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Original Studies |
Departments of Internal Medicine III (N.A.T.M.H., J.W.K., P.deL., H.A.P.P., F.H.deJ., S.W.J.L.), Erasmus University Rotterdam and Dijkzigt University Hospital, 3015 GD Rotterdam; and Julius Center for Patient Orientated Research (R.P.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-a Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.
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Abstract |
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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).
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Introduction |
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TopAbstractIntroductionSubjects, Methods, and MaterialsResultsDiscussionReferences |
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Basal concentrations of plasma cortisol exhibit a wide variation between normal subjects (1). Little is known concerning the question of whether cortisol levels are stable within subjects. Interperson variation and intraperson stability of plasma cortisol levels have not been extensively investigated. For the intraperson constancy, as reported in twins, genetic factors may be of importance (2, 3). The variation in hypothalamo-pituitary-adrenal (HPA) activity between individuals is thought to be a function of many influences, including the individual’s feedback sensitivity, circadian rhythm, and episodic secretion, whereas cortisol binding globulin (CBG) levels also affect cortisol concentrations (3). Over the years, the effects of age and gender on the function of the pituitary-adrenocortical axis have been extensively investigated. These studies, however, have resulted in contradictory results. Both circadian patterns of cortisol and ACTH secretion and random morning plasma cortisol concentrations were reported to be unaltered in the elderly (4, 5, 6, 7). On the other hand, an age-related trend towards increased levels of evening plasma cortisol was reported (8), and increased mean cortisol levels derived from 24-h frequent sampling were found in elderly men but not in women (9). Finally, Waltman et al. (10) reported that aging in humans is not accompanied by a significant increase in spontaneous ACTH or cortisol secretion or by a decrease in HPA sensitivity to GC feedback suppression.
Another controversy in the literature concerns the influence of age and gender on the dexamethasone (DEX) suppression test (DST). The 1-mg overnight DST is a convenient screening procedure for patients with Cushing’s syndrome. Administration of 1 mg of DEX at 2300 h to normal subjects suppresses the nocturnal surge in ACTH production and, as a consequence, cortisol levels are low when measured the next morning (11). In patients suffering from endogenous Cushing’s syndrome of any etiology, cortisol levels are less sensitive to DEX. Another application for this test was found in depressed patients, who may show an insufficient cortisol suppression in reaction to the 1-mg DST as well (12). To interpret this test in geriatric patients, many studies were done to investigate the effect of age per se on the duration and pattern of cortisol suppression by DEX. Also, many drugs and medical conditions may affect the outcome of the DST (13). In some studies (14, 15) there were significant correlations between age and post-DEX cortisol concentrations, whereas in other studies no such correlations could be demonstrated (16, 17). Irrespective of psychiatric disturbances, a decreased sensitivity to GC feedback may be prevalent in the very elderly (>80 yr) (18).
In the present study we investigated whether the autoregulatory negative feedback action of GCs on the HPA axis changes with age. We performed a 1-mg DST in 216 healthy elderly individuals, and 2.5 yr later a 0.25-mg DST was carried out in 164 out of these 216 subjects. In addition, it was investigated whether there was an effect of age or gender on basal and post-DEX cortisol, as well as on the metabolism of DEX. Furthermore it was examined whether there were differences in response to the two doses of DEX administered, and whether the suppression of cortisol was related to baseline cortisol levels. Finally, the two baseline cortisol concentrations in the 164 individuals who underwent two examinations were compared to get an impression about the intraperson stability of these concentrations.
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Subjects, Methods, and Materials |
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TopAbstractIntroductionSubjects, Methods, and MaterialsResultsDiscussionReferences |
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1-mg DST
Participants were seen at the research center after an overnight
fast. Between 0800 and 0900 h blood was drawn by venapuncture to
determine the serum cortisol concentrations (pre-DEX concentrations),
using RIA kits obtained from DPC (Los Angeles, CA). Intra- and
interassay variations were below 8.0% and 9.5%, respectively. Also,
serum concentrations of the liver enzymes alanine aminotransferase
(ALAT), aspartate aminotransferase (ASAT), and 
-glutamyltransferase
(-GT) were determined, using standard methods. At the same time, the
body weight and height of the volunteers were measured, and the body
mass index (BMI, kg/m2) was calculated to be 26.4 ±
0.29 for the men and 26.4 ± 0.39 for the women (mean ±
SE).
In the evening following the first visit to the research center, a 1-mg DST was carried out. Participants were given a tablet of 1 mg DEX and instructed to ingest it at 2300 h. The next morning, fasting blood samples were obtained by venapuncture at the same time as the previous morning. In these samples, cortisol and DEX concentrations were measured. DEX levels were estimated by RIA using an antiserum supplied by IgG Corp. (Nashville, TN) and [3H]-DEX from Amersham (Little Chalfont, UK). Intra- and interassay variations were below 8.5 and 14.2%, respectively. Sensitivity of this assay, defined as mean result of assay of non-DEX containing plasma + 3 SD, was 0.13 nmol/L.
0.25-mg DST
To get more insight into individual variability of feedback sensitivity to GCs, all 216 participants were invited for a second DST 2.5 yr later. Out of this original group, 11 subjects had died and 6 subjects could not be reached. Eventually, 164 individuals (76 men and 88 women with mean ages of 69.1 ± 5.9 and 67.6 ± 5.6 yr, respectively), agreed to participate in a second test. The same procedures were used as described for the 1-mg DST but using 0.25 mg DEX. The samples obtained from the first and the second baseline visit as well as the pre- and post-1- and 0.25-mg DEX samples were determined in separate assays. To investigate possible differences in cortisol concentrations caused by interassay variation, baseline samples obtained at the first and second examination from 20 randomly selected subjects were determined in a single cortisol assay.
0.25-, 0.50-, and 1-mg DST in healthy laboratory personnel
A group of nine healthy laboratory workers (age 26–49 yr) agreed to participate in a series of DSTs with increasing doses of DEX. At intervals of 2 weeks (to ensure the absence of interference with DEX effects from the previous test) we performed three DSTs, using 0.25, 0.50, and 1 mg DEX as described above. None of these individuals were using medication or oral contraceptives.
Statistical analysis
All results are reported as the mean ± SE. Serum cortisol concentrations in men and women were compared using the two-sample Wilcoxon rank-sum test. The Wilcoxon matched pairs signed rank sum test was used to compare serum cortisol concentrations before and after DEX administration and between the two examinations in each person.
To assess the relationships between cortisol and age and between DEX and liver enzymes, BMI, and age, linear regression analysis was used. To calculate the degree of association between these parameters, the Pearson correlation coefficient (r) was calculated. Partial correlation coefficients were used to adjust for several parameters.
Spearman’s rank correlation coefficient (r) was used to assess the association between the DEX concentrations after the administration of the two different doses and between basal cortisol concentrations at the two examinations.
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Results |
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TopAbstractIntroductionSubjects, Methods, and MaterialsResultsDiscussionReferences |
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Table 1
shows the baseline
concentrations of serum cortisol in the whole group of 216 elderly
subjects and in males and females separately. There was no difference
in cortisol concentrations between men and women. Using linear
regression analysis, no significant correlation could be demonstrated
between the baseline serum cortisol concentration and age
(P > 0.2).
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Figure 1A shows the distribution of
cortisol concentrations before and after 1 mg DEX. Out of the 216
healthy individuals, 196 (90.7%) showed a post-DEX cortisol
concentration below 50 nmol/L. Only five individuals (2.3%) had
post-DEX cortisol concentrations above 140 nmol/L, which is the cut-off
point for a normal test result when the DST is used as a screening
procedure for Cushing’s syndrome in our clinic (20). These five
individuals have been further investigated for cortisol resistance and
are reported separately (21).
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, there was no difference between men and women with
regard to their post-DEX cortisol concentrations. There was no
correlation between post-DEX cortisol concentrations and age
(P = 0.3).
Figure 2A shows the distribution of the
early morning plasma DEX concentrations after the administration of 1
mg DEX. None of the individuals investigated had an unmeasurably low
circulating DEX level, indicating that all participants indeed had
ingested the DEX tablets. Six individuals had DEX concentrations below
1.8 nmol/L. Three of them were using antiepileptic drugs.
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shows the results of the linear
regression analysis for the relationship between DEX and several
factors that might influence the metabolism of DEX. In males, there was
a positive correlation between concentrations of DEX and the liver
enzymes ALAT, ASAT, and -GT. After deletion of the results of the 35
men who had supranormal levels of at least one of the enzymes, the
relationship was no longer significant. In females, these correlations
were not significant, despite the fact that in 21 of them increased
levels of at least one of the enzymes was found. In women there was a
significant correlation between DEX concentrations and BMI that was not
present in men. Neither in men nor in women was there a relation
between the DEX concentration and age. Baseline cortisol concentrations
were not correlated with liver function tests in either sex.
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cortisol) and the DEX concentration
(P > 0.4). 0.25-, 0.50-, and 1-mg DST in healthy laboratory personnel
From the results of the 1-mg DST, it became clear that more than
90% of the subjects investigated demonstrated a suppression of
cortisol to levels below 50 nmol/L. Therefore 1 mg DEX might be too
high a suppressive dose to allow the detection of individual
differences in sensitivity of the HPA axis to GCs. A pilot study with
several doses of DEX was subsequently carried out in nine healthy
volunteers. Figure 3A shows the cortisol
and DEX levels after the administration of 0.25, 0.50, and 1 mg DEX.
There was a considerable variability in baseline serum cortisol
concentrations. The administration of increasing doses of DEX resulted
in a dose-dependent increase in mean circulating DEX levels and a
dose-dependent decrease of cortisol levels. The administration of 0.25
mg DEX even enlarged the range of serum cortisol levels: in one subject
the serum cortisol level was suppressed to a level below 50 nmol/L,
whereas in three individuals post-DEX cortisol levels remained above
200 nmol/L. After 0.50 mg DEX, the range became more narrow, and after
the administration of 1 mg DEX, all individuals had a cortisol
concentration below 50 nmol/L.
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, there was a considerable individual variability in
cortisol suppression in reaction to a given DEX concentration. This
variability was not caused by individual differences in CBG
concentrations (data not shown). Using linear regression analysis,
there was no significant relationship between the individual DEX
concentrations and the individual degree of cortisol suppression or the
actual post-DEX cortisol levels (all P values > 0.8).
This suggests that different individuals suppress the HPA axis to a
variable degree in reaction to similar circulating DEX
concentrations. 0.25-mg DST
Anticipating that a lower dose of DEX would indeed allow a better insight into the individual variability of the feedback sensitivity of the HPA axis, all subjects who originally participated in the 1-mg DST were invited to join in a 0.25-mg DST approximately 2.5 yr later.
Table 3 shows the mean baseline levels of
serum cortisol in 164 elderly subjects. The second baseline mean serum
cortisol concentrations turned out to be significantly higher than
those before the 1-mg DST. The original cortisol levels of these 164
subjects amounted to 503.0 ± 11.3 nmol/L, whereas the follow up
baseline cortisol levels were 547.8 ± 1.9 nmol/L
(P < 0.001). Furthermore, in these 164 individuals,
there was a significant difference in cortisol levels between men and
women (P < 0.04). Linear regression analysis for
baseline cortisol levels and age showed no significant correlation
(P > 0.06). Random samples from 20 individuals from
both groups of baseline samples were determined in a single assay. Mean
cortisol concentrations in both groups were identical, and there was no
difference between the sexes (data not shown). This suggests that there
was no age-related change in cortisol concentrations, but that the
differences found should be explained by the interassay variation.
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shows the distribution of cortisol concentrations before and
after 0.25 mg DEX. There was a much wider range in post-DEX cortisol
concentrations than observed after 1 mg DEX (cf. Fig. 1A). A
small number of individuals suppressed their cortisol levels to below a
level of 140 nmol/L (n = 34, 20.7%), whereas only nine
individuals (5.5%) suppressed to levels below 50 nmol/L.
Table 3 shows the serum cortisol concentrations after the
administration of 0.25 mg DEX. There are no differences between men and
women.
The distribution of DEX concentrations after 0.25 mg DEX is shown in
Fig. 2A. Mean DEX concentrations after this low dose of DEX were
significantly lower than after 1 mg DEX (P < 0.001).
On the other hand, as shown in Fig. 2B, subjects who showed the highest
DEX concentrations after the administration of 1 mg DEX, also showed
the highest levels after the administration of 0.25 mg DEX (r =
0.66, P < 0.001). Figure 2B shows only two out of the
six individuals with DEX concentrations below 1.8 nmol/L, because four
of those showing the lowest DEX concentrations after 1 mg DEX did not
participate in the 0.25-mg DST.
Figure 4, A and B show the linear
regression analysis for the relationship between pre- and post-0.25-mg
DEX cortisol concentrations (r = 0.39, P <
0.001), and the DEX concentration and the post-DEX cortisol
concentrations (r = -0.24, P < 0.002). Adjusting
the relationship between pre- and post-DEX cortisol concentrations for
the DEX concentration gives rise to a partial correlation coefficient
of 0.43, P < 0.001. This indicates that those
individuals with the highest baseline cortisol levels have also higher
post-0.25-mg DEX cortisol levels in response to a given DEX
concentration.
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shows the linear regression analysis for the DEX
concentration and cortisol (decrease in cortisol concentration
after 0.25 mg DEX), (ß = 30.7, r = 0.31, P <
0.001). Although there was no correlation between 
cortisol and the
DEX concentration in the pilot study (n = 9), there was an
association between these parameters in this much larger group of
individuals. The finding of a regression coefficient of 30.7 confirms
that the biological activity of DEX is about 30 times higher than the
biological activity of cortisol. Figure 4C also shows that in four
subjects, there was a low cortisol (<230 nmol/L) at DEX levels
above 7 nmol/L. All four subjects showed post-1-mg DEX cortisol
concentrations below 50 nmol/L. This indicates again that the 0.25-mg
DST indeed gives a better insight into individual sensitivity to GCs
than the 1-mg DST. Individual stability of serum cortisol and CBG concentrations
To investigate whether plasma cortisol concentrations were stable
within each person after an interval of 2.5 yr, Spearman’s rank
correlation coefficient (r) was calculated for the baseline cortisol
concentrations that were obtained at the two examinations. Table 4 shows that there are highly significant
correlations between the concentrations determined at an interval of
2.5 yr in both sexes. It can be concluded that subjects with high
cortisol levels at the first examination also had a high level 2.5 yr
later. The small size of the coefficient is probably because of the
interassay variation. The coefficient within the 20 samples measured in
one assay was much larger (r = 0.59). Therefore there is indeed an
intraperson stability in the baseline early morning concentrations of
these parameters.
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Discussion |
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1 mg DST
In man, the major circulating GC hormone is cortisol. Cortisol production in an unstressed individual follows a nycthemeral rhythm, with peak cortisol concentrations shortly before waking and a decline through the day, reaching a nadir at bedtime. Large individual variations both in baseline and stimulated cortisol levels have been reported (1). One of the goals of the present study was to gain more insight into the interindividual variability of feedback sensitivity of the HPA axis, as well as into the intraindividual stability of circulating cortisol values. In 216 healthy elderly individuals, a 1-mg overnight DST was carried out to investigate the variability in feedback sensitivity. Only 5 out of the 216 individuals (2.3%) showed post-DEX cortisol concentrations above 140 nmol/L, which is the cut-off point for a normal test result in our clinic when the DST is used as a screenings procedure for Cushing’s syndrome (20). These results are in accordance with previous studies in which nonsuppression was reported in 4% (14), 9.1% (16), and 5% (17) of subjects. Our data demonstrate that 1 mg DEX is too high a dose to detect individual differences in feedback sensitivity within a normal population, because near total suppression of cortisol levels was observed in most individuals.
Another aspect of this study was to gain more insight into the role of
the metabolism of DEX in its suppressive effects on the HPA axis.
Synthetic steroid hormones are metabolized in the liver before being
eliminated from the organism (22). It is well known that a number of
drugs influence the outcome of a DST by altering the metabolism of DEX:
e.g. sodium phenytoin induces hepatic enzyme activity,
thereby increasing the metabolic clearance of GCs including DEX (23).
In our study population, there were six subjects with a DEX
concentration below 1.8 nmol/L, three of whom were indeed on
antiepileptic drugs. In the other subjects, there was a wide variation
in DEX levels (ranging from 2.0–18.4 nmol/L). Also, obesity might
influence the outcome of a DST. In a study by Crapo et al.
(24), nonsuppression of cortisol after 1 mg DEX was reported in 1.1%
of lean outpatient controls and in 13% of obese controls. Cronin
et al. (25) reported that the degree of adiposity did not
differ between patients with false-positive responses in a DST and
patients with normal responses. The data from our study shows that in
males, the capacity of the liver to metabolize DEX is related to liver
function parameters (ALAT, ASAT, and -GT). In women, DEX metabolism
was not related to liver enzyme levels. This sex difference may be
caused by the larger proportion of men with liver function disturbances
and the larger range of BMI values in women. Baseline and post-DEX
cortisol levels were not related to liver function parameters and/or
BMI in either sex. Still, the influence of liver function disturbances
and BMI on the metabolism of DEX might contribute to the occurrence of
false-positive or false-negative outcomes of the 1-mg DST in the
endocrine clinic in more severely affected individuals. In studies
performed by Meikle (26) and by Weiner (27), it was found that plasma
DEX concentrations of 5.6 nmol/L and 5.1 nmol/L, respectively, at
0800 h postadministration are required to reliably suppress HPA
function. In another study (28) in psychiatric patients, abnormal
results of the DST were closely associated with low plasma levels of
DEX. In a study comparing patients with endogenous depression and
normal controls, it was shown that serum DEX levels were significantly
lower in nonsuppressors than in suppressors (29).
0.25-, 0.50-, and 1-mg DST in healthy laboratory personnel
From the data obtained from the 1-mg DST, it became clear that this dose might suppress the HPA axis too much to allow the detection of individual differences of its feedback regulation. A pilot study with 0.25, 0.50, and 1 mg DEX in nine healthy laboratory workers showed that these lower doses indeed allowed a better discrimination in HPA axis feedback sensitivity. The broadest range of cortisol concentrations was present after the administration of 0.25 mg DEX. This suggests that the 0.25-mg DST may give a good insight into the individual feedback sensitivity of the HPA axis.
0.25-mg DST
Out of the original group of 216 subjects, 164 persons participated in a 0.25-mg DST. The results from the 0.25-mg DST showed a wide range of post-DEX cortisol concentrations from 14–630 nmol/L. It also became clear that there was a close relationship between pre- and post-DEX cortisol concentrations, a relation that was absent in the 1-mg DST. The association became even stronger when, by calculating a partial correlation coefficient, it was adjusted for the actual DEX concentration. These results show that subjects with the highest baseline cortisol concentrations also have the highest post-0.25-mg DEX cortisol concentrations for a given DEX concentration, and indicate that the sensitivity of the feedback regulation of the HPA axis is related to the baseline cortisol concentration of the individual. This means that the set point of the HPA axis baseline levels is related to its feedback sensitivity.
Individual stability of cortisol concentrations
In this study, we were able to measure early morning cortisol concentrations in a large group of healthy subjects twice, at an interval of approximately 2.5 yr. Serum cortisol showed an individual stability, indicating that the HPA axis is set at a stable and reproducible set point for a given individual. As described above, it became clear from the data of the 0.25-mg DST that subjects with the highest baseline cortisol concentrations also had the highest post-DEX cortisol concentrations. It seems that within an individual, there is a set point for HPA activity, which is defined before as well as after a low dose of DEX. A dose of 1 mg DEX has too much suppressive effect to demonstrate this phenomenon, but a dose of 0.25 mg DEX, which results in a subtotal suppression of cortisol levels, leaves the influence of the individual’s set point of the HPA axis intact. Previous studies showed that genetic factors may play a role in the regulation of cortisol levels. Maxwell et al. (2) reported similar unstimulated plasma cortisol levels in a sample of female monozygotic twins. However, this was not found in male monozygotic twins. Meikle et al. (3) observed evidence for a moderate genetic impact on early morning plasma cortisol levels. A study by Kirschbaum et al. (30) investigated cortisol responses to three different stimulation procedures (a CRH test, a physical stimulation procedure, and a psychological stress test), with the focus on the contribution of genetic factors. A decided influence of genetic factors was observed for baseline cortisol levels, as well as for the response to CRH, but heredity appeared to play a minor role in the adrenocortical response to physiological stress. One of the differences between this last study and the present results is that Kirschbaum and co-workers demonstrated a significant intraindividual stability of baseline cortisol concentration in females, whereas levels in males were much less stable. In our study, however, there was a highly significant individual stability of baseline cortisol concentrations in both sexes. Furthermore, the post-0.25-mg DEX cortisol levels were significantly correlated to the baseline cortisol concentrations, both in male and in female elderly individuals.
Effect of age on pre- and post-DEX cortisol concentrations
Studies of age-related changes in basal, nonstimulated HPA function have produced varying results (31). Most studies have demonstrated no change or nonsignificant increases in mean baseline ACTH (6, 8, 10) and serum cortisol levels at older ages (32, 33). The consistent lack of age and gender differences in basal cortisol levels across these various studies strengthens the conclusion that age does not have a major impact on basal nonstimulated cortisol concentrations (31). In the present study, there was no relation between age or gender and basal total cortisol concentrations, neither in the first nor in the second examination. Furthermore, there was no difference between these baseline cortisol concentrations, which were determined at an interval of approximately 2.5 yr. However, it must be stated that our study population included elderly people only, so we were not able to compare baseline cortisol concentrations between young and old subjects.
We found no correlation between post-DEX cortisol concentrations and age, after neither 1 mg nor 0.25 mg DEX administration. Furthermore, there was no difference between males and females in their post-DEX cortisol concentrations using either one of doses of DEX. Two previous studies of healthy individuals have also demonstrated no age-related differences in cortisol suppression after 1 mg DEX (16, 17). In two other studies (14, 15), however, a decreased suppression was reported in older subjects after the 1-mg DST.
The most important conclusions from our study are the observation of an individual stability of baseline cortisol levels, which is closely related to the feedback sensitivity of the HPA axis in response to a low dose of DEX. These observations suggest a genetic influence on the set point of the HPA axis.
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Footnotes |
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Received April 28, 1997.
Revised September 11, 1997.
Accepted September 16, 1997.
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References |
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R. Giordano, M. Bo, M. Pellegrino, M. Vezzari, M. Baldi, A. Picu, M. Balbo, L. Bonelli, G. Migliaretti, E. Ghigo, et al. Hypothalamus-Pituitary-Adrenal Hyperactivity in Human Aging Is Partially Refractory to Stimulation by Mineralocorticoid Receptor Blockade J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5656 - 5662. [Abstract] [Full Text] [PDF]
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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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P. Smit, H. Russcher, F. H. de Jong, A. O. Brinkmann, S. W. J. Lamberts, and J. W. Koper Differential Regulation of Synthetic Glucocorticoids on Gene Expression Levels of Glucocorticoid-Induced Leucine Zipper and Interleukin-2 J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2994 - 3000. [Abstract] [Full Text] [PDF]
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P. Y. Liu, S. M. Pincus, D. M. Keenan, F. Roelfsema, and J. D. Veldhuis Analysis of bidirectional pattern synchrony of concentration-secretion pairs: implementation in the human testicular and adrenal axes Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2005; 288(2): R440 - R446. [Abstract] [Full Text] [PDF]
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 J. P. Girod and D. J. Brotman Does altered glucocorticoid homeostasis increase cardiovascular risk? Cardiovasc Res, November 1, 2004; 64(2): 217 - 226. [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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 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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B. Catargi, V. Rigalleau, A. Poussin, N. Ronci-Chaix, V. Bex, V. Vergnot, H. Gin, P. Roger, and A. Tabarin Occult Cushing's Syndrome in Type-2 Diabetes J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5808 - 5813. [Abstract] [Full Text] [PDF]
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 S. L. King and K. M. Hegadoren Stress Hormones: How Do They Measure Up? Biol Res Nurs, October 1, 2002; 4(2): 92 - 103. [Abstract] [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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E. Rask, B. R. Walker, S. Soderberg, D. E. W. Livingstone, M. Eliasson, O. Johnson, R. Andrew, and T. Olsson Tissue-Specific Changes in Peripheral Cortisol Metabolism in Obese Women: Increased Adipose 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Activity J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3330 - 3336. [Abstract] [Full Text] [PDF]
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R. Pasquali, B. Ambrosi, D. Armanini, F. Cavagnini, E. D. Uberti, G. Del Rio, G. de Pergola, M. Maccario, F. Mantero, M. Marugo, et al. Cortisol and ACTH Response to Oral Dexamethasone in Obesity and Effects of Sex, Body Fat Distribution, and Dexamethasone Concentrations: A Dose-Response Study J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 166 - 175. [Abstract] [Full Text] [PDF]
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C. W. WILKINSON, E. C. PETRIE, S. R. MURRAY, E. A. COLASURDO, M. A. RASKIND, and E. R. PESKIND Human Glucocorticoid Feedback Inhibition Is Reduced in Older Individuals: Evening Study J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 545 - 550. [Abstract] [Full Text]
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G. A. Laughlin and E. Barrett-Connor Sexual Dimorphism in the Influence of Advanced Aging on Adrenal Hormone Levels: The Rancho Bernardo Study J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3561 - 3568. [Abstract] [Full Text]
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D. A. Gust, M. E. Wilson, T. Stocker, S. Conrad, P. M. Plotsky, and T. P. Gordon Activity of the Hypothalamic-Pituitary-Adrenal Axis Is Altered by Aging and Exposure to Social Stress in Female Rhesus Monkeys J. Clin. Endocrinol. Metab., July 1, 2000; 85(7): 2556 - 2563. [Abstract] [Full Text]
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G. C. Inglis, M. C. Ingram, C. D. Holloway, L. Swan, D. Birnie, W. S. Hillis, E. Davies, R. Fraser, and J. M. C. Connell Familial Pattern of Corticosteroids and Their Metabolism in Adult Human Subjects - the Scottish Adult Twin Study J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 4132 - 4137. [Abstract] [Full Text]
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S. D. Hearing, M. Norman, C. Smyth, C. Foy, and C. M. Dayan Wide Variation in Lymphocyte Steroid Sensitivity Among Healthy Human Volunteers J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 4149 - 4154. [Abstract] [Full Text]
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E. Dennison, P. Hindmarsh, C. Fall, S. Kellingray, D. Barker, D. Phillips, and C. Cooper Profiles of Endogenous Circulating Cortisol and Bone Mineral Density in Healthy Elderly Men J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3058 - 3063. [Abstract] [Full Text]
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 J. A. M. Avontuur, F. Boomsma, A. H. van den Meiracker, F. H. de Jong, and H. A. Bruining Endothelin-1 and Blood Pressure After Inhibition of Nitric Oxide Synthesis in Human Septic Shock Circulation, January 19, 1999; 99(2): 271 - 275. [Abstract] [Full Text] [PDF]
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 A. H. S. hassan, V. K. Patchev, P. V. Rosenstiel, F. Holsboer, and O. F. X. Almeida Plasticity of hippocampal corticosteroid receptors during aging in the rat FASEB J, January 1, 1999; 13(1): 115 - 122. [Abstract] [Full Text]
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