Progress in Allergy Management
Bergmann K-C, Ring J (eds): History of Allergy. Chem Immunol Allergy. Basel, Karger, 2014, vol 100, pp 311–316
DOI: 10.1159/000359984
Glucocorticoids
Peter J. Barnes
Airway Disease Section, National Heart and Lung Institute, Imperial College, London, UK
Abstract
Glucocorticoids are the most effective anti-inflam-
matory treatment for allergic diseases, and inhaled glu-
cocorticoids have now become the first-line treatment
for asthma. Glucocorticoids were discovered in the
1940s as extracts of the adrenal cortex and this was fol-
lowed by the isolation of adrenocorticotropic hormone
(ACTH) from pituitary gland extracts. Cortisone and
ACTH were found to be very beneficial in the treatment
of rheumatoid arthritis and Kendall, Reichstein and
Hench received the Nobel Prize in Physiology and Med-
icine for this work in 1950. Bordley and colleagues first
showed that ACTH was very beneficial in the treatment
of allergic diseases in 1949, but the use of systemic glu-
cocorticoids was limited by side effects. Inhaled gluco-
corticoids were discovered from topical steroids devel-
oped for skin inflammation and beclomethasone dipro-
pionate was introduced in 1972, initially in low doses
but later in higher doses, and became the standard
treatment for persistent asthma. Subsequently, inhaled
glucocorticoids were combined with long-acting β2-
agonists in combination inhalers for even greater thera-
peutic benefit. There is now a good understanding of
the molecular basis for the anti-inflammatory effects of
glucocorticoids in allergic diseases. The search for even
safer glucocorticoids based on the dissociation of anti-
inflammatory and side effect mechanisms is currently
ongoing. © 2014 S. Karger AG, Basel
Glucocorticosteroids (also known as glucocorti-
coids or corticosteroids) are the most effective treat- 5
ment for asthma and other allergic diseases and it
has proven extraordinarily difficult to find any new
treatment that comes close to their therapeutic ben-
efit. Glucocorticoids are naturally occurring hor-
mones and their remarkable anti-inflammatory ef-
fects were first discovered in the early 1950s, shortly
after the synthesis of cortisol, the main glucocorti-
coid secreted by the adrenal cortex.
Early Studies with Glucocorticoids
Solomon Solis-Cohen, a physician from Philadel-
phia, first reported in 1900 that orally administered
adrenal gland extract (adrenal substance pills) was
beneficial in asthma [1]. It was assumed that the clin-
ical benefit of adrenal extract was explained by the
adrenaline from the adrenal medulla and the direct
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Fig. 1. Dr. Edward C. Kendall (1886–1972),
chemist who received the Nobel Prize in
Physiology and Medicine in 1950 for the
discovery of glucocorticoids.
Fig. 2. Philip Showalter Hench (1896–
1965), rheumatologist from the Mayo Clin-
ic who shared the Nobel Prize for the dis-
covery of glucocorticoids. 1 2
bronchodilator effect of adrenaline (epinephrine)
was first demonstrated by Kahn in 1907 using pre-
contracted tracheal strips in vitro [2]. However,
since adrenaline is not significantly absorbed after
oral administration it is very likely that the benefits
of orally administered adrenal extract described by
Solis-Cohen were due to its glucocorticoid content
[3]. This was not recognised at the time and it was
not until cortisol was isolated from the adrenal cor-
tex that the idea of glucocorticoids as a therapy for
asthma became clear. The Nobel Prize in Physiology
and Medicine was awarded in 1950 to Edward Ken-
dall, a chemist working at the Mayo Foundation, Ta-
deus Reichstein, a Swiss biochemist, and Philip
Hench, a clinician working at the Mayo Clinic, for
‘discoveries relating to the hormones of the adrenal
cortex, their structure and biological effects’. Ed-
ward Kendall (fig. 1) isolated several steroids from
the adrenal cortex during the 1940s, including corti-
sone (initially known as compound E) and subse-
quently adrenocorticotropic hormone (ACTH),
which was isolated from pituitary gland extracts.
Philip Hench (fig. 2), a rheumatologist at the Mayo
Clinic, was keen to test these drugs in patients with
rheumatoid arthritis, but this was delayed by the dif-
ficulty in preparing enough compound E for admin-
istration and also by his military service. Compound
E (cortisone) was first given by intravenous injection
to patients with rheumatoid arthritis in 1948 and
shown to be very beneficial. This was followed by the
312
demonstration that ACTH was equally effective.
Merck and Company first produced cortisone com-
mercially in 1949. Shortly after Hench’s demonstra-
tion of the clinical efficacy of cortisone and ACTH
in rheumatoid patients, John Bordley (fig.  3), an
ENT specialist, and colleagues at Johns Hopkins
University showed that ACTH had equally dramatic
effects in patients with asthma and allergic rhinitis
[4]. They described 5 patients with asthma, interest-
ingly all of whom had eosinophilic sputum, who im-
proved rapidly with intramuscular injections of
ACTH over a 3-week period, with disappearance of
the sputum. They went on to confirm these observa-
tions in a larger group of patients. As a replacement
for the injections it was subsequently shown that oral
cortisone, widely used at the time to treat several in-
flammatory diseases, was an effective therapy in pa-
tients with difficult-to-control asthma.
First Controlled Trial of Glucocorticoid in
Asthma
However, there was scepticism in the UK about
the efficacy of cortisol, leading to a Medical Research
Council multicentre trial of cortisone in asthma pa-
tients, which was in fact the first placebo-controlled
trial ever performed in asthma [5]. Surprisingly, the
results were disappointing with little clinical im-
provement, which was not sustained during the 2
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Fig. 3. Dr. John E. Bordley (1903–1993) – chaired the Department
of Otolaryngology at Johns Hopkins University in Baltimore and
first demonstrated the beneficial effects of ACTH in treating aller-
gic disease.
months of therapy. This may have reflected the low
dose of cortisone used, the lack of objective measure-
ments of lung function and most likely the inclusion
of many patients who had chronic obstructive pul-
monary disease (COPD), who show little clinical im-
provement with even high doses of glucocorticoids.
The Brompton Hospital in London was one of the
participating centres in this trial and Jack Pepys, who
was professor of allergy and one of the investigators,
carefully selected asthma patients with no evidence
of COPD, showing marked clinical improvement in
these patients.
Despite this poor result oral glucocorticoids be-
came increasingly used in patients with severe asthma,
but it was clear that side effects were a major problem
resulting in the stunting of growth in children, osteo-
porosis and metabolic disturbances. This immediately
suggested the need to give glucocorticoids by inhala-
tion as a way of reducing the systemic side effects.
Glucocorticoids
Inhaled Glucocorticoids
When the severe metabolic and endocrine side
effects of oral glucocorticoid became apparent, it
was thought that a way to reduce this problem was
to deliver the glucocorticoid by inhalation. Howev-
er, cortisone and dexamethasone given by inhalation
proved to be of little benefit. This later turned out to
be because of their lack of topical efficacy and led to
a search for topically active steroids. McKenzie and
Stoughton [6] had discovered that this topical effi-
cacy was correlated with skin blanching, although
the cellular basis for this test is still uncertain. Hy-
drocortisone turned out to be weak in the McKenzie
test, but two synthetic glucocorticoids, beclometha-
sone dipropionate (BDP) and betamethasone 17-val-
erate, gave good skin blanching responses. Both of
these steroids were effective as topical treatments for
eczema and psoriasis, predicting that they may also
be effective by inhalation.
Both of these new steroids were developed for in-
halation. BDP was developed in an inhaled formula-
tion by the team of Sir David Jack (fig. 4) at Allen &
Hanburys/Glaxo, and clinical trials in asthma were
begun in about 1970 [7]. An important paper by Har-
ry Morrow Brown et al. [8] in 1972 established that
inhaled BDP was very effective in reducing the need
for oral glucocorticoids and in many patients
achieved better control. Interestingly, Brown report- 5
ed that the patients who did best had high numbers
of eosinophils in their sputum, an observation that
has been confirmed in many subsequent (and much
more recent) studies [9]. BDP inhalers became avail-
able for the treatment of asthma in 1972. Low doses
of inhaled BDP (100 μg four times daily) were ini-
tially used as a way to reduce the requirement for oral
glucocorticoids. High doses of BDP (250 μg/puff)
were subsequently introduced in order to more ef-
fectively treat patients with more severe asthma [10].
About this time it became clear that inhaled BDP
twice daily was as effective as administration four
times daily and was more convenient for patients
[11]. In addition to BDP other topical glucocorti-
coids were developed for treating asthma. Budesonide
was developed by Ralph Brattsand and colleagues
working for Astra in Sweden, and was the first gluco-
corticoid optimised for inhaled use, with a favourable
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Fig. 4. Sir David Jack FRS (1923–2011), chemist who developed
the first inhaled glucocorticoid for the treatment of asthma.
ratio of topical to systemic effect as a result of the ef-
ficient hepatic metabolism of any swallowed gluco-
corticoid, and was introduced in the early 1980s [12].
Budesonide therefore had a therapeutic advantage
over BDP since systemic side effects were less likely.
This was followed by the development of fluticasone
propionate by Jack’s group at Glaxo, which had an
even more efficient first pass metabolism. Other glu-
cocorticoids were subsequently introduced and, al-
though all work focussed on activating glucocorti-
coid receptors, there were differences in the pharma-
codynamic effects. Mometasone and ciclesonide also
have reduced systemic effects and may be suitable for
once daily dosing in mild asthma patients. Cicle-
sonide is a prodrug that is activated by esterases in
the lower airways so may also have less risk of upper
airway side effects [13].
In parallel with the development of inhaled glu-
cocorticoids for asthma, the same drugs were devel-
oped either as nasal sprays or drops for the treatment
of rhinitis. While inhaled glucocorticoids were ini-
tially used in patients with relatively severe asthma,
with the growing recognition that even patients with
mild asthma have chronic inflammation of the air-
ways, inhaled glucocorticoid came to be used in the
314
majority of patients with persistent asthma, from
mild to severe patients [14]. With the recognition
that the doses of inhaled glucocorticoids needed to
control asthma in the majority of patients were not
associated with significant systemic side effects, their
use was also extended to children. Indeed, inhaled
glucocorticoid gradually came to replace the widely
used cromoglycate that was subsequently found in
controlled trials to be relatively ineffective. The
widespread use of inhaled glucocorticoids in asthma
has almost certainly been the major reason why asth-
ma morbidity, hospital admissions and mortality
have progressively fallen over the last decade. In-
haled glucocorticoids have now become amongst
the most widely used therapies in the world given the
high prevalence of asthma and, to a lesser extent,
COPD. There is now a search for inhaled glucocor-
ticoids with even better therapeutic ratios and less
systemic side effects, including the development of
selective glucocorticoid receptor activator drugs and
dissociated steroids that may not even have a classi-
cal steroid structure [15].
Combination Inhalers
A major breakthrough was the discovery that add-
ing an inhaled long-acting β2-agonist (LABA – sal-
meterol or formoterol) to an inhaled glucocorticoid
produced greater clinical benefit than increasing the
dose of inhaled glucocorticoids. This was fist demon-
strated in a study in general practice patients in the
UK by GlaxoSmithKline in 1994, when it was shown
that patients who were not controlled with 400 μg
daily of BDP were better controlled and showed bet-
ter lung function when salmeterol was added to this
dose rather than increasing the dose of BDP to 1,000
μg daily [16]. At first the results seemed counterin-
tuitive since it was believed that if asthma was not
controlled at a low dose of glucocorticoid it was be-
cause the dose was insufficient and a higher dose
would be effective. It was also known that LABA, un-
like glucocorticoids, did not have any anti-inflam-
matory effects. This study became one of the most
highly cited papers in respiratory medicine and al-
lergy. The unexpected findings were subsequently
confirmed in scores of other studies, all of which
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showed that adding a LABA was more effective than
increasing the dose of inhaled glucocorticoid. For
example, the FACET study, which was the largest
controlled trial in asthma patients at its time of pub-
lication, showed that adding formoterol was more ef-
fective than a 4-fold increase in dose of inhaled glu-
cocorticoids and that this combination was very ef-
fective in severe exacerbations [17]. These studies led
to the development of combination inhalers contain-
ing a glucocorticoid with a LABA and these have now
become the most effective and convenient means of
controlling asthma. Indeed, fluticasone propionate/
salmeterol (Seretide, Advair) has now become the
third biggest selling drug worldwide, with a market
that is increasing throughout the world. The reasons
for the greater efficacy of combination inhalers com-
pared to inhaled glucocorticoids alone relate to their
complementary effects in asthma and there is also a
synergy between the glucocorticoid and β2-agonist
effects [18]. Another reason is the shallow dose-re-
sponse to inhaled glucocorticoids. Although inhaled
glucocorticoids (BDP) have been used to treat asth-
ma since the early 1970s, it is only relatively recently
that dose-response studies have been conducted in
asthma patients. This occurred because it was man-
dated by the Food and Drug Administration (FDA)
when inhaled glucocorticoids were introduced in the
USA in the early 1990s. These dose-response studies
require approximately 100 patients for each dose of
inhaled glucocorticoid, which is why the studies were
only conducted when the FDA requested this infor-
mation. The flat dose-response study was with in-
haled budesonide [19], but similar dose-responses
were subsequently shown with all other inhaled glu-
cocorticoids [20].
Mechanisms of Action
When cortisol was first discovered it was believed
to function mainly as a stress hormone involved in
maintaining body homeostasis and regulating glyco-
gen metabolism. However, its anti-inflammatory ef-
fects became rapidly apparent when Hench studied
its effects in rheumatoid arthritis patients. It was
then shown to reduce the infiltration of inflamma-
tory cells into tissues, but its molecular mechanism
Glucocorticoids
of action has proved difficult to elucidate. It was
shown that radiolabelled cortisol and other gluco-
corticoids bound to specific macromolecular com-
plexes that were subsequently identified as glucocor-
ticoid receptors [21], and that these glucocorticoid
receptors interacted with DNA molecules in the nu-
cleus to affect gene expression. During the 1970s it
was established that the glucocorticoid binding and
DNA sites were distinct as they could be separated
by proteolysis. Around this time it was also shown
that glucocorticoid receptors could activate several
genes and it was therefore assumed that the anti-in-
flammatory effects of glucocorticoids were due to
the activation of genes that had anti-inflammatory
effects. Although several anti-inflammatory genes
were identified this was unlikely to account for the
marked anti-inflammatory effects of glucocorticoids
in suppressing multiple activated inflammatory
genes. Another possibility was that glucocorticoid
receptors could directly inactivate inflammatory
genes, although this was never convincingly demon-
strated and direct inhibition of cytokine genes, for
example, was not found. A more likely explanation
was that glucocorticoids directly inhibited transcrip-
tion factors, such as activator protein-1 or nuclear
factor-κB, which were responsible for the activation
of multiple inflammatory genes [22, 23]. However,
these direct interactions turned out to be more an
artefact of the overexpression systems that were used 5
to demonstrate these molecular interactions [24].
More recently it has been found that low concentra-
tions of glucocorticoids switch off inflammatory
genes through the recruitment of histone deacety-
lase-2, HDAC2, a nuclear enzyme that deacetylates
the hyperacetylated histones associated with activat-
ed inflammatory genes, such as cytokines. In addi-
tion, HDAC2 deacetylates glucocorticoid receptors
which is necessary for them to suppress activated in-
flammatory genes [25].
Future Directions
Glucocorticoids remain the most effective anti-
inflammatory drugs available for the treatment of al-
lergic diseases and it has been difficult to find any
other drugs anywhere near as effective. The main
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limitation of glucocorticoids is their side effects at
high doses. To a large extent this has been overcome
by topical administration, although systemic effects
may be seen at high doses. There have been attempts
to improve glucocorticoid safety by dissociating an-
ti-inflammatory effects from side effect mechanisms
and this has resulted in the identification of several
‘dissociated steroids’ [15]. These drugs are now in
development and it is hoped that the side effects of
oral glucocorticoids may be considerably reduced.
Another approach is to develop non-steroidal anti-
inflammatory treatments. So far this has proven to
be very difficult as most of the drug classes devel-
oped, such as phosphodiesterase-4 and p38 MAP ki-
nase inhibitors, have dose-limiting side effects.

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Prof. P.J. Barnes

Airway Disease Section, National Heart and
Lung Institute, Imperial College
Dovehouse Street
London SW3 6LY (UK)
E-Mail p.j.barnes @ imperial.ac.uk
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