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Molecular Endocrinology, Molecular Medicine Centre, (H.J.H., J.R.S.) and Department of Clinical Neurosciences (M.C.H.), University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, Scotland, United Kingdom; and Molecular Physiology, Wilkie Building (Y.K., J.J.M.), University of Edinburgh, Edinburgh, EH8, Scotland, United Kingdom
Address all correspondence and requests for reprints to: Dr. Megan C. Holmes, Molecular Endocrinology, Molecular Medicine Centre, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, United Kingdom. E-mail: megan.holmes{at}ed.ac.uk
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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11ß-HSD catalyzes interconversion of active glucocorticoids (cortisol, corticosterone) and inert 11-keto forms [cortisone, 11-dehydrocorticosterone (11-DHC)]. 11ß-HSD type 2, a potent NAD-dependent 11ß-dehydrogenase, rapidly inactivates glucocorticoids, thus allowing aldosterone-selective access to intrinsically nonselective MR in the distal nephron in the face of a large molar excess of circulating glucocorticoid (5, 6). The crucial physiological principle illuminated by the action of 11ß-HSD-2 is that corticosteroid action on target cells is determined by enzyme action within the cells, rather than circulating steroid levels alone. Thus, patients or mice lacking 11ß-HSD-2 show excess mineralocorticoid activity, despite having normal circulating levels of the glucocorticoids and very low levels of the mineralocorticoid aldosterone (7, 8). Hence, it is the intracellular concentration of the steroids that is important.
The 11ß-HSD-2 isozyme is not expressed in the pituitary or most regions of the adult central nervous system (CNS), including the PVN and hippocampus (9, 10). In contrast, the brain and pituitary widely express 11ß-HSD type 1 (11, 12, 13, 14), a nicotinamide adenine dinucleotide phosphate [NADP(H)]-dependent isozyme, initially purified from liver. 11ß-HSD-1 is bidirectional in tissue homogenates (15), but it acts as a predominant 11ß-reductase in many intact cells in culture (16, 17, 18, 19), including primary hippocampal neurons (20) and perhaps the brain (21). In principle, 11ß-reductase is anticipated to amplify glucocorticoid action in target cells, exploiting circulating inert 11-keto steroids produced largely by renal 11ß-HSD-2. 11ß-HSD-1 is highly expressed in hippocampal (12, 14) and PVN neurons (13, 22). However, any role of 11ß-HSD-1 in glucocorticoid feedback and HPA function is obscure, with studies hindered by the nonselectivity of available licorice-based inhibitors and their variable access to CNS subregions in vivo (23).
We recently produced mice homozygous for a targeted disruption of the 11ß-HSD-1 gene (24). These mice cannot regenerate active corticosterone from inert 11-dehydrocorticosterone in vivo, confirming that 11ß-HSD-1 is the predominant or sole 11ß-reductase in the body. Despite more than adequate levels of active corticosterone in the plasma, the 11ß-HSD-1-deficient mice show reduced activation of glucocorticoid-sensitive hepatic gluconeogenic enzymes in response to stress or obesity, and consequently, attenuated plasma glucose elevations to these stimuli. These data clearly illustrate the principle that intracellular activation of corticosterone from circulating inert 11-DHC plays an important role in determining effective intracellular glucocorticoid action in the hepatocyte. Indeed, the 11ß-HSD-1 null mice show elevated basal (morning) plasma levels of corticosterone, as well as adrenal hypertrophy. Though adrenal hypertrophy might be anticipated to reflect a requirement for increased steroid synthesis, in the light of a greater, net inactivation of corticosterone in the deficient mice (with no reactivation of 11-DHC by 11ß-reductase), elevated basal levels of corticosterone would not occur if HPA axis regulation is functioning normally. In such a case, there would be elevated corticosterone production, over time, to maintain normal plasma corticosterone levels. We have now, therefore, investigated HPA activity and glucocorticoid feedback in 11ß-HSD-1-deficient mice, to determine whether circulating levels of glucocorticoids are the only signal for central actions of glucocorticoids or whether the glucocorticoid signal is modified by 11ß-HSD-1 in a tissue-specific manner.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Materials
All chemicals were purchased from Sigma (Poole,
UK), unless otherwise stated. Molecular biology reagents were obtained
from Promega Corp. (Southampton, UK).
Circadian experiments
To investigate the diurnal rhythm of glucocorticoids, animals
were killed by decapitation in stress-free conditions at 0800, 1200,
1600, 2000, and 2400 h. Trunk blood was collected in EDTA (0.1%
final concentration), and plasma samples were stored at -80 C before
analysis for corticosterone, 11-DHC, ACTH, and corticosteroid-binding
globulin (CBG) levels. Brains, taken at 0800 h, were rapidly
frozen on dry ice and stored at -80 C. Liver samples were removed into
molybdate buffer for homogenization, and GR binding assays were
performed on the extracts.
Restraint stress
For the acute restraint stress test, mice were placed in a
restraint tube for 10 min and then decapitated immediately, 45 min, or
90 min after the start of restraint. Trunk blood was collected, as
above. At the 90-min time point, brains were taken and stored, as
above.
Glucocorticoid feedback inhibition experiments
To study HPA axis feedback, basal plasma samples were obtained
by tail nick, and then mice received vehicle (corn oil) or cortisol (5
mg kg -1; 100 µl ip, a
dose chosen to cause near-complete HPA axis suppression in wild-type
animals) and were left to recover for 2 h. Synthetic
glucocorticoids, such as dexamethasone, were not used because these may
poorly penetrate the CNS in rodents and are poor 11ß-HSD-1
substrates. Animals were placed in a restraint tube for 10 min and then
killed immediately or after 90 min, and trunk blood was collected and
stored, as above.
Analysis of plasma hormones
Plasma corticosterone was measured by RIA, as described
(25), modified for microtiter plate scintillation
proximity assay. Cross-reactivity with cortisol was less than 8%. ACTH
was quantified by RIA, as described (22), using
commercially available rabbit anti-ACTH antisera (IgG Corp., Nashville,
TN).
11-DHC was measured by RIA. Plasma (20 µl) was incubated, in 50 µl, with rabbit anti-11-DHC antibody (1:10,000 dilution; a gift from Prof. Vecsei and Dr. Haack, Ruprecht-Karls-Universitat, Heidelberg) and [3H]-11-DHC (10,000 cpm) in borate buffer, in a 96-well plate for 1 h at room temperature (RT). Antirabbit scintillation proximity assay (SPA) beads (Amersham Pharmacia Biotech, Little Chalfont, Buckinghamshire, UK; 50 µl) were added, and the plate was sealed and incubated overnight at RT and counted in a Microbeta counter. The assay showed sensitivity to 11-DHC, down to 2.5 nM, and did not cross-react with corticosterone (in the range of 0.5–320 nM). To reduce the concentration of free corticosterone in samples and thus any low-level cross-reactivity, nondenatured samples were used because this preserves the specific binding of corticosterone to CBG, while allowing 11-DHC to remain unbound (26). [3H]-11-DHC was generated from [1,2,6,7-3H]-corticosterone (Amersham Pharmacia Biotech) as described (16). The efficiency of conversion of [1,2,6,7-3H]-corticosterone to [3H]-11-DHC was more than 98%.
Plasma corticosteroid binding capacity was assessed in plasma samples, as outlined (27). Briefly, plasma samples were stripped of endogenous steroids, using dextran-coated charcoal [DCC: methanol-washed charcoal (1 g) coated with dextran T-70 (0.1 g) in 100 ml molybdate buffer] and aliquots incubated with 1 pmol/100 µl [1,2,6,7-3H]-corticosterone (Amersham Pharmacia Biotech), in the presence (nonspecific binding) and absence (total binding) of 2000-fold excess of unlabeled corticosterone, for 1 h at 22 C. Unbound corticosterone was removed using DCC (for 10 min, at 4 C), followed by centrifugation at 3000 x g for 15 min at 4 C. Bound [3H]-corticosterone in the supernatant was counted. CBG in plasma was estimated from specifically-bound [3H]-corticosterone. Results are presented as picomoles of corticosterone bound per milliliter of plasma.
Liver cytosol GR Kd and Bmax
measurements
Liver was homogenized in 3x vol ice-cold molybdate buffer (10
mM Tris-HCl, 2 mM dithiothreitol, 1.5
mM EDTA, 0.1 M sodium molybdate, 10% glycerol,
pH 7.2) using 3 x 10-sec pulses of a Polytron homogenizer. The
homogenate was centrifuged (20,000 x g, 20 min, 4 C),
and the supernatant was further centrifuged (105,000 x
g, 60 min, 4 C) to obtain samples for protein (Bradford
assay; Bio-Rad Laboratories, Inc., Hemel Hempstead,
UK) and receptor assays. For the receptor assays, samples (50 µl)
were diluted to 4 mg/ml in molybdate buffer and incubated
overnight with 25 µl
[1,2,4,6,7-3H]-dexamethasone (final
concentration, 1.5 nM; 3000 cpm/assay tube;
Amersham Pharmacia Biotech) and 25 µl nonradioactive
dexamethasone or corticosterone (final concentration, 0.316
nM–100 µM) at 4 C in
96-well plates. Nonspecific binding was assessed in the presence of
200 µM cold dexamethasone. Free and bound
steroids were separated, using 100 µl DCC, by centrifugation at
1,500 x g for 15 min at 4 C. Supernatants were removed
to a 96-well plate and 2 vol scintillant (Optiphase-Supermix;
Wallac, Finland) added. Plates were sealed, shaken, and
counted. Liver cytosol GR Kd for dexamethasone
(DEX; nM) and Bmax (nmol DEX/g
protein) were calculated using equilibrium binding analysis.
In situ hybridization for GR, MR, and CRH steady-state messenger
RNA (mRNA) expression
Coronal cryostat sections (10 µm), at the level of the
hippocampus and hypothalamic PVN, were mounted onto gelatin and
poly-L-lysine-coated slides and stored at -80 C. In
situ hybridization studies were performed according to Seckl
et al. (28). Tissue sections were fixed in cold
4% paraformaldehyde in 0.1 M phosphate buffer
(pH 7.4) containing 0.02% diethylpyrocarbonate for 10 min at
RT, followed by 3 x 5 min in 2x SSC. For CRH mRNA,
prehybridization buffer containing 50% formamide, 0.6
M NaCl, 0.01 M Tris HCl,
1x Denhardt’s solution, 1 µM EDTA, 0.5 mg/ml
denatured salmon sperm DNA, and 0.125 µg/ml yeast transfer RNA was
applied to the sections; and the slides were incubated at 50 C for
2 h in sealed boxes. Plasmids containing fragments of
complementary DNA (cDNA) for rat GR (673 bp
PstI-EcoRI fragment of rat cDNA), MR (513 bp
EcoRI fragment of rat cDNA), and CRH (518 bp
PvuII-BamHI fragment of rat cDNA) were used as
templates to transcribe radiolabeled sense and antisense riboprobes
using 35S-uridine 5'-triphosphate
(Amersham Pharmacia Biotech). cRNA probes were denatured,
added to the hybridization mixture (10–15 x
106 cpm/ml; 50% formamide, 0.6
M NaCl, 0.01 M Tris HCl,
1x Denhardt’s solution, 1 µM EDTA, 0.1 mg/ml
denatured salmon sperm DNA, 0.125 µg/ml yeast transfer RNA, 10%
dextran sulfate 10 min, at 75 C) and cooled to 55 C before addition of
10 mM dithiothreitol. Hybridization mixture (200
µl/slide) was then added to the sections and incubated overnight (16
h at 50 C) in sealed boxes. After hybridization, the slides were rinsed
twice in 2x SSC for 30 min at RT before ribonuclease A digestion (0.09
µg/ml final concentration in 0.5 M NaCl, 0.01
M Tris HCl, 0.001 M EDTA
for 1 h at 37 C). The slides were washed to a final stringency of
0.1x SSC at 60 C. After dehydration, sections were air-dried and
exposed to autoradiographic film for 1 week at RT. Serial dilutions of
35S-uridine 5'-triphosphate were made on filter
paper and exposed, under identical conditions, to standardize signal
strength. No signal was seen from 35S-labeled
sense RNA probes of similar specific activity hybridized under
identical conditions to the antisense probes (not shown). Films were
quantified by computer densitometry (Research Imaging, St. Catharines,
Canada). For autoradiographs, specific optical density
measurements were obtained after subtraction of background density
(obtained over white matter). Five to 10 readings were taken from each
region of each tissue section (3 sections per mouse). For GR, sections
were dipped in NTB2 photographic emulsion (Eastman Kodak Co., Hemel Hempstead, UK) and stored at 4 C before
development and counterstaining with pyronin (1%, wt/vol). Grain
counting was performed using a microcomputer imaging device
system (Research Imaging).
Statistics
For diurnal rhythms and stress experiments, groups were compared
by genotype and time using 2-way ANOVA. Where significant differences
and a genotype:time interaction were noted, one-way ANOVA with
post hoc Scheffé F-tests was performed for
within-group comparisons, and t tests were used to show
significant differences between groups. For in situ
hybridization histochemistry data, groups were compared by independent
two-tailed Student’s t tests. Some hormonal data were not
normally distributed and were log-transformed before analysis, or, when
this failed to normalize the distribution (e.g. basal ACTH),
data were assessed by the nonparametric Mann-Witney test. Values are
means ± SEM (n), and P <
0.05 was taken as significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Plasma corticosterone levels
in 11ß-HSD-1 -/-
animals were elevated at 0800 h, compared with wild-type controls.
The 11ß-HSD-1 -/- mice
also showed a diurnal rhythm of corticosterone, with a nadir at
0800 h, but had an earlier rise at 1200 h, resulting in a
more extended corticosterone peak. The 11ß-HSD-1-deficient mice
showed significantly greater corticosterone secretion over the 24-h
period (genotype:time interaction, F(4,66) = 3.41,
P = 0.0135).
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). 11-DHC levels in 11ß-HSD-1-deficient mice were
significantly elevated, compared with wild-type animals, over the 24-h
period (genotype:time interaction, F(4,76) = 4.678
P = 0.002).
11ß-HSD-1-/- animals
maintained the diurnal rhythm of 11-DHC, with levels significantly
elevated above morning basal levels by 1200 h and an earlier peak
than wild-type animals.
11ß-HSD-1-deficient mice showed a striking reduction in the amplitude
of the diurnal ACTH rhythm, compared with the wild-type mice. Although
peak levels were similar, nadir plasma ACTH levels were higher in
11ß-HSD-1-/- mice
(P = 0.02, Mann-Witney test; Fig. 1C).
Plasma CBG levels (Table 1) and hepatic
GR binding characteristics (Table 1) were similar in wild-type and
11ß-HSD-1-/- animals,
demonstrating that alterations in these parameters cannot underlie the
changes in basal HPA activity in the
11ß-HSD-1-/- mice. GR
and MR mRNA levels in the hippocampus were also identical between the
genotypes (Table 2). Whereas CRH mRNA
expression in the hypothalamic PVN was similar in wild-type and
11ß-HSD1-/- mice, GR
mRNA levels in the PVN were significantly reduced in
11ß-HSD-1-/- mice
(P < 0.01; Table 2).
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); and overall, the
11ß-HSD-1-/- mice had a
greater corticosterone response to stress, compared with wild-type
(genotype:time interaction, F(3,54) = 5.48, P =
0.0023). Though the initial fall in plasma corticosterone levels was
rapid in both genotypes, 90 min after stress, plasma corticosterone
levels were significantly higher in
11ß-HSD-1-/- mice than
in wild-type (P < 0.05).
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). In marked contrast, 11-DHC levels in
11ß-HSD-1-deficient mice increased dramatically, peaking 10 min after
restraint stress and falling thereafter. The peak levels achieved were
significantly increased in the mutant mice, above those seen in
wild-type mice (genotype:time interaction, F(3,59) = 4.467,
P = 0.0068).
Both 11ß-HSD-1-deficient and wild-type mice showed an immediate
ACTH response to restraint stress. However, the overall ACTH response
to stress was significantly greater in the
11ß-HSD-1-/- mice
(genotype:time interaction, F(3,29) = 6.059, P =
0025). Moreover, ACTH levels remained elevated above basal values for a
longer period (90 min) in the 11ß-HSD-1-deficient animals (Fig. 2C).
Reduced effect of exogenous glucocorticoids on HPA axis activity in
11-HSD-1-deficient mice
Wild-type mice were pretreated, 2 h before stress, with
vehicle or cortisol in a dose chosen (on the basis of pilot studies) to
cause near-full inhibition of the subsequent corticosterone response to
restraint stress (cortisol-treated corticosterone peak,66 ± 17
nM; n = 5). In age- and weight-matched
11ß-HSD-1-/- mice, this
dose of cortisol was significantly less effective in suppressing the
corticosterone rise, 10 min post stress (cortisol, 114 ± 8
nM; n = 4). Thus, at 10 min, immediately on cessation
of stress, wild-type animals pretreated with cortisol had significantly
lower corticosterone levels, compared with
11ß-HSD-1-/- mice
pretreated with cortisol (Fig. 3).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several lines of evidence demonstrate that 11ß-HSD-1-deficient mice have reduced sensitivity to glucocorticoid negative feedback upon the HPA axis. First, despite elevated circulating glucocorticoid levels, there is no down-regulation of several key HPA-associated glucocorticoid target genes and their products, including GR and MR mRNAs in the hippocampus, CRH mRNA in the PVN, and plasma ACTH levels. The latter is particularly unexpected, given the increased adrenal sensitivity to ACTH in these mice (24). Second, after stress, the rate at which plasma corticosterone levels return to basal (post peak) is dependent on the ability of glucocorticoids to terminate the central activation of HPA activity at various sites (pituitary, hypothalamus, and higher centers of the brain) by negative feedback. Despite elevated peak glucocorticoid levels in response to stress and the more efficient clearance of corticosterone, in the absence of 11ß-reductase regeneration from 11-DHC, postpeak (60–90 min) plasma ACTH and corticosterone levels are significantly higher in 11ß-HSD-1-deficient mice than in wild-type controls. Hence, elevated postpeak plasma corticosterone and ACTH implies insensitivity to feedback control. Third, directly to address this, mice were given cortisol in a dose which greatly attenuated the HPA response to a subsequent stress in wild-type mice. 11ß-HSD-1-deficient mice similarly pretreated with cortisol had a significantly greater corticosterone response to stress, despite increased metabolic clearance of cortisol (no regeneration by hepatic 11ß-HSD-1 after metabolism to cortisone by renal 11ß-HSD-2, which is unaltered in the 11ß-HSD-1-deficient mice (24)), confirming a lack of sensitivity to glucocorticoid feedback in these animals.
Insensitivity to negative feedback regulation by glucocorticoid hormones could be obtained in several ways: by decreased free levels of circulating glucocorticoids by elevation of plasma CBG levels, by decreased glucocorticoid levels in relevant tissues caused by altered 11ß-reductase activity, or by changes in tissue GR affinity or numbers at sites of negative feedback regulation (particularly the hippocampus and hypothalamus). However, no changes were observed in CBG levels in 11ß-HSD-1-deficient mice. Indeed, CBG is a hepatic glucocorticoid-inhibited transcript (30). The maintenance of CBG levels in 11ß-HSD-1-deficient mice further supports the notion of reduced effective glucocorticoid action in cells despite plasma glucocorticoid excess. The insensitivity to feedback cannot readily be ascribed to alterations in GR affinity for glucocorticoids, which was unaltered (at least in liver) or in GR or MR mRNA levels in the hippocampus. Hence, the implication is that lack of 11ß-reductase in feedback sites (such as hippocampus, pituitary, and perhaps PVN) leads to attenuated glucocorticoid regeneration within these cells and therefore a reduced effective intracellular glucocorticoid signal in vivo.
However, there is a tissue-specific heterogeneity of glucocorticoid effects in the 11ß-HSD-1-deficient mice. Notably, the animals show reduced GR mRNA in the PVN. This contrasts with maintained GR in the hippocampus and indeed maintained CRH mRNA in the same region of the PVN. These findings suggest that there is a differential sensitivity to corticosterone in different brain areas. Activity of 11ß-HSD-1 is lower in the hypothalamus than the hippocampus and pituitary (12, 14), which is in accord with these findings and supports the notion that the enzyme provides tissue-specific glucocorticoid modulation. Lower GR in PVN might attenuate feedback sensitivity too and may underpin the maintenance of CRH transcripts in the face of hypercorticosteronemia. It is likely that a combination of two processes, reduced GR expression in PVN and loss of 11ß-reductase with consequent decrease in ligand availability to GR, underlies the negative feedback insensitivity in 11ß-HSD-1-deficient mice. The importance of GR in negative feedback sensitivity of the HPA axis has been demonstrated in mice that lack GR throughout the CNS (31). These animals show elevated CRH and corticosterone, but reduced ACTH levels, suggesting the expected dominant role for the receptor, but illustrating the analogous (though less potent) effect of 11ß-HSD-1. However, reduction of GR by antisense expression (32) has less effect on basal corticosterone and ACTH (33) than loss of 11ß-HSD-1, suggesting that absence of enzyme activity in 11ß-HSD-1-deficient mice is the more critical factor contributing to the HPA abnormalities than the modest reduction in GR seen in the PVN in the 11ß-HSD-1-deficient mice.
Interestingly, circulating levels of 11-DHC (which are little bound to
plasma proteins) in mice are 2–7 nM and thus similar to,
if not greater than, basal free corticosterone levels (
1
nM), assuming approximately 95% of circulating
corticosterone is usually bound to CBG. Cortisone levels in humans are
even higher, at around 50 nM (34). Moreover,
approximately 50% of 11-DHC is converted to active corticosterone on a
single pass through the intact rat liver (35). It is
therefore feasible that 11ß-reductase activation of 11-DHC
contributes an appreciable proportion of intracellular active
glucocorticoid. The progressive accumulation of 11-DHC after stress in
wild-type mice is presumably a consequence of increased corticosterone
substrate for renal 11ß-HSD-2 conversion to 11-DHC, which is then
back-converted to corticosterone by 11ß-HSD-1 in liver and elsewhere,
fueling further renal conversion to 11-DHC. The rising 11-DHC
levels presumably also represent an increasing substrate for reduction
in feedback sites, amplifying the glucocorticoid effect.
What of forward HPA drive? The 11ß-HSD-1-deficient mice show maintained circadian rhythmicity and good HPA responses to stress, suggesting that stimulatory pathways are intact. The exaggerated early stress responses of corticosterone are consistent with increased adrenal sensitivity to ACTH with paradoxically maintained ACTH release, presumably caused by the attenuated central sensitivity to the elevated basal glucocorticoid levels. Similar central glucocorticoid insensitivity (but not adrenal hypersensitivity) is seen in transgenic mice with antisense reduced GR expression (33, 36). However, there is a diurnal early peak of HPA activation in the 11ß-HSD-1-deficient mice, suggesting more fundamental alterations in rhythm generation, perhaps at the suprachiasmatic nucleus, which expresses some 11ß-HSD-1 (12) and is sensitive to glucocorticoid modulation. Future studies will address the nature of this finding and the possible relevance of 11ß-HSD-1 in the human CNS and its disorders. Overall, the data suggest a novel and important role for 11ß-reductase in regulation of the HPA axis. The importance of this enzyme in other CNS systems remains to be determined. This is of particular interest in the hippocampus and cerebellum, where 11ß-HSD-1 expression is highest and where glucocorticoids have important effects upon electrophysiological parameters, behavior, and cognition, as well as neuronal development, structure, and survival (3, 37, 38).
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Acknowledgments |
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Footnotes |
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Received June 12, 2000.
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M. C. Holmes, C. T. Abrahamsen, K. L. French, J. M. Paterson, J. J. Mullins, and J. R. Seckl The mother or the fetus? 11beta-hydroxysteroid dehydrogenase type 2 null mice provide evidence for direct fetal programming of behavior by endogenous glucocorticoids. J. Neurosci., April 5, 2006; 26(14): 3840 - 3844. [Abstract] [Full Text] [PDF]
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J. M. Paterson, J. R. Seckl, and J. J. Mullins Genetic manipulation of 11{beta}-hydroxysteroid dehydrogenases in mice Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2005; 289(3): R642 - R652. [Abstract] [Full Text] [PDF]
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 J. W. Tomlinson, E. A. Walker, I. J. Bujalska, N. Draper, G. G. Lavery, M. S. Cooper, M. Hewison, and P. M. Stewart 11{beta}-Hydroxysteroid Dehydrogenase Type 1: A Tissue-Specific Regulator of Glucocorticoid Response Endocr. Rev., October 1, 2004; 25(5): 831 - 866. [Abstract] [Full Text] [PDF]
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F. H. Bloomfield, M. H. Oliver, P. Hawkins, A. C. Holloway, M. Campbell, P. D. Gluckman, J. E. Harding, and J. R. G. Challis Periconceptional Undernutrition in Sheep Accelerates Maturation of the Fetal Hypothalamic-Pituitary-Adrenal Axis in Late Gestation Endocrinology, September 1, 2004; 145(9): 4278 - 4285. [Abstract] [Full Text] [PDF]
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 T. C. Sandeep, J. L. W. Yau, A. M. J. MacLullich, J. Noble, I. J. Deary, B. R. Walker, and J. R. Seckl From The Cover: 11{beta}-Hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics PNAS, April 27, 2004; 101(17): 6734 - 6739. [Abstract] [Full Text] [PDF]
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J. Justesen, L. Mosekilde, M. Holmes, K. Stenderup, J. Gasser, J. J. Mullins, J. R. Seckl, and M. Kassem Mice Deficient in 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Lack Bone Marrow Adipocytes, but Maintain Normal Bone Formation Endocrinology, April 1, 2004; 145(4): 1916 - 1925. [Abstract] [Full Text] [PDF]
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 J. R. Seckl, N. M. Morton, K. E. Chapman, and B. R. Walker Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase in Adipose Tissue Recent Prog. Horm. Res., January 1, 2004; 59(1): 359 - 393. [Abstract] [Full Text]
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