76 research outputs found
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
Clinical aspects of glucocorticoid sensitivity
Recent studies demonstrate that primary (hereditary) abnormalities in the glucocorticoid receptor gene make 6.6% of the normal population relatively 'hypersensitive' to glucocorticoids, while 2.3% are relatively 'resistant.' These abnormalities might explain why some individuals develop severe adverse effects during low dose glucocorticoid therapy, while others do not develop side effects even during long-term therapy with a much higher dose. Awareness of this heterogeneity in glucocorticoid sensitivity in the normal population might eventually allow the prediction of a 'safe' dose of glucocorticoid in individual patients. 'Resistance' to the beneficial clinical effects of glucocorticoid therapy in part of the patients with severe rheumatoid arthritis and asthma is probably rarely related to generalized primary (hereditary) glucocorticoid resistance. In the majority of patients this 'resistance' seems to be acquired and localized to the sites of inflammation, where it reflects high local cytokine production, which interferes with glucocorticoid action. Recognition of localized, acquired glucocorticoid resistance is of great importance indicating as alternative drug therapy with other immune-modulating drugs like cyclosporin and methotrexate. Chronic high dose glucocorticoid treatment in such patients is ineffective in alleviating symptomatology, while generalized side effects occur, reflecting the patient's normal systemic sensitivity to these drugs
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
Decreased ligand affinity rather than glucocorticoid receptor down-regulation in patients with endogenous Cushing's syndrome
OBJECTIVE: Glucocorticoids (GCs) serve a variety of important functions
throughout the body. The synthesis and secretion of GCs are under the
strict influence of the hypothalamo-pituitary-adrenal axis. The mechanisms
of action of GCs are mediated by the intracellular glucocorticoid receptor
(GR). Over the years, many studies have been performed concerning th
Differential hormone-dependent transcriptional activation and -repression by naturally occurring human glucocorticoid receptor variants
The molecular mechanisms underlying primary glucocorticoid resistance or
hypersensitivity are not well understood. Using transfected COS-1 cells as
a model system, we studied gene regulation by naturally occurring mutants
of the glucocorticoid receptor (GR) with single-point mutations in the
regions encoding the ligand-binding domain or the N-terminal domain
reflecting different phenotypic expression. We analyzed the capacity of
these GR variants to regulate transcription from different promoters,
either by binding directly to positive or negative glucocorticoid-response
elements on the DNA or by interfering with protein-protein interactions.
Decreased dexamethasone (DEX) binding to GR variants carrying mutations in
the ligand-binding domain correlated well with decreased capacity to
activate transcription from the mouse mammary tumor virus (MMTV) promoter.
One variant, D641V, which suboptimally activated MMTV promoter-mediated
transcription, repressed a PRL promoter element containing a negative
glucocorticoid-response element with wild type activity. DEX-induced
repression of transcription from elements of the intercellular adhesion
molecule-1 promoter via nuclear factor-kappaB by the D641V variant was
even more efficient compared with the wild type GR. We observed a general
DEX-responsive AP-1-mediated transcriptional repression of the
collagenase-1 promoter, even when receptor variants did not activate
transcription from the MMTV promoter. Our findings indicate that different
point mutations in the GR can affect separate pathways of gene regulation
in a differential fashion, which can explain the various phenotypes
observed
Five patients with biochemical and/or clinical generalized glucocorticoid resistance without alterations in the glucocorticoid receptor gene
Cortisol resistance (CR) is a rare disease characterized by a generalized
reduced sensitivity of end-organs to the actions of glucocorticoids (GCs)
The effect of common genetic variation in 11β-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. 11β-Hydroxysteroid dehydrogenase type 1 (11β-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 11β-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 11β-HSD1 is implicated in human HPA axis regulation and susceptibility to depression. Copyrigh
Interperson variability but intraperson stability of baseline plasma cortisol concentrations, and its relation to feedback sensitivity of the hypothalamo-pituitary-adrenal axis to a low dose of dexamethasone in elderly individuals
In the present study, we investigated whether the negative feedback action
of glucocorticoids (GCs) on the hypothalamo-pituitary-adrenal (HPA) axis
changes with age. We performed a 1-mg dexamethasone (DEX) suppression test
in 216 healthy elderly individuals. To investigate individual variability
of feedback sensitivity in more detail, 2.5 yr later a 0.25-mg DEX
suppression test was carried out in 164 of the same individuals. We
investigated whether there was an effect of age or gender on both basal
and post-DEX cortisol levels, as well as on the concentration of DEX.
Furthermore, we examined whether the reactions to the two doses of DEX
differed, and whether indications for an intraperson stability of baseline
cortisol levels could be found. Neither the pre- nor the post-1-mg DEX
plasma cortisol concentrations showed a correlation with age, and there
were no differences between men and women. The same was true for the pre-
and post-0.25-mg DEX cortisol concentrations. In reaction to 1 mg DEX,
over 90% of the subjects investigated showed a cortisol suppression to
levels below 50 nmol/L. After the administration of 0.25 mg DEX, there was
a much wider range in post-DEX cortisol concentrations. After the
administration of 1 mg DEX, there was a significant correlation between
liver function parameters and plasma DEX concentrations in males, and
there was a correlation between body mass index and plasma DEX
concentration in females. Plasma DEX concentrations after the
administration of 1 mg and 0.25 mg DEX were closely correlated within
subjects (P < 0.001). There was an intraindividual stability of serum
cortisol levels determined at an interval of 2.5 yr. Furthermore, the
individuals with the highest baseline cortisol concentrations also had the
highest post-0.25-mg DEX cortisol concentrations, indicating a close
relationship between basal cortisol levels and the feedback sensitivity of
the HPA axis to a low dose of DEX. These observations suggest a genetic
influence on the set point of the HPA axis. Aging does not seem to lead to
a change in HPA activity as measured by early morning total cortisol
levels. Also, no changes in the sensitivity of the feedback system to DEX
were observed with age. DEX metabolism is influenced by liver function (in
males) and by body mass index (in females)
Systematic evaluation of corticosteroid use in obese and non-obese individuals: A multi-cohort study
Background: Although the use of corticosteroids has been linked to high incidence of weight gain, no data are available concerning the differences in corticosteroid use between a diverse obese population and non-obese individuals. The main purpose of this study was to systematically explore t
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