CORTICOIDES

21/8/2018 Major side effects of systemic glucocorticoids - UpToDate
Authors: Kenneth G Saag, MD, MSc, Daniel E Furst, MD

Section Editor: Eric L Matteson, MD, MPH
Deputy Editor: Monica Ramirez Curtis, MD, MPH
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2018. | This topic last updated: Mar 12, 2018.
INTRODUCTION — Glucocorticoids are important in the treatment of many inflammatory, allergic,

immunologic, and malignant disorders, and the toxicity of glucocorticoids is one of the commonest causes
of iatrogenic illness associated with chronic inflammatory disease. Recognition of these toxicities, many of
which are similar to the findings in spontaneous (endogenous) Cushing's syndrome, is of value in their
prevention and management. (See "Epidemiology and clinical manifestations of Cushing's syndrome".)
The major adverse effects seen with systemic (oral and parenteral) glucocorticoid therapy will be reviewed
here. The adverse effects resulting from the use of inhaled, topical, and intraarticular glucocorticoids;
glucocorticoid withdrawal; use during pregnancy; and the clinical manifestations of endogenous
glucocorticoid excess are discussed in detail separately. (See "Major side effects of inhaled glucocorticoids"
and "General principles of dermatologic therapy and topical corticosteroid use", section on 'Side effects' and
"Joint aspiration or injection in adults: Complications" and "Glucocorticoid withdrawal" and "Safety of
antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation",
section on 'Glucocorticoids' and "Epidemiology and clinical manifestations of Cushing's syndrome".)
FACTORS RELATED TO GLUCOCORTICOID TOXICITY — Numerous toxicities, or adverse effects, have

been attributed to glucocorticoids (table 1). However, the attribution of causality to the glucocorticoids alone
cannot always be clearly established. Other factors that may contribute to such adverse effects include the
nature and severity of the underlying disease being treated and the other medications being concurrently
administered. Estimates of the frequency and severity of adverse effects, as well as the respective dose and
duration of therapy that may result in such adverse effects, are also limited by the modest number of
prospective trials that address this question.
Mechanisms of adverse effects — Glucocorticoids used in chronic disease (eg, prednisone or

prednisolone) do not have significant mineralocorticoid, androgenic, or estrogenic activity; thus, their major
adverse effects result from inhibition of hypothalamic-pituitary-adrenal function and the development of
iatrogenic Cushing's syndrome. (See "Pharmacologic use of glucocorticoids", section on 'Complications of
chronic use' and "Epidemiology and clinical manifestations of Cushing's syndrome".)
The effects of glucocorticoids are mediated by cytosolic glucocorticoid receptors and result from both
genomic and nongenomic mechanisms that also have a role in the therapeutic effects of these agents [1-3].
Genetic polymorphisms in the glucocorticoid receptor and in glucocorticoid metabolism may explain
heterogeneity in glucocorticoid toxicities observed. These effects lead to adverse effects from
transactivation, which leads to increased expression of regulatory and antiinflammatory proteins [2]; by
contrast, many of the clinically desirable effects appear to result primarily from transrepression, which
results in the decreased production of proinflammatory proteins. However, the mechanisms of glucocorticoid
transactivation and transrepression are poorly understood. Nongenomic effects of glucocorticoids include
rapid, nonspecific interactions of glucocorticoids with cellular membranes, nongenomic effects medicated by
cytosolic glucocorticoid receptors, and specific interactions with membrane-bound glucocorticoid receptors
[2].
Dose-related effects — Several retrospective reviews have shown that long-term glucocorticoid use, even
in low doses, is a significant independent predictor of numerous adverse effects and that the risk is both
dose- and duration-dependent [4-7]. As an example, a study of 112 rheumatoid arthritis (RA) patients found
https://www.uptodate.com/contents/major-side-effects-of-systemic-glucocorticoids?search=CORTICOIDS&source=search_result&selectedTitle=… 1/16
that the average daily prednisone dose was the strongest predictor of an adverse effect potentially
attributable to glucocorticoid therapy (odds ratio [OR] = 4.5 for 5 to 10 mg and 32.3 for 10 to 15 mg) (figure
1) [5]. The preselected adverse effects included in the analysis were fracture, serious infections,
gastrointestinal bleed or ulcer, and cataracts. The glucocorticoid-adverse effect association persisted after
statistical adjustment for significant disease severity factors, such as the presence of rheumatoid nodules
and bony erosions. There are also some data that have suggested that very low doses of glucocorticoids
(eg, prednisone <5 mg/day) are associated with fewer adverse effects [8,9].
A linear and threshold pattern of dose-related adverse effects have been described for different adverse
effects. A large retrospective analysis, which included data from 1066 RA patients on glucocorticoids for
more than six months, observed a "linear" pattern with increasing dose for Cushingoid phenotype,
ecchymosis, leg edema, mycosis, parchment-like skin, shortness of breath, and sleep disturbance [4]. A
"threshold" pattern, which described an elevated frequency of events beyond a certain threshold value,
occurred at doses of prednisone greater than 7.5 mg/day in which there was an increased frequency of
glaucoma, depression, and elevated blood pressure. Also, at doses of prednisone greater than 5 mg/day,
there was an increased frequency of weight gain and epistaxis. Cataracts were more common among
patients on glucocorticoids, even when the prednisone dose was less than 5 mg/day.
One study suggests that even short-term glucocorticoid use may be associated with serious adverse
effects. A retrospective cohort study and self-controlled case series that used a nationwide dataset of
private insurance claims in the United States assessed the risk of three adverse effects (sepsis, venous
thromboembolism [VTE], and fracture) in 327,452 adults younger than 65 who received at least one short-
term (<30 days) outpatient prescription over a three-year period [10]. Within 30 days of drug initiation, there
was an increase in the rates of sepsis (incidence rate ratio 5.30, 95% CI 3.80-7.41), VTE (incidence rate
ratio 3.33, 95% CI 2.78-3.00), and fracture (incidence rate ratio 1.887, 95% CI 1.69-2.07), which then
decreased over the subsequent 31 to 90 days. The issue of verification of diagnoses remains a significant
issue in these large databases and means that these results must be viewed with some skepticism. In
addition, time-varying factors such as an exacerbation of a serious inflammatory condition requiring
glucocorticoids but also predisposing to one of the three outcomes could have been differentially distributed
between the risk and baseline periods. Further, the absolute risks of each of the adverse effects was low.
Only 6.3 percent of the prescriptions were for a prednisone-equivalent dose of less than 17.5 mg a day,
suggesting that most of the exposures were to relatively higher doses.
ORGAN-BASED TOXICITY OF SYSTEMIC GLUCOCORTICOIDS — Glucocorticoids have adverse effects

on many organ systems (table 1). Adverse effects range from those that are not necessarily serious but are
displeasing to patients (eg, Cushingoid appearance) to those that are life-threatening (eg, serious
infections). Some adverse effects, such as accelerated reductions in bone mineral density or early
cataracts, may be largely asymptomatic until later manifestations develop that require medical attention (eg,
acute vertebral collapse, cataract requiring surgical extraction). Estimates of the frequency of particular
adverse effects vary between studies and depend in part on the specific condition being treated and on the
glucocorticoid treatment regimen being used [11]. With the exception of cataracts, a potential acceleration in
atherosclerotic vascular disease, and bone effects (osteoporosis and osteonecrosis), all glucocorticoid
toxicity is at least partially reversible over time with glucocorticoid discontinuation. (See 'Pretreatment
considerations and monitoring' below.)
Dermatologic effects and appearance — Many clinically relevant adverse effects of glucocorticoids on the
skin and appearance that have been observed even at lower doses include skin thinning and ecchymoses,
Cushingoid appearance, acne, weight gain, mild hirsutism, facial erythema, and striae. We discuss some of
the major dermatologic effects in more detail below.
● Skin thinning and ecchymoses – Among the most common toxicities attributable to glucocorticoids
are skin thinning and ecchymoses, even at low doses [8]. A large observational study with patient-
reported data from patients with rheumatoid arthritis (RA) on glucocorticoids for at least six months
reported rates of parchment-like skin and ecchymoses in 10 and 17 percent, respectively [4]. The
prevalence of these effects also increased with higher doses of prednisone. In a prospective study with
80 patients, skin changes were observed in 46 percent of patients treated for three months with
prednisone at doses greater than 20 mg/day [12]. The ecchymoses or purpura associated with
glucocorticoid use often affects the sun-exposed areas of the dorsum of the hand and forearm and is
not accompanied by palpable swelling. (See "Approach to the patient with macular skin lesions",
section on 'Solar purpura (senile purpura)'.)
● Cushingoid features – The development of Cushingoid features (redistribution of body fat with truncal
obesity, buffalo hump, and moon face) and weight gain are dose- and duration-dependent and can
develop within the first two months of therapy. A Cushingoid appearance can be quite troubling to
patients and can develop even with low-dose therapy; however, it is uncommon at doses below the
physiologic glucocorticoid-replacement range. Factors that may also contribute to increased weight
include an increased appetite, a common side effect of glucocorticoid therapy, and an increase in food
intake for symptomatic relief in patients with gastropathy or peptic ulcer disease [13]. (See
'Gastrointestinal effects' below and "Epidemiology and clinical manifestations of Cushing's syndrome",
section on 'Progressive obesity'.)
● Weight gain – Several observational studies have assessed the frequency of Cushingoid features and
weight gain. In an observational study of 779 patients with RA, weight gain was more frequent in
patients treated with at least 5 mg/day of prednisone or equivalent for at least six months, compared
with those who had not received any for at least 12 months (22.4 versus 9.5 percent) [4]. However,
there was a threshold effect, such that the rate of weight gain was not increased in those who took less
than 5 mg/day (8.7 percent) or further increased at doses greater than 7.5 mg/day (21.3 percent) [4].
By contrast, Cushingoid features showed a linear increase in frequency with dose rather than a
threshold effect. Among patients who had received <5, 5 to 7.5, and >7.5 mg/day of prednisone or
equivalent, Cushingoid features were observed in 4.3, 15.8, and 24.6 percent of patients, respectively.
In another study with survey data from 2167 long-term users of glucocorticoids (mean prednisone
equivalent dose ± standard deviation [SD] of 16±14 mg/day for ≥60 days), weight gain was the most
common self-reported adverse effect (70 percent of patients) [7]. In those on ≤7.5 mg/day of
prednisone or equivalent, increasing duration of use was significantly associated with weight gain. Also,
in an analysis of four prospective trials of glucocorticoids in RA, the use of 5 to 10 mg/day of
prednisone or equivalent over two years was associated with an increase of mean body weight of 4 to 8
percent [8].
Ophthalmologic effects — The risk of both cataracts and glaucoma is increased in patients on
glucocorticoids and is dose-related [8]. (See "Cataract in adults" and "Open-angle glaucoma: Epidemiology,
clinical presentation, and diagnosis" and "Angle-closure glaucoma".)
● Cataracts – Cataracts commonly occur after prolonged glucocorticoid use. They are usually bilateral
and develop slowly. They typically occur in a posterior subcapsular location and can usually be
distinguished from senile cataracts.
There may be no minimal safe dose with respect to the risk of cataract formation, although risk is dose-
and time-dependent and is more common with prednisone doses greater than 10 mg/day or with
medications that have been administered for more than one year [14-16]. In a study that evaluated 122
patients with RA taking a mean dose of prednisone of 8 mg/day for an average of 6.9 years, 29 percent
developed cataracts compared with 18 percent of matched controls [6]. Another study of patients with
RA receiving a mean dose of 6 mg of prednisone daily for a mean of six years also found cataracts
more common in patients on glucocorticoids than in patients not using prednisone (15 versus 4.5
percent) [5].
● Increased intraocular pressure – Glucocorticoids can also increase intraocular pressure, but these
effects can usually be controlled with appropriate medical therapy [8,17]. This form of glaucoma occurs
most commonly in patients who use glucocorticoid eye drops, although it has been observed in chronic
and, to a lesser extent, acute systemic glucocorticoid use [18]. The risk of glaucoma or worsening
intraocular pressure is greater in patients on glucocorticoids who are otherwise predisposed to this
disorder or who have certain comorbidities, including those with a positive family history of glaucoma
and diabetes mellitus or high myopia [8,19]. In patients with preexisting open- or closed-angle
glaucoma, the use of glucocorticoids will frequently aggravate the condition (46 to 92 and 65 percent,
respectively) [17,20].
● Exophthalmos – Exophthalmos and swelling of the lids and ocular muscles are rare ophthalmologic
complications of glucocorticoids [21,22].
A rare adverse effect of systemic, local, or even topical use of glucocorticoids is central serous
chorioretinopathy [23-25]. This type of chorioretinopathy is associated with edema formation that can
separate the retina from the choroid. Reduction of glucocorticoid dose is the most important element of
treatment if it can be done without causing a dangerous exacerbation of the disease that is being treated
with the glucocorticoids [26].
Cardiovascular effects — Glucocorticoid use has been associated with a variety of adverse cardiovascular
effects including fluid retention, premature atherosclerotic disease, and arrhythmias. Cardiovascular disease
risk is dose-dependent and may be low or absent in patients on low-dose glucocorticoid therapy [27].
● Fluid retention and hypertension – Higher-dose glucocorticoids may promote fluid retention, which is
of particular concern to patients with underlying heart or kidney disease. This is not a problem in normal
subjects because of the phenomenon of mineralocorticoid escape that prevents progressive fluid
overload (see "Pathophysiology and clinical features of primary aldosteronism"). Hypertension is a
known adverse effect of glucocorticoids and has been observed in up to 20 percent of patients with
iatrogenic Cushing's syndrome [28]; however, it is a dose-related adverse effect and is unlikely to occur
at lower doses of glucocorticoids [4]. Some studies have shown that long-term use of prednisone in RA
patients can be associated with a higher risk of hypertension, although the data are inconsistent when
low doses of glucocorticoids are used [29-31]. In patients receiving low doses of glucocorticoids (eg, 10
mg/day of prednisone), significant hypertension may be better explained by age and initial blood
pressure than by the glucocorticoids themselves [32]. The mechanism by which glucocorticoid therapy
can raise the blood pressure is not well understood [33,34]. (See "Epidemiology and clinical
manifestations of Cushing's syndrome", section on 'Hypertension'.)
● Premature atherosclerotic disease – Glucocorticoid use has been associated with increased rates of
myocardial infarction, stroke, heart failure, and all-cause mortality [27,35]. Increasing attention is being
given to the increased risk of premature atherosclerosis in RA and other systemic rheumatic disease.
Thus, the relative risks of cardiovascular events associated with glucocorticoid use may be confounded
by the role of the underlying inflammatory disease of the vascular endothelium. In a large population-
based study comparing 68,781 glucocorticoid users with 82,303 nonusers who had never been
hospitalized for cardiovascular disease, patients who received glucocorticoid doses ≥7.5 mg/day were
more than 2.5 times more likely than patients who did not receive glucocorticoids to experience a
cardiovascular event (defined as myocardial infarction, angina, coronary revascularization,
hospitalization for heart failure, transient ischemic attack [TIA], or stroke) [27]. Similarly, in another large
retrospective case-control study, an increased risk of ischemic heart disease and heart failure was
associated with current glucocorticoid use (adjusted odds ratios [ORs] 2.7 and 1.2, respectively) [35].
Neither of these studies included the role of disease-modifying agents or disease activity among the
patients who were included who had a systemic rheumatic disease.
Studies in which the patients were limited to systemic rheumatic diseases found more variable results
in terms of glucocorticoid use and cardiovascular disease risk. As an example, a prospective cohort
study with 364 polymyalgia rheumatica (PMR) patients followed for a median of 7.6 years found that
there was no increased risk of cardiovascular outcomes in patients treated with glucocorticoids
compared with the group of patients who just received nonsteroidal antiinflammatory drugs (NSAIDs)
[36]. By contrast, a large population-based study of 8384 patients with incident RA found that
glucocorticoid use was associated with a 68 percent increased risk of myocardial infarction [37]. The
risk of myocardial infarction increased by 13 percent for each 5 mg/day increase in glucocorticoid dose.
However, the potential for unmeasured confounders and possible misclassification using administrative
data limit these findings. Also, a randomized trial with 223 early RA patients followed prospectively for
10 years found an increased risk of cerebrovascular events in patients treated with prednisolone
compared with those not receiving prednisolone (hazard ratio [HR] 3.7 [1.2-11.4]) [31]. However, there
were no significant differences between the two treatment groups in composite cardiovascular events
(which included an acute myocardial infarction or an ischemic stroke) or a first coronary event.
The development of iatrogenic Cushing's syndrome may be a marker for patients at a higher risk of
cardiovascular disease. A cohort of 547 patients diagnosed with iatrogenic Cushing's syndrome in a
large general practice database had a significantly greater risk of a cardiovascular event compared with
patients who were receiving similar doses of glucocorticoids but who did not have a diagnosis of
Cushing's syndrome and patients who did not receive glucocorticoids [38]. (See "Epidemiology and
clinical manifestations of Cushing's syndrome", section on 'Cardiovascular risk'.)
● Arrhythmias – An association of glucocorticoid use with risk of atrial fibrillation and flutter has been
reported several studies [39-41]. In a population-based case-control study, current glucocorticoid use
was more common among 20,221 patients with atrial fibrillation or flutter compared with the 202,130
population controls (6.4 versus 2.6 percent) [41]. Currently using glucocorticoids was associated with a
significant increased risk of atrial fibrillation or flutter, compared with never having used glucocorticoids
(adjusted OR 1.9). Risk was increased for new users and long-term users, but not for former users
(ORs 3.6, 1.7, and 1.0, respectively) and was unrelated to whether or not pulmonary or cardiovascular
disease was present.
Serious adverse cardiovascular toxicities, including sudden death, have been reported in occasional
patients who have been given pulse infusions of glucocorticoids (eg, 1 g/day of methylprednisolone for
multiple infusions) [42]. In many of these cases, however, it was difficult to determine whether this
adverse effect was more likely attributable to glucocorticoids or to the underlying disorder necessitating
the therapy. Thus, cardiac monitoring is indicated in patients with significant cardiac disease who are
treated with pulse glucocorticoid therapy, especially those on diuretics, the use of which may also be
associated with electrolyte disturbances such as hypokalemia.
● Possible hyperlipidemia – The effect of glucocorticoids on atherosclerotic vascular disease is thought

to be mediated in part by elevated nonfunctional lipoprotein levels. However, studies analyzing this
issue have had mixed results, and beneficial effects of glucocorticoids on dyslipidemia have also been
observed. In one report, moderate- to low-dose prednisone (20 mg/day tapered to 5 mg/day over three
months) had no significant adverse effect on lipoprotein levels if other risk factors were taken into
account [43]. Another observational study concluded that glucocorticoid use was associated with a
more favorable lipid profile in older adults (≥60 years) [44]. Studies in patients with systemic lupus
erythematosus (SLE) have indicated that the adverse effects of glucocorticoids on lipid profiles are
dose-dependent, occurring only at prednisone doses greater than 10 mg/day [45-47]. Interpretation of
these data is complicated by the difficulty of distinguishing effects due to disease activity from effects
directly related to the medications themselves [48]. A rodent study found that the combination of
prednisone and atorvastatin improves the lipid profile better than either drug alone; however, we are
unaware of direct data in humans.
Glucocorticoids may act by leading sequentially to peripheral insulin resistance, hyperinsulinemia, and
increased hepatic very low-density lipoprotein (VLDL) synthesis. However, glucocorticoid-induced
reduction in corticotropin (ACTH) release also contributes to the lipid changes. In one report, for
example, the administration of ACTH for three weeks to nine hyperlipidemic, glucocorticoid-treated
patients (five of whom were transplant recipients) led to substantial reductions in total and low-density
lipoprotein (LDL) cholesterol and triglycerides and to an increase in high-density lipoprotein (HDL)
cholesterol [49]. ACTH may act, in part, by upregulating LDL-receptor activity.
Gastrointestinal effects — Glucocorticoids increase the risk for adverse gastrointestinal effects, such as
gastritis, ulcer formation, and gastrointestinal bleeding. The estimated relative risks of glucocorticoids alone
for gastrointestinal adverse effects vary from 1.1 (not significant) to 1.5 (marginally significant) [50,51].
However, the combination of glucocorticoids and NSAIDs results in a synergistic increase in the incidence
of gastrointestinal events as shown by the following findings from two meta-analyses:
● Glucocorticoid use is associated with a nearly twofold increased risk of a gastrointestinal adverse effect
among patients also taking NSAIDs when compared with those who use NSAIDs alone [52].
● The use of NSAIDs and glucocorticoids is associated with a fourfold increased risk of a gastrointestinal
adverse effect compared with nonuse of either drug [51].
Whether substitution of a selective cyclooxygenase (COX)-2 inhibitor for a nonselective NSAID would lower
this risk is unclear.
In addition to upper gastrointestinal morbidity, other complications associated with glucocorticoid use
include visceral perforation [53-55] and hepatic steatosis (fatty liver) that can rarely lead to systemic fat
embolism or cirrhosis [56,57]. Although glucocorticoids have also been implicated in causing acute
pancreatitis [58-60], other studies, particularly in patients with SLE, have shown that the disease is
causative, rather than the drugs, and that the drugs may be beneficial therapeutically [61,62]. However, the
role of glucocorticoids in causing acute pancreatitis remains uncertain. (See "Etiology of acute
pancreatitis".)
Glucocorticoids may mask the symptoms of serious gastrointestinal disease, an effect that may account, in
part, for the increased risk of perforated sigmoid diverticular abscess associated with their use [55].
Bone and muscle effects
● Osteoporosis – Osteoporosis is a well-known adverse effect of glucocorticoid use and is discussed in

detail elsewhere. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis" and
"Prevention and treatment of glucocorticoid-induced osteoporosis".)
● Osteonecrosis – Osteonecrosis (avascular or ischemic necrosis of bone) has also been associated
with glucocorticoid use, particularly with high doses of glucocorticoids. Glucocorticoid-induced
osteonecrosis is discussed separately. (See "Osteonecrosis (avascular necrosis of bone)", section on
'Glucocorticoids'.)
● Myopathy – Myopathy is an infrequent complication of glucocorticoid therapy. It presents as painless

proximal motor weakness in both the upper and lower extremities. Glucocorticoid-induced myopathy is
discussed in detail separately. (See "Glucocorticoid-induced myopathy".)
More acute and severe weakness noted in critically ill patients has been attributed at least in part to the
use of glucocorticoids. Variously referred to as critical illness myopathy and acute quadriplegic
myopathy, it has also been suspected to be due to an interaction between glucocorticoids and
neuromuscular blocking agents. This is discussed in more detail elsewhere. (See "Neuromuscular
weakness related to critical illness", section on 'Critical illness myopathy'.)
Neuropsychiatric effects — Glucocorticoids induce a range of psychiatric and cognitive symptoms, which
depend upon dose and duration of therapy [63]. In most patients, these symptoms are mild and reversible,
but emotional lability, hypomania, mania, depression, psychosis, delirium, confusion, or disorientation
(which are more common in older patients), and cognitive changes including memory deficits may occur
[64,65]. Disturbances in sleep are reported, especially with split doses that may interfere with the normal
pattern of diurnal cortisol production. Akathisia (motor restlessness) is a common glucocorticoid side effect.
The risk of developing a given neuropsychiatric disorder following glucocorticoid therapy may be increased
among patients with a past history of that condition [65]. Older patients may be at higher risk for depression,
mania, delirium, confusion, or disorientation [65]. We describe several conditions in more depth below:
● Mood disorders – Patients receiving glucocorticoids often experience an improved sense of well-being
within several days of starting the medications; mild euphoria or anxiety may also be seen [64,66,67].
Hypomanic reactions and activated states are more common early in therapy than is depression, but
the prevalence of depression is greater in patients on more longstanding therapy, even on low to
moderate doses [64,66,68]. Patients with a family history of depression or alcoholism are at increased
risk for affective diseases when given glucocorticoids [69].
More severe psychiatric symptoms can occur within a few days in patients receiving high doses of
glucocorticoids. As an example, in one prospective but uncontrolled study of 50 patients receiving over
75 to 100 mg of prednisone or equivalent for greater than a week for various ophthalmologic
indications, hypomanic symptoms were induced in approximately 30 percent, and depressive
symptoms in approximately 10 percent, of patients by the end of one week [70]. No patient became
overtly psychotic, demented, or delirious.
● Psychosis – Psychosis can occur but does so almost exclusively at doses of prednisone above 20
mg/day given for a prolonged period [8,71,72]. Approximately 10 percent of patients have persistent
symptoms that may require treatment despite reduction of glucocorticoid dose [73]. Response to
antipsychotic drug treatment is typically complete and occurs within two weeks of initiation of
neuroleptics. Hypoalbuminemia may be a risk factor for glucocorticoid-induced psychosis in patients
with SLE [74]. Patients with SLE who are on higher glucocorticoid doses present a particular problem
since it is often difficult to differentiate psychosis due to prednisone from neuropsychiatric lupus, which
may require high-dose glucocorticoid treatment. (See "Neuropsychiatric manifestations of systemic
lupus erythematosus" and "Clinical manifestations, differential diagnosis, and initial management of
psychosis in adults", section on 'Substance-induced psychoses'.)
● Memory impairment – Memory impairment has been associated with glucocorticoid use. As an
example, a cohort study of 115 RA patients found that glucocorticoid use was a predictor of poor
cognition when controlling for depression, disease severity and duration, and C-reactive protein (CRP)
level [75]. Another report found that patients treated with prednisone doses of 5 to 40 mg/day for at
least one year had a partial loss of explicit memory; older patients were more susceptible to memory
impairment with less protracted treatment [63,76]. The effect on memory began as early as three
months after the initiation of therapy. Approximately 1 percent of patients may be affected by more
severe and persisting cognitive disturbances beginning during glucocorticoid treatment; this has been
termed steroid dementia. In some patients, this condition may not remit for between 1 and 11 months
after discontinuing the medication.
● Other symptoms – In a retrospective analysis involving 372,696 patients in general practices in the
United Kingdom, there was a five- to sevenfold increased risk of completed or attempted suicide among
patients receiving glucocorticoids, compared with patients with the same diagnoses who were not
receiving such medications; however, the absolute risk was extremely low, approximating 0.1 cases per
100 patient-years of therapy [65]. Younger patients were at higher risk. The observational nature of the
study and potential for unknown confounding variables limit study interpretation.
Rare cases of pseudotumor cerebri have been associated with glucocorticoid use, although higher
doses are often effective in alleviating this generally self-limiting disorder [77]. Akathisia can occur even
in patients taking low doses. An increased risk of panic disorder may be present [65].
Metabolic and endocrine effects
● Hyperglycemia – Systemic glucocorticoids cause a dose-dependent, usually mild, increase in fasting

glucose levels and a greater increase in postprandial values in patients without preexisting diabetes
mellitus, but the development of de novo diabetes in a patient with initially normal glucose tolerance is
uncommon [78]. In a case-control study of Medicaid recipients, the relative risk of developing
hyperglycemia requiring glucose-lowering therapy increased progressively with increasing
glucocorticoid dose [79]. The relative risk increased from 1.8 in patients treated with the equivalent of
less than 10 mg/day of prednisone to 10.3 in those with the equivalent of more than 30 mg/day of
prednisone [79]. Risk factors for new-onset hyperglycemia during glucocorticoid therapy are thought to
be the same as those for other patients, including a family history of diabetes, increased age, obesity,
and a history of gestational diabetes [80]. Transient hyperglycemia can also occur after intraarticular
glucocorticoid therapy. (See "Comorbidities that impact management of osteoarthritis", section on
'Diabetes mellitus'.)
Patients with diabetes mellitus or glucose intolerance exhibit higher blood glucose levels while taking
glucocorticoids, leading to increased difficulty with glycemic control. In addition, new-onset
hyperglycemia or, rarely, a nonketotic hyperosmolar state or diabetic ketoacidosis develops without
warning in patients with early subclinical diabetes or glucose intolerance [30,78,79].
The mechanism by which glucocorticoids cause hyperglycemia is multifactorial, including augmentation

of hepatic gluconeogenesis, inhibition of glucose uptake in adipose tissue, and alteration of receptor
and postreceptor functions [1,81-83]. It is also possible that some underlying disorders for which
glucocorticoids are used, such as RA, may independently predispose to a higher rate of glucose
intolerance [84].
● Hypothalamic-pituitary-adrenal axis suppression – Administration of exogenous glucocorticoids can

suppress the hypothalamic-pituitary-adrenal (HPA) axis. Abrupt cessation or rapid withdrawal of
glucocorticoids in such patients may cause symptoms of adrenal insufficiency. The approach to
withdrawal of glucocorticoids, HPA axis suppression, and the clinical manifestations of adrenal
insufficiency are presented separately [85]. (See "Glucocorticoid withdrawal" and "Pharmacologic use
of glucocorticoids", section on 'HPA axis suppression' and "Clinical manifestations of adrenal
insufficiency in adults".)
Immune system effects — Systemic glucocorticoids have many effects upon innate and acquired immunity
that predispose to infection, resulting in a dose-dependent increase in the risk of infection, especially with
common bacterial, viral, and fungal pathogens. Glucocorticoids may be associated with a greater infection
risk among patients with RA, compared with other antirheumatic medications, such as the anti-tumor
necrosis factor (TNF)-alpha agents [86]. In one large study of RA patients, current and recent doses were
most strongly associated with such risk, but the data also suggested a cumulative risk effect from doses
taken during the preceding two to three years [87]. The risk of infection with glucocorticoid therapy and the
mechanisms underlying such risk are discussed in more detail elsewhere. (See "Glucocorticoid effects on
the immune system".)
In addition to glucocorticoid dose, factors influencing infection risk include the underlying disorder, the
presence of concomitant immunosuppressive therapies, hospitalizations, lymphopenia, and diabetes
mellitus [86,88]. Older patients and those with lower functional status are also at higher risk for infection. In
addition, patients taking glucocorticoids may not manifest signs and symptoms of infection as clearly, due to
the inhibition of cytokine release and associated reduction in inflammatory and febrile responses. This can
impair early recognition of infection. (See "Glucocorticoid effects on the immune system", section on
'Infection risk' and "Glucocorticoid effects on the immune system".)
Inhaled and topical glucocorticoids are usually not implicated in increased risk of systemic infections, in
contrast to the effects seen with systemic agents. The side effects of inhaled and topical glucocorticoids are
reviewed elsewhere. (See "Major side effects of inhaled glucocorticoids" and "General principles of
dermatologic therapy and topical corticosteroid use", section on 'Side effects'.)
Hematologic effects — Pharmacologic doses of glucocorticoids often result in an increased white blood
cell count (leukocytosis) that is due primarily to an increase in neutrophils (neutrophilia). This phenomenon
is due to a decreased proportion of neutrophils that are adhering to the endothelium. This effect of
glucocorticoids is discussed in detail elsewhere. (See "Approach to the patient with neutrophilia", section on
'Medications'.)
SPECIAL POPULATIONS
Young children — Growth impairment is commonly seen in children receiving glucocorticoids. The effect is
most pronounced with daily therapy, may be less with an alternate-day regimen, and can occur with inhaled
glucocorticoids. The effects of glucocorticoid therapy on growth in children is discussed in detail separately.
(See "Causes of short stature", section on 'Glucocorticoid therapy'.)
Children are more susceptible to cataract formation compared with adults. (See "Cataract in children",
section on 'Glucocorticoids'.)
Pregnancy — The risks associated with glucocorticoid use during pregnancy and lactation are discussed
elsewhere. (See "Safety of antiinflammatory and immunosuppressive drugs in rheumatic diseases during
pregnancy and lactation", section on 'Glucocorticoids'.)
PRETREATMENT CONSIDERATIONS AND MONITORING — We try to limit the adverse effects of

glucocorticoids by taking the following steps:
● Use of the lowest dose of glucocorticoids for the shortest period of time needed to achieve the
treatment goals
● Management of preexisting comorbid conditions that may increase risk when glucocorticoids are
required
● Monitoring of patients under treatment for adverse effects who may benefit from additional intervention
Assess for risk factors for complications — Preexisting conditions that should be assessed for and
treated when glucocorticoids are to be instituted include [89]:
● Diabetes mellitus
● Poorly controlled hypertension
● Heart failure and peripheral edema
● Cataract or glaucoma
● Peptic ulcer disease
● Presence of infection
● Low bone density or osteoporosis
Patients who also require concomitant treatment with nonsteroidal antiinflammatory drugs (NSAIDs) or
anticoagulants may require prophylaxis to prevent gastroduodenal toxicity. (See "NSAIDs (including aspirin):
Primary prevention of gastroduodenal toxicity".)
Immunization requirements — Patients who require an extended course of glucocorticoids should receive
appropriate immunizations prior to the institution of therapy (table 2).
The safety of live virus vaccines in specific patient groups is described briefly below but is reviewed in detail
separately. (See "Measles, mumps, and rubella immunization in adults" and "Vaccination for the prevention
of chickenpox (primary varicella infection)" and "Vaccination for the prevention of shingles (herpes zoster)"
and "Immunizations in hematopoietic cell transplant candidates and recipients" and "Immunizations in solid
organ transplant candidates and recipients" and "Immunizations in adults with cancer" and
"Nonpharmacologic therapies and preventive measures for patients with rheumatoid arthritis", section on
'Vaccinations'.)
In general, live virus vaccines may be administered to patients who have taken:
● Prednisone or its equivalent in doses of less than 20 mg/day for 14 days or less
● Glucocorticoids used for long-term physiologic replacement
● Glucocorticoids administered topically, by aerosol, or by intraarticular or bursal injection, provided that

there is no clinical or laboratory evidence of immunosuppression
If higher doses of glucocorticoids are taken, the combination measles-mumps-rubella (MMR) vaccine and
other live virus vaccines should not be administered for one month after the cessation of glucocorticoid
therapy. The immune response to other vaccines may be compromised by glucocorticoid administration in
doses in excess of those noted above.
Prevention of opportunistic infection — As described above, it is well known that glucocorticoids are
associated with an increased risk of infection (see 'Immune system effects' above). In some circumstances,
the use of prophylaxis for an opportunistic infection with Pneumocystis jirovecii pneumonia (PCP) is
recommended. However, this varies with the dose and duration of glucocorticoid therapy, as well as for the
underlying disease being treated (see appropriate topic reviews).
Prevention of osteoporosis — Depending on the length of the course of glucocorticoid treatment,

osteoporosis prevention may be pursued at the start of therapy. Adequate dietary calcium and vitamin D
intake should be encouraged. Guidance for the prevention and treatment of glucocorticoid-induced
osteoporosis is discussed in detail separately. (See "Prevention and treatment of glucocorticoid-induced
osteoporosis".)
Monitoring for adverse effects — Much of the monitoring performed in patients on glucocorticoids is
already performed as part of the ongoing routine preventive care appropriate for age and the underlying
disease being treated. Patients should be routinely asked about adverse effects related to glucocorticoids.
During treatment with glucocorticoids and depending upon individual risk factors such as dose and duration
of glucocorticoid usage, other medications being used, and comorbidities, particular attention should be
given to [89]:
● Osteoporosis
● Infection
● Diabetes or glucose intolerance
● Cataracts or glaucoma
Patients on prolonged moderate- to high-dose therapy should be examined periodically by an

ophthalmologist to promote early detection of cataracts and glaucoma.
Symptomatic diabetes mellitus or asymptomatic but clinically significant hyperglycemia that are
glucocorticoid-induced are generally treated pharmacologically in the same way that they are in patients
with diabetes mellitus or glucose intolerance in the absence of glucocorticoid therapy. Glucocorticoid-
induced hyperglycemia improves with reduction in the dose of glucocorticoid and usually reverses when the
medication is stopped, although some patients develop persistent diabetes [90,91]. (See "Management of
type 2 diabetes mellitus in children and adolescents", section on 'Pharmacologic agents' and "Overview of
medical care in adults with diabetes mellitus", section on 'Glycemic control'.)
https://www.uptodate.com/contents/major-side-effects-of-systemic-glucocorticoids?search=CORTICOIDS&source=search_result&selectedTitle… 10/16
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics"
and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want
in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail
these topics to your patients. (You can also locate patient education articles on a variety of subjects by
searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Oral steroid medicines (The Basics)")
SUMMARY AND RECOMMENDATIONS
● The adverse effects of glucocorticoids are both dose- and duration-dependent. The effects of
glucocorticoids are mediated by cytosolic glucocorticoid receptors and result from both genomic and
nongenomic mechanisms that also have a role in the therapeutic effects of these agents. Genetic
polymorphisms in the glucocorticoid receptor and in glucocorticoid metabolism may explain
heterogeneity in glucocorticoid toxicities observed. (See 'Mechanisms of adverse effects' above and
'Dose-related effects' above.)
Glucocorticoids have adverse effects on many organ systems (table 1). Adverse effects range from
those that are not necessarily serious but are displeasing to patients (eg, Cushingoid appearance) to
those that are life-threatening (eg, serious infections). Some adverse effects, such as accelerated
reductions in bone mineral density or early cataracts, may be largely asymptomatic until later
manifestations develop that require medical attention (eg, acute vertebral collapse, cataract requiring
surgical extraction). The following organ systems can be affected by systemic glucocorticoids to varying
degrees (see 'Organ-based toxicity of systemic glucocorticoids' above):
• Dermatologic effects and appearance (see 'Dermatologic effects and appearance' above)
• Ophthalmologic effects (see 'Ophthalmologic effects' above)
• Cardiovascular effects (see 'Cardiovascular effects' above)
• Gastrointestinal effects (see 'Gastrointestinal effects' above)
• Bone and muscle effects (see 'Bone and muscle effects' above)
• Neuropsychiatric effects (see 'Neuropsychiatric effects' above)
• Metabolic and endocrine effects (see 'Metabolic and endocrine effects' above)
• Immune system effects (see 'Immune system effects' above)
• Hematologic effects (see 'Hematologic effects' above)
● We try to limit the adverse effects of glucocorticoids by taking the following steps (see 'Pretreatment
considerations and monitoring' above):
• Use of the lowest dose of glucocorticoids for the shortest period of time needed to achieve the
treatment goals
• Management of preexisting comorbid conditions that may increase risk when glucocorticoids are
required
• Monitoring of patients under treatment for adverse effects who may benefit from additional
intervention
● Additional considerations prior to longer-term therapy with systemic glucocorticoids include addressing
appropriate immunization requirements, prevention of opportunistic infections, and prevention of
osteoporosis. (See 'Immunization requirements' above and 'Prevention of opportunistic infection' above
and 'Prevention of osteoporosis' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
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21/8/2018 Major side effects of systemic glucocorticoids - UpToDate

Authors: Kenneth G Saag, MD, MSc, Daniel E Furst, MD

INTRODUCTION — Glucocorticoids are important in the treatment of many inflammatory, allergic,

FACTORS RELATED TO GLUCOCORTICOID TOXICITY — Numerous toxicities, or adverse effects, have

Mechanisms of adverse effects — Glucocorticoids used in chronic disease (eg, prednisone or

ORGAN-BASED TOXICITY OF SYSTEMIC GLUCOCORTICOIDS — Glucocorticoids have adverse effects

● Possible hyperlipidemia – The effect of glucocorticoids on atherosclerotic vascular disease is thought

Bone and muscle effects

● Osteoporosis – Osteoporosis is a well-known adverse effect of glucocorticoid use and is discussed in

● Myopathy – Myopathy is an infrequent complication of glucocorticoid therapy. It presents as painless

Metabolic and endocrine effects

● Hyperglycemia – Systemic glucocorticoids cause a dose-dependent, usually mild, increase in fasting

The mechanism by which glucocorticoids cause hyperglycemia is multifactorial, including augmentation

● Hypothalamic-pituitary-adrenal axis suppression – Administration of exogenous glucocorticoids can

PRETREATMENT CONSIDERATIONS AND MONITORING — We try to limit the adverse effects of

● Poorly controlled hypertension

● Heart failure and peripheral edema

● Peptic ulcer disease

● Low bone density or osteoporosis

● Glucocorticoids used for long-term physiologic replacement

● Glucocorticoids administered topically, by aerosol, or by intraarticular or bursal injection, provided that

Prevention of osteoporosis — Depending on the length of the course of glucocorticoid treatment,

● Diabetes or glucose intolerance

Patients on prolonged moderate- to high-dose therapy should be examined periodically by an

SUMMARY AND RECOMMENDATIONS

• Ophthalmologic effects (see 'Ophthalmologic effects' above)

• Cardiovascular effects (see 'Cardiovascular effects' above)

• Gastrointestinal effects (see 'Gastrointestinal effects' above)

• Neuropsychiatric effects (see 'Neuropsychiatric effects' above)

• Immune system effects (see 'Immune system effects' above)

• Hematologic effects (see 'Hematologic effects' above)

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 7988 Version 18.0

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