Long-term glucocorticoid concentrations as a risk factor for childhood obesity and adverse body-fat distribution.

BACKGROUND: Childhood obesity is an important risk factor for premature development of the metabolic syndrome (MetS) at adulthood. There is need for understanding of the mechanisms underlying the MetS and obesity. Patients with Cushing's disease suffer from similar metabolic complications, leading to the hypothesis that inter-individual cortisol variation may contribute to the onset of obesity. In addition, glucocorticoid receptor (GR)-gene polymorphisms resulting in differential glucocorticoid (GC) sensitivity, have been associated with an adverse metabolic profile. AIM: To study associations of GC levels in scalp hair, as a marker of long-term systemic GC concentrations, and genetically determined GC sensitivity with obesity and body-fat distribution in children. METHODS: We performed a cross-sectional study of cortisol and cortisone concentrations over a 3-month period, measured by LC-MS/MS (Liquid Chromatography Tandem Mass Spectrometry) in hair of 3019 6-year-old children participating in the Generation R study. Genotyping of GR-gene polymorphisms was performed. RESULTS: Of all children, 4.3% was obese and 13.4% overweight. Cortisol was significantly associated with risk of obesity (odd ratio (OR): 9.4 (3.3-26.9)) and overweight (OR: 1.4 (1.0-2.0)). Cortisone was associated with risk of obesity (OR: 1.9 (1.0-3.5)). Cortisol and cortisone were significantly positively associated with body mass index, fat mass (FM) index and android/gynecoid FM ratio. GR polymorphisms were not associated with adiposity parameters. CONCLUSION: Long-term cortisol concentrations are strongly associated with an increased risk of childhood obesity and adverse body-fat distribution. Future research may reveal whether these are causal relations and may be a target for therapy.

Socioeconomic status in children is associated with hair cortisol levels as a biological measure of chronic stress.

INTRODUCTION: Low socioeconomic status (SES) may be associated with a high risk of lifestyle-related diseases such as cardiovascular diseases. There is a strong association between parental SES, stress and indicators of child health and adult health outcome. The exact mechanisms underlying this association have not yet been fully clarified. Low SES may be associated with chronic stress, which may lead to activation of the hypothalamic-pituitary-adrenal (HPA)-axis, resulting in a higher circulating level of the stress hormone cortisol. Therefore, chronic stress may mediate the association between low SES and elevated cortisol levels and its adverse outcomes. AIM: We investigated whether SES was associated with a chronic measure of cortisol exposure in a child population. METHODS: Cortisol and cortisone were measured in scalp hair in 270 children and adolescents, aged 4-18 years, enrolled through school visits. Neighborhood level SES was based on a score developed by the Netherlands Institute for Social Research using postal codes, and this includes neighborhood measures of income education and unemployment. Maternal and paternal education level were used as indicators of family SES. RESULTS: Neighborhood level socioeconomic status score was significantly associated with hair cortisol (ß=-0.103, p=0.007, 95%CI [-0.179, -0.028]) and hair cortisone (ß=-0.091, p=0.023, 95%CI [-0.167, -0.015]), adjusted for age and sex. Additionally, hair cortisol was significantly correlated with maternal education level and hair cortisone was significantly correlated with paternal education level. CONCLUSION: The results of our study suggest that the widely shown association between low family SES and adverse child health outcomes may be mediated by chronic stress, given the chronically higher levels of cortisol in children and adolescents in families with low SES. It is especially notable that the association between SES and cortisol was already found in children of young age as this can have major consequences, such as increased risk of cardio metabolic diseases in later life.

Polymorphisms in the glucocorticoid receptor gene and in the glucocorticoid-induced transcript 1 gene are associated with disease activity and response to glucocorticoid bridging therapy in rheumatoid arthritis.

Glucocorticoids (GC) are widely used in rheumatoid arthritis (RA). Ongoing active disease due to GC resistance may unfavorably influence long-term disease outcome in RA. We studied the association between the presence of glucocorticoid receptor (GR) and glucocorticoid-induced transcript 1 (GLCCI1) gene polymorphisms, which modulate GC sensitivity, and baseline disease activity score (DAS) and efficacy of GC bridging therapy in RA. We prospectively studied in vivo GC sensitivity in 138 patients with recent-onset or longstanding RA. In vivo GC sensitivity was expressed as the relative decrease in DAS following 2 weeks of standardized GC therapy. All patients were genotyped for the GR polymorphisms BclI (rs41423247), N363S (rs6195), 9ß (rs6198), ER22/23EK (rs6189 + rs6190), and the GLCCI1 variant rs37972 and subsequently divided in groups carrying a polymorphism associated with increased GC sensitivity (BclI-G allele, N363S-G allele, GLCCI1-C allele) or decreased GC sensitivity (9ß-G allele, ER22/23EK-A/A allele, GLCCI1-T allele). Differences in baseline DAS and relative decrease in DAS in the different genotype groups were analyzed using analysis of covariance and linear regression. Baseline DAS was higher in patients who carried polymorphisms of the GR and GLCCI1 genes associated with decreased GC sensitivity. GLCCI1 genotype, but not GR genotypes, was associated with improvement in DAS in male patients with RA. The GLCCI1 gene minor allele (rs37972) may be associated with less efficient GC bridging therapy in male RA patients. Carriers of the BclI-G, N363S-G, or GLCCI1-C alleles had lower levels of baseline disease activity, suggesting a role for the GLCCI1 and GR gene in regulation of GC sensitivity to endogenously produced cortisol.

Elevated hair cortisol concentrations in children with adrenal insufficiency on hydrocortisone replacement therapy.

BACKGROUND: Glucocorticoid replacement therapy in patients with adrenal insufficiency needs to be tailored to the individual patient based on body composition and clinical signs and symptoms as no objective method for assessment of treatment adequacy is available. Current treatment regimens are often not satisfactory, which is shown by the adverse metabolic profile and doubled mortality rates in treated adrenal insufficiency patients. Measurement of cortisol concentrations in hair reflect the long-term systemic cortisol exposure and may be of use in refinement of hydrocortisone treatment. OBJECTIVE: We aimed to study whether long-term cortisol (hydrocortisone) levels, as measured in scalp hair, are similar in children with adrenal insufficiency and healthy children. MATERIAL AND METHODS: We set up a case control study, measuring anthropometric characteristics and hair cortisol concentrations (HCC) in 54 hydrocortisone substituted children with adrenal insufficiency (AI patients) in the age of 4-18 years and 54 healthy children matched for gender and age. RESULTS: Mean HCC were significantly higher in AI patients compared with healthy controls (mean 13·3 vs 8·2 pg/mg, P = 0·02). AI patients also had a higher BMI (P < 0·001) and waist circumference (WC) (P = 0·02). HCC was significantly associated with BMI (P = 0·002) and WC (P = 0·002). HCC explained 13% of the difference in BMI and 29% of the difference in WC between AI patients and controls. CONCLUSION: Hydrocortisone-treated AI patients have increased HCC and adverse anthropometric characteristics compared with healthy controls. HCC measurement may be of value in identifying overtreatment and thereby improve hydrocortisone replacement therapy.

High long-term cortisol levels, measured in scalp hair, are associated with a history of cardiovascular disease.

BACKGROUND: Stress is associated with an increased incidence of cardiovascular disease. The impact of chronic stress on cardiovascular risk has been studied by measuring cortisol in serum and saliva, which are measurements of only 1 time point. These studies yielded inconclusive results. The measurement of cortisol in scalp hair is a novel method that provides the opportunity to measure long-term cortisol exposure. Our aim was to study whether long-term cortisol levels, measured in scalp hair, are associated with cardiovascular diseases. METHODS: A group of 283 community-dwelling elderly participants were randomly selected from a large population-based cohort study (median age, 75 y; range, 65-85 y). Cortisol was measured in 3-cm hair segments, corresponding roughly with a period of 3 months. Self-reported data concerning coronary heart disease, stroke, peripheral arterial disease, diabetes mellitus, and other chronic noncardiovascular diseases were collected. RESULTS: Hair cortisol levels were significantly lower in women than in men (21.0 vs 26.3 pg/mg hair; P < .001). High hair cortisol levels were associated with an increased cardiovascular risk (odds ratio, 2.7; P = .01) and an increased risk of type 2 diabetes mellitus (odds ratio, 3.2; P = .04). There were no associations between hair cortisol levels and noncardiovascular diseases. CONCLUSIONS: Elevated long-term cortisol levels are associated with a history of cardiovascular disease. The increased cardiovascular risk we found is equivalent to the effect of traditional cardiovascular risk factors, suggesting that long-term elevated cortisol may be an important cardiovascular risk factor.

Expression of 11ß-hydroxysteroid dehydrogenase type 1 in the human hypothalamus.

The hypothalamus is a major target for glucocorticoids and a key structure for hypothalamic-pituitary-adrenal (HPA) axis setpoint regulation. The enzyme 11ß hydroxysteroid dehydrogenase type 1 (11ßHSD1) modulates glucocorticoid signalling in various tissues at the prereceptor level by converting biologically inactive cortisone to its active form cortisol. The present study aimed to assess 11ßHSD1 expression in the human hypothalamus. We studied 11ßHSD1 expression in five frozen and four formalin-fixed, paraffin-embedded human hypothalami (obtained from the Netherlands Brain Bank) by the polymerase chain reaction and immunocytochemistry, respectively. 11ßHSD1 mRNA was expressed in the area of the suprachiasmatic nucleus, which is the biological clock of the brain, in the supraoptic nucleus and paraventricular nucleus (PVN), and in the infundibular nucleus, which is the human homologue of the rodent arcuate nucleus. 11ßHSD1 was detected by immunocytochemistry in the same nuclei. In the PVN, neuronal 11ßHSD1 immunoreactivity colocalised with corticotrophin-releasing hormone (CRH), arginine vasopressin and oxytocin, as shown by dual fluorescence staining. Our data demonstrate that 11ßHSD1 is widely expressed in the human hypothalamus. Its colocalisation with CRH in the PVN suggests a role in modulation of glucocorticoid feedback of the HPA axis, whereas the expression of 11ßHSD1 in additional and functionally diverse hypothalamic nuclei points to a role for the enzyme in the regulation of metabolism, appetite and circadian rhythms.

A novel tool in the diagnosis and follow-up of (cyclic) Cushing's syndrome: measurement of long-term cortisol in scalp hair.

BACKGROUND: Measurement of cortisol in 24-h urine collections and midnight saliva are standard screening tests for Cushing's syndrome (CS). These tests reflect cortisol levels during a maximum of 24 h and do not provide historical information. Therefore, they can yield normal results in case of cyclic CS, which is a rare disorder that is characterized by alternating episodes of endogenous cortisol excess and normal cortisol secretion. The measurement of cortisol in scalp hair is a novel tool that might be helpful to establish the diagnosis of (cyclic) CS. Our aim was to study whether hair cortisol timelines correspond with clinical course in patients with CS and whether we could create retrospective timelines of cortisol exposure that correspond with symptomatic periods in patients suspected of cyclic CS. METHODS: Scalp hair was collected in 14 patients with confirmed CS and six patients suspected of cyclic CS. Cortisol was extracted from the hair samples with methanol, and an ELISA was used to measure cortisol levels in hair extracts. A group of 96 nonobese individuals were used as a control group. RESULTS: Hair cortisol levels were significantly elevated in CS patients (P<0.0001). Sensitivity and specificity of hair cortisol measurements for CS were 86 and 98%, respectively. Hair cortisol timelines of patients with CS and cyclic CS corresponded with clinical course. CONCLUSION: Hair samples can provide a historical timeline that corresponds with clinical course in patients with (cyclic) CS. This new diagnostic tool can contribute significantly to early recognition of patients suffering from cyclic CS.

Long-term cortisol levels are not associated with nasal carriage of Staphylococcus aureus.

Staphylococcus aureus (S. aureus) colonizes the anterior nares in part of the population and the persistent carrier state is associated with increased infection risk. Knowledge concerning the determinants of S. aureus nasal carriage is limited. Previously, we found that glucocorticoid receptor polymorphisms influence carrier risk, suggesting involvement of glucocorticoids. Our aim was to study long-term cortisol levels in non-carriers, intermittent, and persistent carriers of S. aureus. We hypothesized that cortisol levels are higher in carriers, since cortisol-induced immune suppression would enhance S. aureus colonization. We determined nasal carrier state and long-term hair cortisol levels in 72 healthy subjects. Nasal swabs were collected twice with an interval of 2 weeks. Cortisol levels were determined in hair segments of 3 cm, which corresponds to a period of roughly 3 months. Of all 72 participants, 38 were non-carriers, 10 were intermittent carriers, and 24 were persistent carriers of S. aureus. Cortisol levels did not differ between these carrier groups (p=0.638). Long-term cortisol levels are not associated with S. aureus nasal carriage.

The effect of common genetic variation in 11ß-hydroxysteroid dehydrogenase type 1 on hypothalamic-pituitary-adrenal axis activity and incident depression.

BACKGROUND: Accumulating evidence suggests that hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA axis) is involved in depression. 11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) converts inert cortisone to active cortisol and is implicated in HPA axis regulation in animal studies. The aim of our study was to identify polymorphisms in 11ß-HSD1 gene (HSD11B1) with consistent associations with increased HPA axis activity and relate those polymorphisms to depression. METHODS: Twelve single-nucleotide polymorphisms (SNPs), including 11 tagging SNPs, were selected using the HapMap database and genotyped in 4228 participants of the population-based Rotterdam Study. The outcome measures were salivary cortisol levels after awakening, 30 min later, at 1700 h, at bedtime, and plasma levels of androstenedione (in women only). SNPs that were significantly associated with cortisol as well as androstenedione levels were also related to incident depression. RESULTS: rs11119328 was associated with higher cortisol saliva samples collected at bedtime as well as higher androstenedione levels (P value after correction for multiple testing: 0.01 and 0.04, respectively). Carriers of this polymorphism had an increased risk of an incident depression (hazard ratio 1.28, 95% confidence interval 1.03-1.59). Two other SNPs, which were in high linkage disequilibrium with rs11119328, were related to higher cortisol levels but not with androstenedione levels. CONCLUSIONS: We identified one SNP, which was associated with increased salivary cortisol levels at nadir as well as higher androstenedione levels. Moreover, this SNP was also associated with a higher risk of an incident depression. This suggests that 11ß-HSD1 is implicated in human HPA axis regulation and susceptibility to depression.

Glucocorticoid sensitivity in Behçet's disease.

OBJECTIVE: Glucocorticoid (GC) sensitivity is highly variable among individuals and has been associated with susceptibility to develop (auto-)inflammatory disorders. The purpose of the study was to assess GC sensitivity in Behçet's disease (BD) by studying the distribution of four GC receptor (GR) gene polymorphisms and by measuring in vitro cellular GC sensitivity. METHODS: Healthy controls and patients with BD in three independent cohorts were genotyped for four functional GR gene polymorphisms. To gain insight into functional differences in in vitro GC sensitivity, 19 patients with BD were studied using two bioassays and a whole-cell dexamethasone-binding assay. Finally, mRNA expression levels of GR splice variants (GR-α and GR-ß) were measured. RESULTS: Healthy controls and BD patients in the three separate cohorts had similar distributions of the four GR polymorphisms. The Bcll and 9ß minor alleles frequency differed significantly between Caucasians and Mideast and Turkish individuals. At the functional level, a decreased in vitro cellular GC sensitivity was observed. GR number in peripheral blood mononuclear cells was higher in BD compared with controls. The ratio of GR-α/GR-ß mRNA expression levels was significantly lower in BD. CONCLUSIONS: Polymorphisms in the GR gene are not associated with susceptibility to BD. However, in vitro cellular GC sensitivity is decreased in BD, possibly mediated by a relative higher expression of the dominant negative GR-ß splice variant. This decreased in vitro GC sensitivity might play an as yet unidentified role in the pathophysiology of BD.

Glucocorticoid receptor gene haplotypes are not associated with birth anthropometry, blood pressure, glucose and insulin concentrations, and body composition in subjects born small for gestational age.

OBJECTIVE: Smaller size at birth has been associated with an increased risk of metabolic and cardiovascular disorders in adult life. Fetal programming of the hypothalamic-pituitary-adrenal axis has been suggested as a possible explanation. Fetal glucocorticoid (GC) overexposure has effects that suggest a role of GCs in this programming. The effects of GCs are mediated through the GC receptor (GR or NR3C1). Several functional polymorphisms have been described, which are associated with relative GC resistance or hypersensitivity. Our aim is to compare frequencies of GR haplotypes, characterized by the R23K, N363S, Bcl1, or 9ß polymorphisms, in subjects born small for gestational age (SGA) and associate birth anthropometry data, response to GH treatment, blood pressure, glucose and insulin concentrations, and body composition with these haplotypes. DESIGN: In total, 418 SGA subjects and 697 healthy controls were enrolled in this study. Methods Anthropometry data were obtained, as well as blood samples to determine fasting glucose and insulin concentrations. Dual energy X-ray absorptiometry scans were used to measure the amount of fat and lean mass. RESULTS: No differences were found between GR haplotype frequencies in SGA children compared with healthy controls. No associations were found between GR haplotypes and birth length and birth weight, growth response during GH treatment, blood pressure, glucose and insulin concentrations, and body composition. CONCLUSION: GR haplotypes and their effect on GC sensitivity do not seem to play a significant role in GH-induced catch-up growth and the risk factors of developing metabolic and cardiovascular disorders in adult life of SGA children.

Working memory performance is associated with common glucocorticoid receptor gene polymorphisms.

Cortisol has a modulatory influence on cognitive functions in humans. Both impairing and enhancing effects of cortisol administration have been shown for hippocampus-dependent declarative memory, and impairing effects have been shown for prefrontal-cortex-dependent working memory function. Given the high density of glucocorticoid (GC) receptors in the prefrontal cortex, we investigated whether common polymorphisms of the GC receptor (GR) gene (ER22/23EK, N363S, BclI, 9 beta A3669G) modulate the influence of cortisol administration on working memory. Working memory performance was investigated in 169 subjects on 10 mg hydrocortisone (cortisol) and placebo using an item recognition task. No impairing effect of hydrocortisone treatment became evident. However, a sex x genotype interaction on general working memory performance was revealed (p = 0.02). While female heterozygous carriers of the 9 beta G allele displayed faster reaction times than the other genotype groups, 9 beta G heterozygous men were relatively slower. Heritability estimates for memory are roughly 50%, indicating that common genetic polymorphisms have an important impact on cognitive performance. Our results suggest that variants of the GR gene might explain some of the variance attributable to genetic factors. Furthermore, it can be speculated that they modulate the individual vulnerability for memory impairments related to stress-related psychiatric disorders.

Tissue mRNA expression of the glucocorticoid receptor and its splice variants in fatal critical illness.

BACKGROUND: Critical illness results in activation of the hypothalamic-pituitary-adrenal (HPA) axis, which might be accompanied by a peripheral adaptation in glucocorticoid sensitivity. Tissue sensitivity is determined by the active glucocorticoid receptor GRalpha, of which two splice variants involving the hormone-binding domain exist, GRbeta and GR-P. OBJECTIVE: To study tissue mRNA expression of the GR and its splice variants in fatal critical illness. DESIGN AND METHODS: We assessed mRNA expression of the GRalpha, GRbeta and GR-P variants in liver (n = 58) and muscle (n = 65) of patients who had died after intensive care, and had been randomized for insulin treatment. We analysed whether GR mRNA expression was associated with insulin treatment, cortisol levels and glucocorticoid treatment. RESULTS: GRalpha and GR-P mRNA constituted 87 +/- 8% and 13 +/- 2%, respectively, of total GR mRNA in liver. GRbeta mRNA could only be amplified in five liver samples. All variants were present in most muscle samples (alpha = 96 +/- 11%, P = 3.9 +/- 0.4%, beta = 0.010 +/- 0.002%). GR expression was not associated with insulin therapy. A strong positive relationship was observed between the different GR variants in both liver and muscle (P < 0.001 for all). Serum cortisol levels were negatively associated with liver GRalpha and muscle GR-P expression (P < 0.05). mRNA expression of both liver GRalpha and GR-P, but not muscle GR, was substantially lower in patients who had received exogenous glucocorticoids (P < 0.01). CONCLUSION: We demonstrate the presence of GRalpha and GR-P mRNA in liver and of GRalpha, GRbeta and GR-P mRNA in muscle, with no evidence for altered splicing in critical illness. In contrast to muscle GR, liver GR expression was substantially lower in patients receiving exogenous glucocorticoids.

Salivary cortisol is related to atherosclerosis of carotid arteries.

BACKGROUND: Dysregulation of the hypothalamic-pituitary-adrenal axis has been suggested as an independent risk factor for ischemic heart disease. The aim of our study was to evaluate whether two markers of the hypothalamic-pituitary-adrenal axis activity, the level of salivary cortisol and the diurnal salivary cortisol pattern, are associated with atherosclerosis of the carotid arteries in an elderly population. METHODS AND RESULTS: A total of 1866 participants of the Rotterdam Study, a population-based cohort study in the elderly, provided four salivary cortisol samples throughout 1 d, and underwent ultrasonography to examine the presence of plaques in the common, internal, and bifurcation sites of both carotid arteries. Two summary measures of the separate cortisol values were computed: area under the curve (AUC), which is a measure of total cortisol exposure while awake; and the slope, which is a measure of diurnal cortisol decline. RESULTS: Total cortisol exposure while awake (AUC) was associated with higher plaque scores (beta = 0.08 per sd of AUC, 95% confidence interval 0.00-0.16; P = 0.04) in a fully adjusted linear regression model. Persons with an AUC in the highest tertile had a higher number of plaques of carotid arteries compared with those in the lowest tertile (3.08 vs. 2.80, 95% confidence interval of difference 0.09-0.48; P = 0.005). There was no relation between diurnal cortisol decline and plaque score. CONCLUSION: Our results support the hypothesis that increased total cortisol exposure is independently associated with atherosclerosis of the carotid arteries.

Glucocorticoid receptor gene polymorphisms and glucocorticoid sensitivity of subdermal blood vessels and leukocytes.

A considerable variability in the sensitivity to glucocorticoids (GCs) exists between individuals and these differences have been implicated in the etiology of psychiatric diseases such as depression. Glucocorticoid receptor (GR) gene polymorphisms might account in part for variability in GC responsiveness. We assessed the association between four common GR gene (NR3C1) polymorphisms (ER22/23EK, N363S, BclI, 9beta) and markers of glucocorticoid sensitivity in two target tissues (subdermal blood vessels, peripheral leukocytes) in 206 healthy individuals. The BclI GG genotype group showed the least degree of skin blanching, reflecting a lower GC sensitivity of subdermal blood vessels (p=.01). No association between GR genotype and GC sensitivity of peripheral leukocytes was observed. In the same subjects we previously observed an association between GR genotype and GC sensitivity of the pituitary. Polymorphism of the GR gene might constitute a vulnerability or protection factor for stress related disorders and altered GC sensitivity.

Glucocorticoid receptor gene polymorphisms associated with more aggressive disease phenotype in MS.

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system, in which unknown environmental factors are thought to trigger disease in genetically susceptible persons. Glucocorticoids (GCs) play an important role in controlling chronic inflammatory diseases, like MS. Three polymorphisms in the glucocorticoid receptor (GR) gene (N363S, ER22/23EK and the Bcl I C/G) have been shown to alter glucocorticoid sensitivity, and therefore may influence disease course. We investigated the influence of these polymorphisms on clinical and MRI parameters. The ER22/23EK polymorphism was associated with a more aggressive MS phenotype, measured both clinically and on MRI.

A pilot study exploring the role of glucocorticoid receptor variants in primary biliary cirrhosis and primary sclerosing cholangitis.

BACKGROUND: In primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) significant therapeutic effects of glucocorticoids have not been documented. The most important clinical problem in patients with these diseases is fatigue, which is occasionally invalidating. Abnormalities in the hypothalamo-pituitary-adrenal axis have been suggested as a cause of fatigue. Most effects of glucocorticoids are mediated by the glucocorticoid receptor (hGR alpha). Recently a causative role for a splicing variant of the glucocorticoid receptor (hGR beta) has been proposed in glucocorticoid resistance in asthma and ulcerative colitis, whereas another splicing variant (hGR P) might be associated with glucocorticoid-resistant haematological malignancies. The aims of the present pilot study were to assess abnormalities in glucocorticoid receptor expression and to relate these abnormalities to the development of fatigue and to disease activity and severity in autoimmune cholestatic liver disease. METHODS: Five fatigued and five nonfatigued patients with PBC or PSC were included, and the results were compared with healthy controls. RESULTS: The expression of hGR P was not different from controls, but hGR beta mRNA was significantly increased (p=0.02) and hGR alpha mRNA decreased (p=0.015). There were no significant differences between fatigued and nonfatigued patients. A significant negative correlation between the serum activity of alkaline phosphatase and hGR alpha and hGR P mRNA was found. CONCLUSION: Although there was no relation with fatigue, abnormalities in hGR expression appear to occur in patients with these diseases, and may play a role in its pathophysiology and the poor response to glucocorticoid treatment.

Expression in hematological malignancies of a glucocorticoid receptor splice variant that augments glucocorticoid receptor-mediated effects in transfected cells.

Glucocorticoids play an important role in the treatment of a number of hematological malignancies, such as multiple myeloma. The effects of glucocorticoids are mediated through the glucocorticoid receptor alpha, the abundance of which can be modulated by alternative splicing of the glucocorticoid receptor mRNA. Two splice variants of the glucocorticoid receptor mRNA have been described: glucocorticoid receptor beta, which reportedly has a dominant negative effect on the actions of the glucocorticoid receptor alpha, and glucocorticoid receptor P, of which the effects are unknown. In this study, we have investigated the expression levels of these two splice variants at the mRNA level in multiple myeloma cells and in a number of other hematological tumors. Although the glucocorticoid receptor beta mRNA was, if at all, expressed at very low levels, considerable amounts (up to 50% of the total glucocorticoid receptor mRNA) glucocorticoid receptor P mRNA was present in most hematological malignancies. In transient transfection studies in several cell types and in multiple myeloma cell lines, the glucocorticoid receptor P increased the activity of the glucocorticoid receptor alpha. These results suggest that the relative levels of the glucocorticoid receptor alpha and the glucocorticoid receptor P may play a role in the occurrence of glucocorticoid resistance in tumor cells during the treatment of hematological malignancies with glucocorticoids.

IFN-beta1b augments glucocorticoid-induced suppression of tumor necrosis factor-alpha production by increasing the number of glucocorticoid receptors on a human monocytic cell line.

We studied the effect of recombinant interferon-beta1b (IFN-beta1b) on the sensitivity to glucocorticoids (GC) and on the number of GC receptors (GCR) in the human monocytic cell line THP-1. We found that IFN-beta1b augments the suppressive effect that dexamethasone has on the stimulated production of tumor necrosis factor-alpha (TNF-alpha), most likely related to the increased number of GCR observed after exposure to IFN-beta1b. This provides a possible clue to the mechanism of action of IFN-beta in multiple sclerosis.

Fertility and body composition after laparoscopic bilateral adrenalectomy in a 30-year-old female with congenital adrenal hyperplasia.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is caused by an inborn defect in the 21-hydroxylase gene (CYP21), leading to virilization of female patients and causing ambiguous genitals in the majority of female infants. Adult women may suffer from loss of libido, irregular or absent cycles, and reduced fertility, despite intensive medical treatment. These problems have stimulated the search for alternative treatment modalities. We present an adult female patient, who was difficult to treat medically and whose clinical situation markedly improved after laparoscopic bilateral adrenalectomy. The procedure was well tolerated and without side effects. Postoperatively the elevated serum progesterone and 17-hydroxyprogesterone levels, as well as the undetectable LH levels, normalized. The procedure resulted in marked clinical improvement. Within 12 months after surgery she lost 11 kg in weight. This weight loss consisted mainly of adipose tissue. Acne disappeared, and she had a regular 4-week menstrual cycle, with progesterone levels that are compatible with a luteal phase. The introduction of laparoscopic techniques may give an impulse to the application of surgical therapy at a larger scale in patients with 21-hydroxylase deficiency who are difficult to treat with adrenal suppression therapy.