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Original Studies |
Departments of Internal Medicine III (N.A.T.M.H., J.W.K., P.d.L., H.A.P.P., F.H.J., S.W.J.L.), Epidemiology and Biostatistics (H.B.), and Endocrinology & Reproduction (A.O.B.), Dijkzigt University Hospital and Erasmus University Rotterdam, 3015 GD Rotterdam, The Netherlands; and Julius Center for Patient Orientated Research (R.L.S., D.E.G.), Utrecht University Medical School, 3508TA Utrecht, The Netherlands
Address all correspondence and requests for reprints to: Nannette A. T. M. Huizenga, Department of Internal Medicine III, Dijkzigt University Hospital, Room Bd 277, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
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Abstract |
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In a group of 216 elderly persons, 13 heterozygotes for the N363S polymorphism were identified by PCR/single strand conformation polymorphism analysis. In 2 dexamethasone (DEX) suppression tests (DSTs), using 1 and 0.25 mg DEX, the circulating cortisol and insulin concentrations were compared between N363S carriers and controls. In the 1-mg DST, there were no differences between N363S carriers and controls, with respect to adrenal suppression, but there was a significantly higher (P < 0.05) insulin response in N363S carriers. In the 0.25-mg DST, a significantly larger (P < 0.05) cortisol suppression and higher (P < 0.05) insulin response were seen in N363S carriers. Comparison of blood pressure, body mass index (BMI), and bone mineral density (BMD) between the N363S carriers and controls showed that N363S carriers had a higher (P < 0.05) BMI but normal blood pressure. There was an obvious trend towards lower age-, BMI-, and sex-adjusted BMD in the lumbar spine in N363S carriers. GR characteristics measured in 41 controls and 9 N363S carriers in peripheral mononuclear leucocytes showed no differences between N363S carriers and controls, with respect to GR number and ligand binding affinity. However, there was a trend towards greater sensitivity to DEX in the carriers’ lymfocytes, in a mitogen-induced cell proliferation assay. In transfection assays, the capacity of the codon 363 variant to activate mouse mammary tumor virus promotor-mediated transcription in COS-1 cells was unaltered, when compared with the wild-type GR.
We conclude that in 6.0% of our study population, a polymorphism in codon 363 of the GR gene was found. Individuals carrying this polymorphism seemed healthy at clinical examination but had a higher sensitivity to exogenously administered glucocorticoids, with respect to both cortisol suppression and insulin response. Life-long exposure to the mutated allele may be accompanied by an increased BMI and a lowered BMD in the lumbar spine but does not affect blood pressure.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsIn vitro resultsDiscussionReferences |
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Variability in the sensitivity to GCs is also observed in patients treated with GCs. GCs are important therapeutic agents used for the treatment of various inflammatory and autoimmune diseases. Although plasma concentrations of GCs can be ascertained, their functional effects on target tissues are very difficult to predict (13). In clinical observations, a considerable variability among subjects is seen in their sensitivity to GC therapy, both with regard to efficacy and to the prevalence and severity of side effects.
In a previous study, 2 DEX suppression tests (DSTs) were performed in
216 elderly individuals, to gain insight into the sensitivity to GCs in
the normal population (Huizenga et al. 1997, submitted).
Furthermore, a general screening of the GR-gene in 40 persons was
performed using PCR/SSCP analysis (14). Based on indications that a
previously reported polymorphism in the 3'-region of exon 2 [which
encodes for the transactivation domain of the GR of the GR gene
(Asn363Ser, N363S, Fig. 1C
)] might be
associated with an increased sensitivity to GCs (14), we reexamined our
study population for this polymorphism and analyzed whether its
presence was associated with increased GC-sensitivity.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsIn vitro resultsDiscussionReferences |
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Two DSTs were carried out as described previously (Huizenga et al., 1997, submitted). In brief, participants were seen at the research centre after an overnight fast. Blood was drawn by venapuncture to determine serum cortisol and insulin concentrations. Participants were given a tablet of 1.00 mg DEX and instructed to ingest it at 2300 h. Next morning, fasting blood samples were obtained at the same time as the previous morning. In these samples, cortisol, insulin, and DEX concentrations were measured. Circulating cortisol DEX concentrations were determined as described previously (Huizenga et al., 1997, submitted). Serum insulin concentrations were determined using a commercially available RIA (Medgenix Diagnostics, Brussels, Belgium). Intra- and interassay variations were 8.0 and 13.7%, respectively.
Two and a half years later, all 216 participants were invited for a 0.25-mg DST; 164 subjects agreed to participate in this second test (76 men and 88 women, with mean ages of 69.1 ± 5.9 and 67.6 ± 5.6 yr, respectively). The same procedures were used as described for the 1-mg DST. In the fasting and post 0.25-mg DEX samples, glucose concentrations were determined using routine standard laboratory methods.
Both as part of the baseline examinations of the Rotterdam Study and at the second determination, body weight and height were measured to calculate body mass index (BMI, kg/m2), and sitting blood pressure was measured at the right upper arm with a random-zero sphygmomanometer. Bone mineral density (BMD) measurements were performed by dual-energy x-ray absorptiometry using a DPX-L densitometer (Lunar Radiation Corporation, Madison, WI). Standard positioning was used with anterior-posterior scans of the lumbar spine and the right proximal femur. In cases of a history of hip fracture or prothesis implantation, the left femur was scanned. Using standard software, the vertebrae L2 to L4 and the femoral neck were analyzed. Quality assurance included calibration with the standard of the machine and was performed routinely every morning. The in vivo coefficient of variation for the BMD measurements was 0.9% in the lumbar spine and 3.2% in the femoral neck (16).
PCR/SSCP analysis of the GR gene
DNA was isolated from peripheral blood leucocytes of all subjects using standard techniques. PCR amplification and SSCP analysis of the 3'-region of exon 2 of the GR gene were carried out using primer sequences and amplification and electrophoresis conditions previously described by Koper et al. (14).
Whole-cell DEX-binding assay and mitogen-induced proliferation assay
From 41 randomly selected controls and 9 carriers of the N363S mutation (see Results), 40 mL heparinized blood was drawn for a whole-cell DEX-binding assay and a mitogen-induced proliferation assay. GR characteristics in mononuclear leucocytes and the sensitivity of mononuclear leucocytes to the inhibition of phytohemagglutinin-stimulated incorporation of [3H]-thymidine by DEX were determined as described previously (3).
Cell culture and transfections
Monkey kidney (COS-1) cells were maintained in DMEM-Ham’s F-12 tissue culture medium (Life Technologies, Gaithersburg, MD), supplemented with 5% dextran-coated charcoal-treated FCS (Life Technologies). For transcription regulation studies, cells were plated at 1.0 x 105 cells/well (10 cm2), grown for 24 h, and transfected overnight by calcium phosphate precipitation, as described previously (17). Cells were transfected with 250 ng GR expression plasmid and 250 ng reporter plasmid per well. After transfection, experimental media were added. After an incubation period of 24 h, cells were harvested for the luciferase (LUC) assay, as described previously (18).
Statistical analysis
Results are reported as mean ± SE unless otherwise stated. Serum cortisol, insulin and glucose concentrations, blood pressure, BMI, BMD, and receptor characteristics were compared between N363S carriers and controls using Student’s t test. To control for possible confounders, the analyses were adjusted for BMI, if appropriate, using multiple linear regression analysis. Values for BMD were expressed as Z-scores (number of standard deviations below or above the age-, BMI-, and sex-standardized average value obtained from 2446 males and 3368 females who participated in the baseline visit for the Rotterdam study) (16).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsIn vitro resultsDiscussionReferences |
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). Sequence analysis of the fragment showed an A-to-G point
mutation at complementary DNA (cDNA) position 1220, resulting in an
asparagine-to-serine change at codon 363 (Fig. 1B). The mutation was
found to be heterozygous in all cases. The subjects without the mutation in codon 363 (controls) and the 13 persons heterozygous for the polymorphism (N363S carriers) have been investigated further, with respect to their hypothalamo-pituitary-adrenal-axis and sensitivity to GCs.
In vivo results
The group of N363S carriers consisted of four men and nine women, whereas in the control-group, the sexes were equally divided. There was one female N363S carrier who showed an additional mutation in the 5'-prime part of exon 2 of the GR gene. She was further investigated for CR (14) and left out of all comparisons.
At the first examination, no significant difference in age between the
groups was present, as shown in Table 1a.
The N363S carriers had a higher mean BMI, compared with controls, which
did not reach statistical significance (P = 0.07).
Systolic and diastolic blood pressures were not different between the
groups (Table 1a).
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). In the control group, the sexes were equally divided; the
group of N363S carriers now consisted of 5 women and 3 men. At the
second examination, the N363S carriers had a significantly higher BMI,
as compared with the control group (P < 0.04). In the
first determination, there was no statistically significant difference
in BMI between controls and N363S carriers in this subgroup (26.1
± 0.28 in controls vs. 28.1 ± 1.30 in N363S carriers,
P = 0.09). As in the first examination, there were no
differences between the groups, with respect to systolic or diastolic
blood pressure.
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Cortisol concentrations. Table 2a shows the concentrations of fasting
serum cortisol before and after administration of 1 mg DEX, the DEX
concentration, and the cortisol suppression in reaction to DEX (
cortisol). There were no differences between the controls and the N363S
carriers, either in basal levels or in response to the administration
of 1 mg DEX.
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provides the same parameters before and after the
administration of 0.25 mg DEX. Again, there were no differences in
baseline cortisol, but there was a larger decrease in cortisol
concentration ( cortisol) in response to 0.25 mg DEX in the N363S
carriers than in controls (280.5 nmol/L in controls vs.
373.9 nmol/L in N363S carriers, P < 0.09, unadjusted
data). This difference in cortisol was statistically significant
when the data were adjusted for BMI (443.8 in controls vs.
553.6 in N363S carriers, P < 0.05). Adjusting for BMI
was necessary because there was a statistically significant difference
in BMI between controls and N363S carriers, and BMI is known to
influence the cortisol concentration. The actual DEX concentrations
were equal in both groups (P = 0.50), so the higher
response in the N363S carriers was not caused by higher DEX
concentrations.
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shows the fasting insulin
concentrations before and after the administration of 1 and 0.25
mg DEX, respectively, and the increase in insulin levels in response to
DEX administration. To be certain that only the data from subjects with
a normal carbohydrate tolerance were analyzed, subjects with
hyperinsulinemia or diabetes mellitus (fasting insulin or glucose
concentrations above 25 mU/L or 7.8 mmol/L, respectively) were excluded
from this analysis (20 controls excluded, n = 178; and 2 N363S
carriers excluded, n = 10). There was a significant increase in
insulin concentrations in response to the administration of 1 mg DEX
among the remaining 188 subjects (12.9 ± 0.53 mU/L before and
19.1 ± 0.80 mU/L after DEX administration, respectively,
P < 0.001). There were no significant differences
between the groups in fasting or post-DEX insulin concentrations, but
there was a significantly larger increase in insulin levels in the
N363S carriers in response to 1 mg DEX (P < 0.01),
compared with controls. As mentioned before, these differences in
insulin response were not caused by differences in DEX concentrations
between the two groups (Table 2a).
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BMD. In Fig. 2, the mean values
and SD for BMD in the lumbar spine and the femoral neck in
controls and N363S carriers expressed as Z-scores are shown. The figure
shows that in the lumbar spine, there was a trend towards lower BMD in
the N363S carriers, compared with controls (z-scores: -0.48
vs. 0.02 respectively, P = 0.08). In the
femoral neck, there were no differences in BMD between the two groups
(P = 0.67).
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In vitro results |
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TopAbstractIntroductionMaterials and MethodsResultsIn vitro resultsDiscussionReferences |
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Figure 3 shows the results from
50 whole-cell DEX-binding assays and mitogen-induced proliferation
assays (41 randomly selected controls and 9 N363S carriers). The number
of receptors (n, Fig. 3A) and the dissociation constant
(Kd, Fig. 3B) were not different in both groups (n =
7056 ± 200 in controls, n = 7242 ± 645 in N363S
carriers; Kd = 10.6 ± 0.63 in controls,
Kd = 8.5 ± 1.14 in N363S carriers, respectively).
Also, no statistically significant difference in 50% of the maximal
inhibition (IC50) values between the N363S carriers and
controls was found; as shown in Fig. 3C, there was a trend towards a
lower IC50 in the N363S carriers (IC50 =
47.7 ± 9.6 in controls, IC50 = 21.8 ± 6.4 in
N363S carriers, respectively).
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).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsIn vitro resultsDiscussionReferences |
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A 1-mg DST, carried out to assess differences in GC sensitivity, showed
no differences in early morning post-DEX cortisol concentrations.
Because 1 mg may be a relatively high dose (93% of the subjects
suppressed to a level 
50 nmol/L), we also carried out a 0.25-mg
DST. In this experiment, post-DEX cortisol concentrations showed a much
broader range than after 1 mg DEX (Huizenga et al., 1997,
submitted). The decease in early morning cortisol levels ( cortisol)
was significantly greater in N363S carriers than in controls. The
absolute post-DEX cortisol levels also were lower in N363S carriers,
but this difference was not statistically significant.
Another parameter for the sensitivity to exogenously administered GCs is the fasting insulin concentration before and after DEX administration. It has been recognized for a long time that GCs impair insulin-mediated glucose metabolism and induce insulin resistance (19). In this study, fasting insulin levels before DEX were similar in the two groups, but in response to the administration of 1 mg DEX, there was a significantly larger increase in the serum insulin levels in N363S carriers than in controls. After the administration of 0.25 mg DEX, there was a slight drop in insulin concentrations in the control group, whereas in the N363S carriers, mean insulin concentrations rose. It seems that in controls, 0.25 mg DEX is not sufficient to induce insulin resistance, whereas in the N363S carriers, this low dose of DEX forces the insulin concentrations to increase, to maintain a normal plasma glucose concentration. These data support the assumption that N363S carriers have an increased sensitivity to GCs.
With respect to the potential long-term effects of the codon 363 mutation, three parameters were investigated: BMI, blood pressure, and BMD. GCs are involved in the syndrome of abdominal obesity caused by stimulatory effects on lipid accumulation in adipose tissue (20). Patients with Cushing’s syndrome have a centripetal fat distribution, resulting in a higher BMI. This seems to be caused by an increased lipoprotein lipase activity in combination with a lowered capacity for fat mobilization in the central regions (21). The net effect of hypercortisolemia is an increase at triglyceride storage in visceral adipocytes (22). At the second examination, the N363S carriers had a significantly higher BMI than controls, whereas at the first examination, there was a trend towards a higher BMI in the N363S carriers. The higher BMI observed in in these persons supports the view that they are more sensitive to effects of GCs. There were, however, no differences in blood pressure between the two groups, neither at the first nor at the second examination.
It is well known that patients under treatment with GCs show a reduced bone mass and an increased fracture risk. GCs have been found to influence bone and calcium metabolism at several levels (23, 24). The effects of GCs on BMD are more profound on trabecular bone than on cortical bone (24). The data from the present investigation indeed demonstrate a lower BMD in the lumbar spine of the N363S carriers, compared with control subjects. However, this difference in BMD did not reach statistical significance. In the femoral neck, there were no differences in BMD between the groups.
Other investigations previously have found the N363S polymorphism in a
CR patient, who also showed a splice-site deletion (10), and in the
small-cell long-cancer cell lines DMS-79 (25) and COR L24 (26). These
authors found no significant difference in the capacity of this variant
GR, relative to the wild-type, to activate transcription of the CAT
gene in an MMTV-driven reporter construct after transfection into COS-1
cells. Our own results, using the more sensitive MMTV-LUC system, also
do not indicate a difference between N363S and wild-type GR in this
respect. Apart from transcriptional activation, GR also is involved in
transcriptional repression of target genes. It does so either by
binding directly to so-called negative glucocorticoid-responsive
elements (27, 28) or via interactions with factors such as activating
protein-1 (AP-1) (29, 30) or nuclear factor-
B (21, 22, 23), thereby
preventing these factors from activating their target genes.
Cotransfection experiments have shown that the codon 363 variant has an
unaltered capacity to repress target genes via negative
glucocorticoid-responsive elements or via the above mentioned
transcription factors (31).
Our results of the whole-cell DEX-binding assays demonstrate no differences between the variant- and the wild-type GR in this respect, but because the mutation is located in the N-terminal part of the GR, no alterations in the number of receptors or the ligand binding capacity in peripheral mononuclear leucocytes from N363S carriers were expected. The mitogen-induced proliferation assay, on the other hand, reflects the cellular response to GCs (32). One would expect to find alterations in the suppressibility of mitogen-stimulated thymidine incorporation in cultured leucocytes from N363S carriers. Indeed, a trend towards lower IC50 values in the N363S carriers, compared with controls, was observed; but these differences did not reach statistical significance, probably as a result of the wide range of values obtained in controls.
In summary, we have shown significant effects of the N363S mutation on changes in insulin and cortisol levels after the administration of DEX, indicating increased sensitivity to acutely increased GC levels. Long-term effects of increased sensitivity to endogenous GCs (which might be partly compensated by counterregulatory mechanisms) could be reflected in the trends towards increased BMI and decreased BMD in trabecular bone. In this connection, it is of interest that about 5% of the patients treated with GCs develop severe side effects soon after starting the therapy; N363S carriers might be included in this subpopulation. The apparent discrepancy between these in vivo effects and our inability to confirm this increased sensitivity to GCs in vitro is likely to be caused by the earlier-mentioned broad spectrum of regulatory mechanisms in which GCs and their receptors are involved. We showed earlier that GR mutations can effect transcriptional activation and repression differently (31). It could well be that COS-1 cells lack the transcription factors determining the effect of the N363S mutation in vivo and that this is an impediment for the study of subtle effects of this mutation in vitro.
Finally, our results may indicate that this polymorphism is linked to an additional genetic alteration in a gene of which the product is involved in the observed phenotypic differences. This yet-unknown factor might interact with the GR protein to exert its effect. However, for diagnostic purposes, the recognition of a point mutation in the GR gene linked to a phenotypic difference may prove very useful, whether this may solely, in part, or not at all be a consequence of altered GR function. A next step will be to investigate whether the codon 363 polymorphism might predict an increased sensitivity to the development of early and/or serious side effects during therapy with GCs.
In conclusion, our findings show that in vivo, the codon 363 variant of the GR is associated with an increased sensitivity to GCs in the direct response to exogenously administered DEX. BMI and BMD might also be effected by this variant GR. The molecular basis for this increased sensitivity remains to be elucidated.
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Footnotes |
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Received April 28, 1997.
Revised September 11, 1997.
Accepted September 30, 1997.
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H. Russcher, P. Smit, E. L. T. van den Akker, E. F. C. van Rossum, A. O. Brinkmann, F. H. de Jong, S. W. J. Lamberts, and J. W. Koper Two Polymorphisms in the Glucocorticoid Receptor Gene Directly Affect Glucocorticoid-Regulated Gene Expression J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5804 - 5810. [Abstract] [Full Text] [PDF]
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W. J.E. Tissing, J. P.P. Meijerink, M. L. den Boer, B. Brinkhof, E. F.C. van Rossum, E. R. van Wering, J. W. Koper, P. Sonneveld, and R. Pieters Genetic Variations in the Glucocorticoid Receptor Gene Are Not Related to Glucocorticoid Resistance in Childhood Acute Lymphoblastic Leukemia Clin. Cancer Res., August 15, 2005; 11(16): 6050 - 6056. [Abstract] [Full Text] [PDF]
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Y.-Z. Liu, V. Dvornyk, Y. Lu, H. Shen, J. M. Lappe, R. R. Recker, and H.-W. Deng A Novel Pathophysiological Mechanism for Osteoporosis Suggested by an in Vivo Gene Expression Study of Circulating Monocytes J. Biol. Chem., August 12, 2005; 280(32): 29011 - 29016. [Abstract] [Full Text] [PDF]
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 J. C. C. Rocha, C. Cheng, W. Liu, S. Kishi, S. Das, E. H. Cook, J. T. Sandlund, J. Rubnitz, R. Ribeiro, D. Campana, et al. Pharmacogenetics of outcome in children with acute lymphoblastic leukemia Blood, June 15, 2005; 105(12): 4752 - 4758. [Abstract] [Full Text] [PDF]
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I. S. Federenko, M. Nagamine, D. H. Hellhammer, P. D. Wadhwa, and S. Wust The Heritability of Hypothalamus Pituitary Adrenal Axis Responses to Psychosocial Stress Is Context Dependent J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6244 - 6250. [Abstract] [Full Text] [PDF]
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E. F. C. van Rossum, P. G. Voorhoeve, S. J. te Velde, J. W. Koper, H. A. Delemarre-van de Waal, H. C. G. Kemper, and S. W. J. Lamberts The ER22/23EK Polymorphism in the Glucocorticoid Receptor Gene Is Associated with a Beneficial Body Composition and Muscle Strength in Young Adults J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 4004 - 4009. [Abstract] [Full Text] [PDF]
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 E. R. Bleecker Roundtable Discussion Chest, August 1, 2004; 126(2_suppl_1): 159S - 161S. [Full Text] [PDF]
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S. Wust, E. F. C. van Rossum, I. S. Federenko, J. W. Koper, R. Kumsta, and D. H. Hellhammer Common Polymorphisms in the Glucocorticoid Receptor Gene Are Associated with Adrenocortical Responses to Psychosocial Stress J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 565 - 573. [Abstract] [Full Text] [PDF]
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A. Stevens, D. W. Ray, E. Zeggini, S. John, H. L. Richards, C. E. M. Griffiths, and R. Donn Glucocorticoid Sensitivity Is Determined by a Specific Glucocorticoid Receptor Haplotype J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 892 - 897. [Abstract] [Full Text] [PDF]
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A. A. Syed, J. A. E. Irving, C. P. F. Redfern, A. G. Hall, N. C. Unwin, M. White, R. S. Bhopal, K. G. M. M. Alberti, and J. U. Weaver Low Prevalence of the N363S Polymorphism of the Glucocorticoid Receptor in South Asians Living in the United Kingdom J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 232 - 235. [Abstract] [Full Text] [PDF]
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 E. F.C. van Rossum and S. W.J. Lamberts Polymorphisms in the Glucocorticoid Receptor Gene and Their Associations with Metabolic Parameters and Body Composition Recent Prog. Horm. Res., January 1, 2004; 59(1): 333 - 357. [Abstract] [Full Text]
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 I. Fleury, P. Beaulieu, M. Primeau, D. Labuda, D. Sinnett, and M. Krajinovic Characterization of the BclI Polymorphism in the Glucocorticoid Receptor Gene Clin. Chem., September 1, 2003; 49(9): 1528 - 1531. [Full Text] [PDF]
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 R. Rosmond, B. J. Morris, R. C.Y. Lin, and X. L. Wang Glucocorticoid Receptor Gene and Coronary Artery Disease: Right Idea, Wrong Gene Variant? * Response Hypertension, August 1, 2003; e4(2): . [Full Text] [PDF]
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R. C.Y. Lin, X. L. Wang, and B. J. Morris Association of Coronary Artery Disease With Glucocorticoid Receptor N363S Variant Hypertension, March 1, 2003; 41(3): 404 - 407. [Abstract] [Full Text] [PDF]
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H. Vermeer, B. I. Hendriks-Stegeman, B. van der Burg, S. C. van Buul-Offers, and M. Jansen Glucocorticoid-Induced Increase in Lymphocytic FKBP51 Messenger Ribonucleic Acid Expression: A Potential Marker for Glucocorticoid Sensitivity, Potency, and Bioavailability J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 277 - 284. [Abstract] [Full Text] [PDF]
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 E. F.C. van Rossum, J. W. Koper, N. A.T.M. Huizenga, A. G. Uitterlinden, J. A.M.J.L. Janssen, A. O. Brinkmann, D. E. Grobbee, F. H. de Jong, C. M. van Duyn, H. A.P. Pols, et al. A Polymorphism in the Glucocorticoid Receptor Gene, Which Decreases Sensitivity to Glucocorticoids In Vivo, Is Associated With Low Insulin and Cholesterol Levels Diabetes, October 1, 2002; 51(10): 3128 - 3134. [Abstract] [Full Text] [PDF]
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 M. R. Yudt and J. A. Cidlowski The Glucocorticoid Receptor: Coding a Diversity of Proteins and Responses through a Single Gene Mol. Endocrinol., August 1, 2002; 16(8): 1719 - 1726. [Abstract] [Full Text] [PDF]
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J. W. Tomlinson, N. Draper, J. Mackie, A. P. Johnson, G. Holder, P. Wood, and P. M. Stewart Absence of Cushingoid Phenotype in a Patient with Cushing's Disease due to Defective Cortisone to Cortisol Conversion J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 57 - 62. [Abstract] [Full Text] [PDF]
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M. G. Dobson, C. P. F. Redfern, N. Unwin, and J. U. Weaver The N363S Polymorphism of the Glucocorticoid Receptor: Potential Contribution to Central Obesity in Men and Lack of Association with Other Risk Factors for Coronary Heart Disease and Diabetes Mellitus J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 2270 - 2274. [Abstract] [Full Text]
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 R. Rosmond, C. Bouchard, and P. Björntorp Tsp509I polymorphism in exon 2 of the glucocorticoid receptor gene in relation to obesity and cortisol secretion: cohort study BMJ, March 17, 2001; 322(7287): 652 - 653. [Full Text]
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P.L.P. Brand Inhaled corticosteroids reduce growth. Or do they? Eur. Respir. J., February 1, 2001; 17(2): 287 - 294. [Abstract] [Full Text] [PDF]
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M. Ebrecht, A. Buske-Kirschbaum, D. Hellhammer, S. Kern, N. Rohleder, B. Walker, and C. Kirschbaum Tissue Specificity of Glucocorticoid Sensitivity in Healthy Adults J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3733 - 3739. [Abstract] [Full Text]
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M. Bergendahl, A. Iranmanesh, T. Mulligan, and J. D. Veldhuis Impact of Age on Cortisol Secretory Dynamics Basally and as Driven by Nutrient-Withdrawal Stress J. Clin. Endocrinol. Metab., June 1, 2000; 85(6): 2203 - 2214. [Abstract] [Full Text]
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 T.M. O'CONNOR, D.J. O'HALLORAN, and F. SHANAHAN The stress response and the hypothalamic-pituitary-adrenal axis: from molecule to melancholia QJM, June 1, 2000; 93(6): 323 - 333. [Abstract] [Full Text] [PDF]
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N. A. T. M. Huizenga, P. de Lange, J. W. Koper, W. W. de Herder, R. Abs, J. H. L. M. v. Kasteren, F. H. de Jong, and S. W. J. Lamberts Five Patients with Biochemical and/or Clinical Generalized Glucocorticoid Resistance without Alterations in the Glucocorticoid Receptor Gene J. Clin. Endocrinol. Metab., May 1, 2000; 85(5): 2076 - 2081. [Abstract] [Full Text]
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A. G. Hillmann, J. Ramdas, K. Multanen, M. R. Norman, and J. M. Harmon Glucocorticoid Receptor Gene Mutations in Leukemic Cells Acquired in Vitro and in Vivo Cancer Res., April 1, 2000; 60(7): 2056 - 2062. [Abstract] [Full Text]
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R. C. Y. Lin, W. Y. S. Wang, and B. J. Morris Association and Linkage Analyses of Glucocorticoid Receptor Gene Markers in Essential Hypertension Hypertension, December 1, 1999; 34(6): 1186 - 1192. [Abstract] [Full Text] [PDF]
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R. C Y Lin, W. Y S Wang, and B. J Morris High penetrance, overweight, and glucocorticoid receptor variant: case-control study BMJ, November 20, 1999; 319(7221): 1337 - 1338. [Full Text]
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 I. R. Reid Glucocorticoid Osteoporosis: Reid IR Glucocorticoid osteoporosis J Intensive Care Med 1999, 14231-242 J Intensive Care Med, September 1, 1999; 14(5): 231 - 242. [PDF]
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 S. Takami, Z. Y. H. Wong, M. Stebbing, and S. B. Harrap Linkage analysis of glucocorticoid and beta 2-adrenergic receptor genes with blood pressure and body mass index Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1379 - H1384. [Abstract] [Full Text] [PDF]
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G. P. Chrousos and P. W. Gold A Healthy Body in a Healthy Mind--and Vice Versa--The Damaging Power of "Uncontrollable" Stress J. Clin. Endocrinol. Metab., June 1, 1998; 83(6): 1842 - 1845. [Full Text]
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