method using a latex-enhanced immunoephelometric assay. Interleukin 6 was determined by a commercially available immulite assay. RESULTS: After a follow-up of 4 years, 73 (19%) of 381 noncarriers died, while none of the 21 ER22/23EK carriers had died (P = 0.03). C-reactive protein levels were about 50% lower in ER22/23EK carriers (P = 0.01). There were no differences in interleukin 6 levels. CONCLUSION: Carriers of the ER22/23EK polymorphism have better survival than noncarriers, as well as lower C-reactive protein levels.

Aged↗

PubMed2004

Deficiency of 17,20-lyase causing giant ovarian cysts in a girl and a female phenotype in her 46,XY sister: case report.

A 13-year-old girl was referred because of progressive abdominal pain caused by ovarian torsion and giant ovarian cysts. Secondary sexual characteristics were absent. Hormone analysis revealed markedly elevated serum levels of progesterone and 17-hydroxyprogesterone in combination with very low peripheral concentrations of C19 steroids (dehydroepiandrosterone and androstenedione) and estrogens. Serum concentrations of FSH and LH exceeded the upper limit of normal levels in adult women. The patient's 16-year-old 46,XY sibling showed a female phenotype with similar hormonal disturbances. Both siblings were found to be compound heterozygotes for two mutations in the CYP17 gene: an R347C mutation in one allele and a 25-base pair deletion in exon 1 in the other. The resulting block in 17,20-lyase activity caused an inability to synthesize androgens and estrogens, and increased levels of gonadotrophins due to a lack of negative feedback. The increased levels of gonadotrophins most likely stimulated growth of the ovarian cysts. The administration of a GnRH antagonist reduced the size of the cysts within a few weeks. At present, the girl is being treated with a combination of a GnRH agonist and hormone replacement therapy.

17-alpha-Hydroxyprogesterone↗