morgan hassan-smith eje 2016

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European Journal of Endocrinology
www.eje-online.org © 2016 European Society of Endocrinology
Printed in Great Britain
Published by Bioscientifica Ltd.
DOI: 10.1530/EJE-15-1237
175:2 R81–R87
S A Morgan and others Tissue-specic cortisol excess
European Journal of
Endocrinology
(2016) 175, R81–R87
175:2
10.1530/EJE-15-1237
MECHANISMS IN ENDOCRINOLOGY
Tissue-specific activation of cortisol
in Cushing’s syndrome
Stuart AMorgan1,2, Zaki KHassan-Smith1,2 and Gareth GLavery1,2
1Institute of Metabolism and Systems Research, Institute of Biomedical Research, University of
Birmingham, Birmingham, UK and 2Centre for Endocrinology Diabetes and Metabolism, Birmingham
Health Partners, University of Birmingham, Birmingham, UK
Review
Correspondence
should be addressed
to G G Lavery
Email
G.G.Lavery@bham.ac.uk
Abstract
Glucocorticoids are widely prescribed for their anti-inammatory properties, but have ‘Cushingoid’ side effects
including visceral obesity, muscle myopathy, hypertension, insulin resistance, type 2 diabetes mellitus, osteoporosis,
and hepatic steatosis. These features are replicated in patients with much rarer endogenous glucocorticoid (GC) excess
(Cushing’s syndrome), which has devastating consequences if left untreated. Current medical therapeutic options that
reverse the tissue-specic consequences of hypercortisolism are limited. In this article, we review the current evidence
that local GC metabolism via the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a central role in
mediating the adverse metabolic complications associated with circulatory GC excess – challenging our current view
that simple delivery of active GCs from the circulation represents the most important mode of GC action. Furthermore,
we explore the potential for targeting this enzyme as a novel therapeutic strategy for the treatment of both
endogenous and exogenous Cushing’s syndrome.
Introdu ction
Due to their potent anti-inflammatory and
immunosuppressive properties, estimates suggest that
approximately 1–2% of the population of the UK and
the USA take prescribed glucocorticoids (GCs) to treat
a broad spectrum of autoimmune and inflammatory
diseases (1, 2). Despite their effectiveness, the majority of
these patients experience an adverse systemic side-effect
profile including: visceral obesity, muscle myopathy,
hypertension, insulin resistance, type 2 diabetes mellitus,
osteoporosis, and hepatic steatosis (3, 4). Collectively,
these ‘Cushingoid’ features contribute to increased
cardiovascular morbidity and mortality (5). Endogenous
GC excess (Cushing’s syndrome) is a rare diagnosis in
comparison (incidence up to 2 per million per year) (6),
but has devastating consequences if untreated (7).
Although modern therapies, such as transsphenoidal
surgery for Cushing’s disease, have dramatically improved
prognosis, there is evidence that excess mortality persists
Invited Author’s profile
Prof Gareth G Lavery is a Wellcome Trust Senior Research Fellow at the Institute of Metabolism and Systems
Research, University of Birmingham. He has a research background in understanding the redox regulation of
glucocorticoid metabolism and its impact upon metabolic physiology. His current interests include the tissue-
specific management of glucocorticoid excess and delineating biosynthetic pathways that impact on the metabolic
redox status of skeletal muscle.

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Review S A Morgan and others Tissue-specic cortisol excess
even after disease remission (8). Furthermore, there is an
inherent failure rate of first-line therapy with persistent
and recurrent disease rates of between 10–24% and
5–22%, reported respectively in studies from large
specialist centers (8, 9). Second-line therapies including
radiotherapy and bilateral adrenalectomy are associated
with lifelong hormonal deficiencies. Current medical
therapeutic options that reverse the tissue-specific
consequences of circulatory GC excess are limited by both
efficacy and side effects, and new treatment strategies are
urgently needed to improve long-term outcomes.
Recently, local GC metabolism via the enzyme
11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)
has been implicated in mediating the adverse
metabolic complications associated with circulatory
GC excess – challenging our current view that simple
delivery of active GCs from the circulation represents
the most important mode of GC action (10). In this
article, we review the current evidence for the role of
11β-HSD1 in this regard, and explore the potential for
targeting this enzyme as a novel therapeutic strategy
for the treatment of both endogenous and exogenous
Cushing’s syndrome.
11β-HSD1 and prereceptor GC metabolism
The availability of human cortisol (corticosterone in
rodents) to bind and activate the GC receptor (GR) is
controlled by 11β-hydroxysteroid dehydrogenases (11β-
HSD1 and 11β-HSD2). These isozymes are products
of separate genes and are members of the short-chain
dehydrogenase/reductase superfamily. 11β-HSD2 is highly
expressed in mineralocorticoid target tissues including
the salivary gland, kidney, and colon (11). The cognate
ligand of the mineralocorticoid receptor is aldosterone,
however, cortisol has a similar binding affinity to this
receptor. The role of 11β-HSD2 is to protect this receptor
from unwanted activation by cortisol by inactivating it to
cortisone.
By contrast, 11β-HSD1 expression is more widely
distributed (12), with high expression detected in key
metabolic tissues including adipose tissue, liver, and
skeletal muscle. 11β-HSD1 activity is bidirectional,
able to act as both an oxoreductase (activating GCs)
and a dehydrogenase (inactivating GCs). However, in
intact cells (13), oxoreductase activity predominates.
This is supported by the higher affinity of 11β-HSD1
for the human inactive GC, cortisone (Km
= 0.3 μM),
compared with cortisol (Km
= 2.1 μM) (14). 11β-HSD1 is
tethered to the endoplasmic reticulum (ER) membrane,
with the catalytic domain located within the lumen of
the ER (15). A high concentration of NADPH within
the ER lumen, generated by hexose-6-phosphate
dehydrogenase (H6PDH), is thought to be responsible
for maintaining the oxoreductase directionality of 11β-
HSD1. In H6PDH knockout mice, 11β-HSD1 activity
switches from reductase to dehydrogenase, underscoring
the importance of this enzyme in maintaining the
directionality of 11β-HSD1 (16).
Role of 11β-HSD1 in Cushing’s syndrome
The role of 11β-HSD1 in the development of Cushing’s
syndrome first came into the spotlight with a clinical
study performed by Tomlinson etal. (17) reporting on a
rare case of a patient with pituitary-dependent Cushing’s
disease who appeared to be protected from the classical
Cushing’s phenotype. Specifically, this patient had normal
fat distribution, absence of myopathy, and normal blood
pressure. Subsequent investigation revealed a functional
defect in 11β-HSD1 activity, as evidenced by serum and
urinary biomarkers. Similarly, Arai et al. (18) described
a patient with a cortisol-producing adrenocortical
adenoma lacking the phenotype of Cushing’s syndrome,
and again a defect in 11β-HSD1 activity was identified.
These clinical observations appeared to suggest that tissue
intrinsic 11β-HSD1 activity is the major determinant
of the adverse metabolic manifestations of circulatory
GC excess. Recently, we tested this premise using a
mouse model of exogenous Cushing’s syndrome (10).
In this study, we demonstrated that 11β-HSD1 knockout
mice were protected from the adverse metabolic side
effects associated with circulatory GC excess including
hypertension, hepatic steatosis, myopathy, and dermal
atrophy. Additionally, these mice were protected from
increased adiposity of both the omental and subcutaneous
depots, paralleled by a blunted induction of lipolytic
gene expression program in these tissues. In agreement
with reduced lipid mobilization, these mice were spared
from elevated serum free fatty acids. In an effort to
pinpoint the 11β-HSD1 expressing tissue(s) involved in
driving the metabolic side effects associated with GC
excess, we generated tissue-specific 11β-HSD1 deletions
in liver and adipose tissue. Whereas the liver-specific
11β-HSD1 knockout mice developed a full Cushingoid
phenotype, the adipose-specific 11β-HSD1 knockouts
were protected from the induction of lipolysis in adipose
tissue, circulating fatty acid excess, and hepatic steatosis,

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Review S A Morgan and others Tissue-specic cortisol excess
demonstrating that GCs generated locally within adipose
tissue are central in driving the hepatic manifestations
of GC excess (i.e. through increasing adipose tissue lipid
mobilization and oversupply to the liver) (10). However,
in contrast to the global 11β-HSD1 knockout mice, the
adipose-specific 11β-HSD1 knockouts were not protected
hypertension, increased adiposity, myopathy, or dermal
atrophy induced by circulatory GC excess. This implies
that GCs, reactivated by 11β-HSD1 within tissues other
than the adipose tissue, is central in driving these
extrahepatic Cushingoid features.
But how does 11β-HSD1 govern intracellular access
to circulating GCs? We postulate that exogenously
administered cortisol contributes to GR activation by
three distinct mechanisms (Fig. 1). First, the direct effect
of cortisol diffusing into the cell from the circulation,
where it binds and activates the cytoplasmic GR.
Secondly, circulating cortisol may be inactivated to
cortisone by 11β-HSD2, largely in the kidneys, and once
delivered to key metabolic target tissues is reactivated to
cortisol by 11β-HSD1 to allow GR activation. Also, the
stromal vascular fraction of adipose tissue expresses 11β-
HSD2 (19), representing an additional source of substrate
for adjacent adipocytes. Although, elevated urinary
cortisone levels have been reported in patients diagnosed
with endogenous/exogenous Cushing’s syndrome and
Cushing’s disease (20), whether circulating levels are
also elevated in these patients remains to be confirmed.
Thirdly, GCs stimulate 11β-HSD1 expression and activity
in a GR-dependent manner, further fuelling intracellular
GC excess. We and others have demonstrated this feed-
forward action in key metabolic tissues including adipose
tissue (10, 21, 22, 23, 24). Despite this, Mariniello etal. (25)
found no differences in adipose tissue 11β-HSD1 mRNA
expression between patients with Cushing’s syndrome and
normal weight controls, although increased reactivation
of GCs by 11β-HSD1 in this tissue was not investigated in
this study.
These studies challenge the idea that simple delivery
of active GCs from the circulation represents the most
important mode of GC action, and raises an intriguing
question: Is Cushing’s a cortisone disease? This concept
makes physiological sense, in terms of individual tissues
regulating precisely their GC availability – rather than it
being dictated by a distant gland. In support, a negative
association between circulating cortisone levels and
bone mineral density and osteocalcin has been reported,
independent of circulating cortisol levels, implying that
11β-HSD1 activity within osteoblasts regulates bone
mineral density (26).
Selective 11β-HSD1 inhibition – therapeutic
implications for Cushing’s syndrome
Transsphenoidal surgery is the first-line therapy for
the treatment of Cushing’s disease; however, there are
scenarios where alternative treatment options are required,
such as in persistent/recurrent hypercortisolemia, in
preparation for operative intervention, while awaiting
effects of radiotherapy, or where surgery is not an
option. Recent outcome studies suggest that although
mortality has greatly improved in Cushing’s disease, there
appears to be persisting excess risk in spite of control of
Figure 1
Schematic representation of the key mechanisms by which
circulating activated GCs (e.g. cortisol and prednisolone) result
in activation of the GR within key metabolic tissues: (1) active
GCs diffuse from the circulation into the cells of key metabolic
tissues, where they subsequently bind and activate the GR
directly; (2) circulating active GCs are inactivated by 11β-HSD2
in the kidney/colon, the resultant inactive metabolites (e.g.
cortisone and prednisone) enter the circulation and diffuse
into the cells of key metabolic tissues, where they are
subsequently reactivated by 11β-HSD1 in the vicinity of the
GR; (3) GCs positively regulate 11β-HSD1 expression/activity in
a GR-dependent manner – further fuelling increased local GC
availability.

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European Journal of Endocrinology
175:2 R84
Review S A Morgan and others Tissue-specic cortisol excess
hypercortisolism over long-term follow-up. This may
suggest a ‘legacy’ effect of initial GC excess exposure, or it
could highlight the importance of long-term ‘subclinical’
exposure (8, 9).
Clinically, GCs are used for their powerful
immunosuppressive effects in a broad range of medical
applications. They are, however, limited by their adverse
metabolic effects, and this has been an area of great
recent research interest. The development of selective GR
agonists (27) that target the transrepressive effects of GCs
over the transactivating actions is a rational approach, but
has yet to deliver a clinical drug (28, 29).
Current pharmacological strategies for Cushing’s
disease are either pituitary directed (dopamine
agonists, somatostatin analogs, and retinoic acid)
or focused on blocking cortisol secretion and effect
(steroidogenesis inhibitors and GR antagonists) (30).
Current therapies have low to modest rates of urinary
free cortisol or clinical normalization as monotherapy.
Furthermore, they are associated with side effects
including hyperglycemia (pasireotide, a somatostatin
analog), gastrointestinal symptoms, and symptoms
associated with adrenal insufficiency (steroidogenesis
inhibitors, GR antagonists). Recent studies suggest
that combination therapy is associated with improved
efficacy (31, 32). Overall, there is a need for larger studies
of current and new agents with long-term assessment of
associated morbidity and mortality. Since prereceptor
GC metabolism by 11β-HSD1 may play a critical role
in driving the Cushingoid features associated with
circulatory GC excess, therapeutically targeting this
enzyme may offer an alternative, potentially more
efficacious, approach in the treatment of both exogenous
and endogenous Cushing’s syndrome (Fig. 2).
To date, a number of selective 11β-HSD1 inhibitors
have been developed, although none has been tested in
the setting of circulatory GC excess. Previous studies using
this class of drug have found them to have beneficial
effects upon glucose tolerance, insulin sensitivity, and
dyslipidemia when administered to rodent models of
obesity, type 2 diabetes, and the metabolic syndrome,
including db/db, ob/ob, KKAy, ApoE–/–, and Ldlr 3KO
mice (33, 34, 35, 36, 37). Furthermore, clinical studies
using compounds developed by both Incyte Corporation
(Wilmington, DE, USA) and Merck have since been
administered to patients with type 2 diabetes and those
‘failing’ metformin therapy. In agreement with the rodent
studies, these compounds modestly improve blood glucose
control, insulin sensitivity, as well as lipid profiles (38, 39,
40, 41). However, their further commercial development
for their use in this context has been precluded by the
small magnitude of their glucose-lowering effect.
If therapeutically targeting 11β-HSD1 were to be used
to abrogate the Cushingoid side effects associated with
circulatory GC excess, then adipose tissue (rather than
liver) would need to be the primary target, specifically to
limit the detrimental hepatic manifestations of GC excess
(10). Importantly, selective compounds have already
been developed, which are pharmacologically active in
this tissue (42). It is likely that targeting 11β-HSD1 in
other key metabolic tissues such as the skeletal muscle
would also be highly beneficial, specifically to relieve the
extrahepatic manifestations of circulatory GC excess such
as myopathy.
In the context of exogenous Cushing’s syndrome,
cotreatment with a selective 11β-HSD1 inhibitor is likely
to benefit patients prescribed GCs with similar kinetics to
those of endogenous cortisol. This includes prednisolone
and prednisone widely prescribed in Europe and the
USA, respectively. These synthetic GCs have similar
binding affinities to 11β-HSD1 and 2 as cortisol and
cortisone, and are metabolized by these enzymes in an
Figure 2
The therapeutic potential of using a selective 11β-HSD1
inhibitor to abrogate the systemic metabolic complications
associated with circulatory GC excess in both exogenous and
endogenous Cushing’s syndrome. FFA, free fatty acid.

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Review S A Morgan and others Tissue-specic cortisol excess
analogous manner (43). As such, selectively targeting
the reactivation aspect of this inactivation/reactivation
loop has the potential to limit intracellular prednisolone
levels, which may be central in driving the systemic side
effects associated with commonly prescribed GCs.
There are hypothetical concerns that 11β-HSD1
inhibition may be associated with hypothalamic–
pituitary–adrenal axis activation and androgenic side
effects may have failed to materialize in clinical studies.
Increases in adrenocorticotrophic hormone and DHEAS
within the normal range have been reported, but these
were off-set by increases in sex hormone-binding globulin
and were not associated with symptoms (39). Although
these compounds appear to be well tolerated in short-
term studies, the consequences of long-term 11β-HSD1
suppression in humans are unknown, and further studies
are necessary to ensure that symptoms suggestive of
tissue-specific GC deficiency are not encountered.
An important consideration that might influence
their therapeutic potential is their impact on both
acute and chronic inflammation. During an acute
inflammatory response, 11β-HSD1 expression is increased
in macrophages, and the local increased GCs availability
is thought to have a beneficial anti-inflammatory effect.
Based on this premise, it was anticipated that 11β-HSD1
would worsen acute inflammation. Indeed, this is what is
seen in 11β-HSD1 knockout mice following the induction
of sterile peritonitis. However, the peritonitis was actually
found to resolve at the same rate as the wildtype animals
(44). Similarly, cardiac function was much better preserved
in 11β-HSD1 knockout mice following myocardial
infarction, despite initially having comparatively higher
levels of local inflammation (45, 46). Although these
studies imply that loss of 11β-HSD1 may not have an
adverse impact on an acute inflammatory response, a
study using a mouse model of arthritis and carrageenan-
induced pleurisy found 11β-HSD1-deficiency to result in
the converse (47).
Chronic inflammation, on the other hand, arises
from acute inflammation that fails to resolve, and this has
been postulated to play a role in the development and
propagation of type 2 diabetes, visceral obesity, as well as
other aspects of the metabolic syndrome (48). As discussed
above, selective 11β-HSD1 inhibitors have been shown to
have beneficial effects on these ‘chronic inflammatory
diseases’. As such, although there is evidence that 11β-
HSD1 inhibition impedes the resolution of certain
acute inflammation conditions, their impact on chronic
inflammatory diseases is beneficial. However, this aspect
of their efficacy needs urgent testing in a clinical setting.
Conclusions
Taken together, current data suggest that GC reactivation
by 11β-HSD1 is key to the development of the adverse
metabolic profile associated with circulatory GC excess –
underscoring 11β-HSD1 as a potentially novel therapeutic
target in the treatment of both endogenous and
exogenous Cushing’s syndrome (Fig. 2). If these rodent
findings translate into clinical studies in man, then there
is no doubt that this class of agent will add significantly
to the repertoire of drugs available to the clinician to limit
the adverse side effects experienced by patients taking
prescribed GCs. Certainly, clinical studies of subjects with
hypercortisolism protected from Cushingoid features,
due to loss of 11β-HSD1 function are encouraging
(17, 18). However, there remain important issues that
need to be clarified, such as the consequences of long-term
11β-HSD1 suppression, the influence of these compounds
on the immunosuppressive properties of prescribed GCs,
and their effects on the endogenous control of acute
inflammation. As such, clinical studies are urgently needed
to fully evaluate the use of this class of compound in the
context of circulatory GC excess. These studies could be
focused on Cushing’s disease patients with persistent or
recurrent disease following first-line therapies or in those
who are not surgical candidates, where it is clear that there
is real clinical need. It is also interesting to speculate that
selectively targeting 11β-HSD1 may be of great benefit, as
an adjunctive therapy in 1 – 2% of the population taking
prescribed GCs, where Cushingoid side effects remain a
major burden; however, questions regarding their effects
on underlying inflammatory disease need to be answered.
Declaration of interest
The authors declare that there is no conict of interest that could be
perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specic grant from any funding agency in
the public, commercial, or not-for-prot sector.
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Received 5 January 2016
Revised version received 23 February 2016
Accepted 7 March 2016