NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.

Corticosteroid Adverse Effects

Authors

Muhammad Yasir1; Amandeep Goyal2; Sidharth Sonthalia3.

Affiliations
1 Allama Iqbal Medical College/JHL, Lahore
2 University of Kansas Medical Center
3 SKINNOCENCE: The Skin Clinic

Last Update: July 3, 2023.

Continuing Education Activity

Corticosteroids are hormone mediators produced by the cortex of adrenal glands that further categorize into
glucocorticoids, mineralocorticoids, and androgenic sex hormones. They are used in a plethora of conditions,
commonly called steroid-responsive disorders and dermatoses. Corticosteroids constitute a double-edged sword -
significant benefit with a low incidence of adverse effects can be expected if used in proper dosage and for a limited
duration; however, wrong dose and/or duration and unmindful withdrawal after prolonged administration can have
catastrophic effects. Corticosteroids are used across all medical specialties. This activity reviews the must-know
properties of this group of drugs, their broad indications and contraindications, ways of administration, adverse event
profile, practical aspects of the pharmacokinetics of different molecules, monitoring essentials, approach to maximize
the benefit and minimize adverse effects, and clinically relevant drug-interactions pertinent for all specialists whether
used in isolation or administered by an interprofessional team.

Objectives:

Review the anti-inflammatory, anti-proliferative, and immunosuppressive actions of corticosteroids.

Summarize the monitoring required for corticosteroid therapy.

Describe the possible adverse effects of corticosteroid therapy.

Explain the importance of improving care coordination among the interprofessional team to enhance the
delivery of care to patients requiring corticosteroids.

Access free multiple choice questions on this topic.

Indications
Corticosteroids are hormone mediators produced by the cortex of adrenal glands that are further categorized into
glucocorticoids (major glucocorticoid produced by the body is cortisol), mineralocorticoids (major mineralocorticoid
produced in the body is aldosterone), and androgenic sex hormones. Endogenous cortisone was first isolated in 1935
and synthesized in 1944. In 1948, Dr. Philip S Hench published administered cortisone (called Compound E at that
time) to a 29-year-old woman who was bed-ridden secondary to active rheumatoid arthritis. The patient was able to
walk after three days of treatment. This case was published in 1949, and in 1950, Philip S. Hench, Edward C. Kendall,
and Tadeusz Reichstein were awarded the Nobel Prize in Physiology or Medicine "for their discoveries relating to the
hormones of the adrenal cortex, their structure, and biological effects."[1]

Glucocorticoids (GCs) are a group of drugs structurally and pharmacologically similar to the endogenous hormone
cortisol with various functions like anti-inflammatory, immunosuppressive, anti-proliferative, and vaso-constrictive
effects. Their actions are used medically for the treatment of various conditions indicated below. The list of
indications of glucocorticoids is extremely long. We have categorized and mentioned the most important and broad-
spectrum indications below.

As a Replacement Therapy
 Adrenocortical insufficiency (Addison disease)

Congenital adrenal hyperplasia (CAH)

Systemic Symptomatic Treatment

Acute

Allergic reactions and anaphylactic shock (vasoconstrictive effects)

Asthma (bronchodilatory effects)

Antiemetic treatment, for example, nausea due to chemotherapy)

Toxic pulmonary edema

Acute exacerbation of autoimmune diseases such as multiple sclerosis, vitiligo, uveitis, rheumatoid arthritis,
SLE, etc.

Acute exacerbation of chronic obstructive pulmonary disease (COPD)

Cerebral edema: Recommended only in specific conditions like elevated intracranial pressure due to the
neoplasm or central nervous system (CNS) infection; generally avoided in moderate to severe brain injury

Long-Term

Chronic inflammatory diseases (asthma, chronic obstructive pulmonary disease, inflammatory bowel disease)

Rheumatic diseases (sarcoidosis, Sjogren syndrome, SLE)

Graves' ophthalmopathy

Local symptomatic treatment: anterior uveitis, steroid-responsive dermatoses (SRD), tenosynovitis, and
osteoarthritis or juvenile idiopathic arthritis

Prophylactic

Organ transplant (to prevent rejection due to their immunosuppressive action)

Preterm delivery (to allow fetal lung maturity)

Mineralocorticoids are primarily involved in the regulation of electrolyte and water balance by modulating ion
transport in the epithelial cells of the collecting ducts of the kidney. The use of mineralocorticoid drugs is limited to
their replacement therapy in acute adrenal crisis and Addison disease.

Due to several roles played by corticosteroids in the human body, they see extensive use in medical practice to treat
various diseases. As a result, their side-effects have, in turn, become another significant medical issue requiring
special attention.

Mechanism of Action
Anti-Inflammatory and Immunosuppressive Effects

The anti-inflammatory and immunosuppressive effects of glucocorticoids are dose-dependent, with

immunosuppressive effects seen mostly at higher doses. The pharmacological anti-inflammatory and
immunosuppressive effects of glucocorticoids are extensive and can occur via genomic or non-genomic mechanisms.
Most effects of glucocorticoids are via the genomic mechanisms, which takes time, while immediate effects via the
non-genomic mechanisms can occur with high doses of glucocorticoids (such as pulse therapy). Clinically, it is not
possible to separate these effects.

Genomic Mechanisms
Being small, lipophilic substances, glucocorticoids readily pass the cell membrane by diffusion and enter the
cytoplasm of the target cells, where most of their action is mediated by binding to the intra-cytoplasmic glucocorticoid
receptors. Glucocorticoid receptors have two isoforms, α, and β. Glucocorticoids bind to the α-isoform only.
Glucocorticoid resistance in some patients has been partly attributed to higher levels of the β-isoform in these
patients.[2] The binding of the glucocorticoid to the glucocorticoid receptor results in the shedding of heat-shock
proteins, which are otherwise bound to the glucocorticoid receptor, which results in the formation of the activated
glucocorticoid receptor-glucocorticoid complex, which easily translocates to the nucleus. In the nucleus of the target
cells, this complex reversibly binds to several specific DNA sites resulting in stimulation (transactivation) and
suppression (transrepression) of a large variety of gene transcription. Tranpression of transcription factors such as
nuclear factor-κB [NF-κB], activator protein-1, and interferon regulatory factor-3 results in suppression of synthesis
of pro-inflammatory cytokines such as IL-1, IL-2, IL-6, IL-8, TNF, IFN-gamma, Cox-2, VEGF, and prostaglandins.
Transactivation of transcription factors, including glucocorticoid response elements (GREs), leads to activation of the
synthesis of anti-inflammatory cytokines such as IL-10, NF-κB inhibitor, and lipocortin-1.

Non-Genomic Mechanisms

The immediate effects of high dose-glucocorticoids are mediated via non-genomic mechanisms. At high doses,
glucocorticoids bind the membrane-associated glucocorticoid receptors on target cells such as T-lymphocytes,
resulting in impairment of receptor signaling and immune response of the T lymphocytes. High-dose glucocorticoids
also interact with the cycling of calcium and sodium across the cell membrane resulting in a rapid decrease in
inflammation.

By altering the cytokine production via the genomic and non-genomic mechanisms, glucocorticoids lead to
suppression of the immune system and decreased inflammation. They target a wide variety of cells, including T-
lymphocytes, macrophages, fibroblasts, neutrophils, eosinophils, and basophils. Notably, glucocorticoids have almost
no effect on B-cell function and immunoglobulin production. The downstream effects of glucocorticoids are
summarized below:

Inhibition of neutrophil adhesion to endothelial cells and demargination of neutrophils from the marginal pool
of blood vessels causing neutrophilic leukocytosis

A decrease in the number of lymphocytes, macrophages, monocytes, eosinophils, and basophils (decreased
myelopoiesis and release from bone marrow, and increased apoptosis)

Decreased proliferation of fibroblasts

Decreased MHC-Class II and Fc receptor expression on macrophages and monocytes

Decreased phagocytosis and antigen presentation by macrophages

Decreased cytokine production by macrophages and lymphocytes

Decreased proliferation of fibroblasts.

Reduction in the formation of arachidonic acid derivatives by the promotion of synthesis of lipocortin-A that
inhibits phospholipase A2

Inhibition of metalloproteinases collagenase and stromelysin, which are otherwise responsible for cartilage
degradation

Effects on the Hypothalamic-Pituitary-Adrenal (HPA) Axis

Glucocorticoids exert negative feedback effects on the HPA axis. They directly suppress adrenocorticotropic hormone
(ACTH) and corticotropin-releasing hormone (CRH) secretion. Additionally, by suppressing the release of pro-
inflammatory cytokines that stimulate ACTH and CRP secretion, glucocorticoids further suppress ACTH and CRH
secretion indirectly in inflammatory diseases. Chronic HPA axis suppression by glucocorticoids leads to functional
adrenal atrophy (sparing the mineralocorticoid producing outer adrenal cortex that is functionally independent of
ACTH). The risk of this functional adrenal atrophy and insufficiency is challenging to predict and varies from patient
to patient but is largely dependant on the dose and duration of glucocorticoid therapy. The adrenal function generally
recovers by slow tapering of glucocorticoids.

Mineralcorticoid Effects

Glucocorticoids bind to mineralocorticoid receptors (MRs) and produce their mineralocorticoid effect (i.e., increasing
sodium and decreasing potassium), but only when used at the high dose and for an extended period.

Administration
Several preparations of glucocorticoids are available, each with varying efficacy. Dexamethasone and betamethasone
are long-acting with the highest glucocorticoid efficacy with a biological half-life of 36 to 54 hours. Cortisone and
cortisol are short-acting with a biological half-life of under 12 hours and are not frequently used. Prednisone,
prednisolone, methylprednisolone, and triamcinolone are intermediate-acting with a biological half-life of 18 to 36
hours. The glucocorticoid and mineralocorticoid effects of each available preparation vary, with cortisol and cortisone
having almost 1 to 1 glucocorticoid and mineralocorticoid effects while all others with almost no mineralocorticoid
effects. Equivalent glucocorticoid doses can be calculated for these various preparations. 5 mg of prednisone is
equivalent in its glucocorticoid effects to 5 mg of prednisolone, 4 mg of methylprednisolone, 4 mg of triamcinolone,
0.75 mg of dexamethasone, 0.60 mg of betamethasone, 20 mg of cortisol, and 25 mg of cortisone.

Intravenous Administration

Parenteral intravenous administration of high doses of glucocorticoids may be warranted in emergencies, such as
septic shock, COPD exacerbation, and severe acute asthma. Pulse therapy of glucocorticoids (1000 mg intravenous
methylprednisolone divided over 3 to 4 daily doses) for several days has been studied in several rheumatological
conditions. This approach is recommended only for organ-threatening or life-threatening situations, including lupus
nephritis (Class III or IV), giant cell arteritis with vision loss, ANCA-associated vasculitis, etc. Americal College of
Rheumatology also recommends using intravenous glucocorticoids in patients with acute gout who are unable to take
medications orally.

Oral Administration

Oral preparations are usually useful in both acute and chronic indications. For acute exacerbations of underlying
chronic illness (such as asthma, COPD, gout, pseudogout, rheumatoid arthritis (RA), systemic lupus erythematosus
(SLE), etc.), short duration of moderate to high doses of oral corticosteroids is usually efficacious in treating the flare.
Tapering dose packs starting at high doses and tapering daily over 7 to 9 days are commercially available and can be
used in these situations as well. Long-term oral corticosteroid therapy may be necessary for chronic illnesses such as
polymyalgia rheumatica, SLE, RA, vasculitis, myositis, IgG4-related disease, chronic myelogenous leukemia (CML),
lymphoma, leukemia, multiple sclerosis, organ transplantation, etc. Clinicians must make every effort to use the
glucocorticoids at the lowest possible dose and for the shortest possible duration in these cases. A slow taper shall be
attempted in patients with prolonged exposure to glucocorticoids to prevent adrenal crisis.

Local Administration

Glucocorticoid administration can be via several non-systemic routes, including intra-articular joint injections for
joint inflammation, inhalational for asthma, topical for dermatological problems, ocular drops for eye conditions, and
intra-nasal for seasonal rhinitis. Clinicians generally avoid intramuscular (IM) glucocorticoids due to the risk of local
muscle atrophy due to depot effect, and the only indications for intramuscular glucocorticoids are for IM
triamcinolone acetonide for specific inflammatory disorders and IM injection of betamethasone to a pregnant mother
less than 37 weeks of gestation to stimulate fetal lung maturity. When appropriate, a non-systemic route is preferable
to the systemic route of administration to minimize systemic adverse effects.

Adverse Effects
Factors Influencing the Adverse Effects of Glucocorticoids

Given the diversity in the mechanism of action of glucocorticoids, they can cause a wide array of adverse effects
ranging from mild to severe, some of which are unavoidable. Of all the factors influencing the adverse effects of
glucocorticoids, dose and duration of therapy are the most important independent and well-documented risk factors. It
is usually at “supra-physiologic” doses of corticosteroid administration where multiple and especially severe adverse
effects of glucocorticoids occur, ranging from mild suppression of hypothalamic-pituitary axis to severe, life-
threatening infections.[3] However, long-term use of low to moderate doses of glucocorticoids can also lead to several
serious adverse effects.[4][5] Adverse effects of corticosteroids are both dose and time-dependent.[6] Some adverse
effects follow a linear dose-response pattern where the incidence increases with an increase in the dose (ecchymosis,
cushingoid features, parchment-like skin, leg edema, and sleep disturbance). Other adverse effects may follow a
threshold dose-response pattern with an elevated frequency of events beyond a specific threshold value (weight gain
and epistaxis at prednisone dose greater than 5 mg daily, glaucoma, depression, hypertension at prednisone dose
greater than 7.5 mg daily, etc.).

Several other factors may influence the adverse effects of glucocorticoids. Older age, comorbid conditions (such as
diabetes mellitus), concomitant use of other immunosuppressive agents, severity and nature of the underlying disease,
and poor nutritional status can all influence the occurrence and magnitude of side effects.

Musculoskeletal Adverse Effects

Glucocorticoids induced Osteoporosis is one of the well-known and devastating adverse effects of long-term use of
glucocorticoids. Up to 40% of patients on long-term glucocorticoids develop bone loss leading to fractures.[7] Several
mechanisms play a role, including osteoclast activation by promoting RANK-ligand as well as a decrease in function
and number of osteoblasts and osteocytes. The trabecular bone is initially affected, with cortical bone loss seen with
longer-term use. The loss of trabecular bone can occur within the first 6 to 12 months of therapy.

Steroid-induced myopathy, which is a reversible painless myopathy and is a direct result of muscle breakdown, can
occur in both the upper and lower extremities, usually with high-dose long-term use of glucocorticoids. Muscle
enzymes (CK and Aldolase) are typically normal, and findings on electromyography are non-specific. Muscle biopsy
reveals Type-II fiber atrophy without inflammation. Withdrawal of glucocorticoids and exercises usually results in the
resolution of myopathy. “Critical illness myopathy” may also develop in patients admitted in the intensive care unit
(ICU) requiring large doses of IV glucocorticoids and neuromuscular blocking agents. It characteristically presents
with a severe, diffuse, proximal, and distal weakness that develops over several days. Although it is usually reversible,
critical illness myopathy can lead to prolonged ICU admissions, increased length of hospital stays, severe necrotizing
myopathy, and increased mortality.

Osteonecrosis can be seen especially with long-term use of prednisone more than 20 mg daily. Patients with SLE and
children are at higher risk. Hips and knees are the most commonly involved joints with less common involvement of
shoulders and ankles. Pain is the initial feature, which may eventually become severe and debilitating. Magnetic
resonance imaging is the most sensitive test, especially for early detection. Plain radiographs may be negative initially
but can be useful for follow-up. Treatment is by decreased weight-bearing and immobilization initially, but surgery
and/or joint replacement may be necessary if severe.

Metabolic and Endocrine Adverse Effects

Systemic glucocorticoids cause a dose-dependent increase in fasting glucose levels and a more significant 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. Risk factors for new-onset hyperglycemia during
glucocorticoid therapy appear to be the same as those for other patients. However, patients with diabetes mellitus or
glucose intolerance exhibit higher blood glucose levels while taking glucocorticoids, leading to increased difficulty
with glycemic control.[8]

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 early. Cushingoid features showed a linear
increase in frequency with dosing. Glucocorticoid therapy is the most common cause of Cushing syndrome. The
clinical presentation in the pediatric population is similar to that in adults and includes truncal obesity, skin changes,
and hypertension. In children, growth deceleration is also a feature.

Administration of glucocorticoids can suppress the hypothalamic-pituitary-adrenal (HPA) axis decreasing

corticotropin-releasing hormone (CRH) from the hypothalamus, adrenocorticotropic hormone (ACTH) from the
anterior pituitary gland, and endogenous cortisol. Prolonged ACTH suppression cause atrophy of adrenal glands, and
abrupt cessation or rapid withdrawal of Glucocorticoids in such patients may cause symptoms of adrenal
insufficiency. The clinical presentation of adrenal suppression is variable. Many of the signs and symptoms are non-
specific and can be mistaken for symptoms of intercurrent illness or the underlying condition that is receiving
treatment (weakness/fatigue, malaise, nausea, vomiting, diarrhea, abdominal pain, headache usually in the morning,
fever, anorexia/weight loss, myalgia, arthralgia, psychiatric symptoms, poor growth and weight gain in children).
Adrenal suppression is the most common cause of adrenal insufficiency in children and is associated with higher
mortality in the pediatric population. In adults, the symptoms of adrenal suppression are non-specific; therefore, the
condition may go unrecognized until exposure to physiological stress (illness, surgery, or injury), resulting in an
adrenal crisis. Children with adrenal crisis secondary to adrenal suppression may present with hypotension, shock,
decreased consciousness, lethargy, unexplained hypoglycemia, seizures, and even death.

The impairment of growth in young children and delay in puberty commonly presents in children receiving
glucocorticoids for chronic illnesses like nephrotic syndrome and asthma. The effect is most pronounced with daily
therapy and less marked with an alternate-day regimen and can also occur with inhaled glucocorticoids. Although
growth impairment can be an independent adverse effect of corticosteroid therapy, it can also be a sign of adrenal
suppression.

Infections

Moderate to high dose use of glucocorticoids poses a significant risk of infections, including common mild infections
as well as serious life-threatening infections. There is a linear increase in the risk with dose and duration of therapy,
especially with common bacterial, viral, and fungal pathogens. Concomitant use of other immunosuppressive agents
and the elderly age further increases the risk of infections.[9][10] Prednisone dose of less than 10 mg daily pose
minimal to no risk of infection. Patients taking glucocorticoids may not manifest common signs and symptoms of
infection as clearly, due to the inhibition of cytokine release and the associated reduction in inflammatory and febrile
responses leading to a failure in early recognition of infection.

Cardiovascular Adverse Effects

Mineralocorticoid effects, especially as seen with cortisol and cortisone, can lead to fluid retention, edema, weight
gain, hypertension, and arrhythmias by increasing renal excretion of potassium, calcium, and phosphate. Hypertension
usually occurs with higher doses only.[11] Long-term use of medium-high dose glucocorticoids has implications in
premature atherosclerosis in a dose-dependent pattern.[12]

Dermatologic Adverse Effects

Several cutaneous adverse effects can occur even at a low dose use of glucocorticoids, although the risk increases
linearly with the increasing dose and duration of glucocorticoid therapy. Although cutaneous adverse effects appear to
be clinically significant by physicians, they are usually of most concern to the patients.[13] These adverse effects
include ecchymosis, skin thinning and atrophy, acne, mild hirsutism, facial erythema, stria, impaired wound healing,
thinning of hair, and perioral dermatitis.

Ophthalmologic Adverse Effects

The risk of cataracts is significantly high in patients taking prednisone more than 10 mg daily for more than one year,
with a dose-dependence in a linear fashion. However, an increased risk of cataracts has been reported even with low-
dose glucocorticoids.[14] Cataracts are usually bilateral and slowly progressing.[15] Increased intraocular pressure,
especially in patients with a family history of open-angle glaucoma, is seen in patients receiving intraocular
glucocorticoids and high dose systemic glucocorticoids.[16] Glaucoma is often painless and can lead to visual field
loss, optic disc cupping, and optic nerve atrophy. After discontinuing systemic therapy, the elevation in intraocular
pressure usually resolves within a few weeks, but the damage to the optic nerve is often permanent. A rare adverse
effect of systemic or even topical use of glucocorticoids is central serous chorioretinopathy; this leads to the formation
of subretinal fluid in the macular region, which leads to separation of the retina from its underlying photoreceptors.
This condition manifests as central visual blur and reduced visual acuity.[17][18]

Gastrointestinal (GI) Adverse Effects

Glucocorticoids increase the risk of adverse GI effects, such as gastritis, gastric ulcer formation, and GI bleeding.
[19] The use of NSAIDs and glucocorticoids is associated with a 4-fold increased risk of a GI adverse effect
compared with the use of either drug alone. Other complications associated with glucocorticoid use include
pancreatitis, visceral perforation, and hepatic steatosis (fatty liver) that can rarely lead to systemic fat embolism or
cirrhosis.

Neuropsychiatric Adverse Effects

Patients receiving glucocorticoids often experience an improved sense of well-being within several days of starting
the medications; mild euphoria or anxiety may also occur. Hypomanic reactions and activated states are more
common early in the therapy than depression, but the prevalence of depression is greater in patients on more
longstanding therapy. Psychosis can occur but does so almost exclusively at doses of prednisone above 20 mg per day
given for a prolonged period. 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 increase among
patients with a history of the condition. Rare cases of pseudotumor cerebri have also correlated with glucocorticoid
use.[20]

There is specific documentation of neuropsychiatric adverse effects with glucocorticoid therapy in children with acute
lymphoblastic leukemia (ALL) receiving dexamethasone or prednisone for the induction and maintenance of
treatment.[21] The risk is higher in preschool-age children, and the symptoms typically present during the first week
of glucocorticoid therapy.[22][23] Glucocorticoid-induced acute neuropsychiatric impairment may present with a
wide variety of behavioral symptoms, including euphoria, aggression, insomnia, mood fluctuations, depression, manic
behavior, and even frank psychosis.[24] Although these psychiatric disturbances tend to wear off with time on
cessation of glucocorticoid therapy, a small minority of the patients may experience persistent symptoms even after
discontinuing the drug.[25]

Contraindications
General contraindications include hypersensitivity.

Systemic

Systemic fungal infections

Intrathecal administration

Cerebral malaria

Concomitant live or live attenuated virus vaccination (if using glucocorticoids in immunosuppressive doses)

Idiopathic thrombocytopenic purpura (IM administration)

Use in premature infants (formulations containing benzyl alcohol)

Topical

Dermatological: Bacterial, viral, or fungal infection of the mouth or throat (triamcinolone)

Ophthalmic: Acute untreated purulent ocular infections, fungal or mycobacterial ocular infections, viral
conjunctivitis, or keratitis

Clinicians can administer live virus vaccines to patients who are on:

Prednisone or it

s equivalent in doses of less than 20 mg per day for 14 days or less

Glucocorticoids used for long-term physiologic replacement

 Glucocorticoids administered topically, by aerosol, or by intra-articular or bursal injection, provided that there
is no clinical or laboratory evidence of immunosuppression

Monitoring
Baseline Assessment and Monitoring

Preexisting conditions that should be assessed for and treated when starting glucocorticoids include:

Diabetes mellitus

Poorly controlled hypertension

Heart failure and peripheral edema

Cataract or glaucoma

Peptic ulcer disease

Presence of infection

Low bone density or osteoporosis

Psychiatric illness

Before initiating long-term systemic glucocorticoid therapy, the clinician should perform a thorough history and
physical examination to assess for risk factors or preexisting conditions that may potentially be exacerbated
by glucocorticoid therapy, such as above.[26]

Baseline measures of body weight, height, blood pressure, BMD (bone mineral density) via DEXA scan, and
ophthalmological examination should be obtained along with laboratory assessments that include a complete blood
count (CBC), blood glucose values (Fasting blood sugar, 2-hour OGTT, Hb1Ac), and lipid profile (LDL-C, HDL-C,
TC, non-HDL-C, TG). In children, the clinician should also examine nutritional and pubertal status.[27]

Subsequent Monitoring

Assessment of Bone Health

American College of Rheumatology has published specific guidelines addressing this issue to help prevent and
manage GiOp.[28]

All adults receiving prednisone 2.5 mg or more daily for more than three months shall be encouraged to
optimize calcium and vitamin D intake, and shall be counseled to quit smoking, have a balanced diet and be
engaged in regular weight-bearing exercises, and limit alcohol intake to 1 to 2 alcoholic beverages in a day.

Clinical fracture risk reassessment shall be performed at baseline and every 12 months in patients receiving
long-term glucocorticoids.

Bone mineral density (BMD) measurement via DEXA scan shall be performed ideally before or within six
months after the initiation of glucocorticoid therapy in all adults 40 years of age or more, and in adults younger
than 40 years of age if there is a history of osteoporotic fractures or other risk factors for osteoporosis.

In adults 40 years of age or more, the 10-year fracture risk assessment is necessary using the FRAX tool (a
diagnostic tool that incorporates clinical factors and bone mineral density at the femoral neck).[29]

Based on the above data, in addition to the dose and duration of glucocorticoid therapy, patients fall into three
fracture risk categories: low risk, moderate risk, and high risk. Their fracture risk category shall dictate further
management.

Bisphosphonates, teriparatide, or denosumab shall be recommended in patients less than 40 years of age but in
the moderate or high fracture risk category.
 Bisphosphonates, teriparatide, denosumab, or raloxifene shall be recommended in patients 40 years of age or
more in the moderate or high fracture risk category.

Oral bisphosphonates are preferred in all these patients.

Lateral spine X-ray shall be considered in adults 65 years of age or older to evaluate for vertebral fractures.

Consider referral to endocrinologist/rheumatologist if fracture risk is high and/or BMD is declining.

Assessment of Hypothalamic: Pituitary-Adrenal (HPA) Function

The HPA axis should undergo assessment if the patient has received systemic corticosteroids for more than two
consecutive weeks or more than three cumulative weeks in the last six months or if the patient has persistent
symptoms of adrenal suppression. Screening is by measuring early morning salivary cortisol after tapering off the
dose of cortisol. If morning cortisol is normal, but the patient has symptoms of adrenal suppression, perform a low-
dose ACTH stimulation test to confirm the diagnosis. Consider endocrinology referral for confirmation of diagnosis.

Assessment of Growth (Children and Adolescents)

Growth in children and adolescents on chronic glucocorticoid therapy shall be monitored every six months and
plotted on a growth curve.

Assessment of Dyslipidemia and Cardiovascular Risk (Adults)

Lipid profile shall be monitored one month after glucocorticoid initiation and then every 6 to 12 months. Glycemic
control requires assessment via screening for classic symptoms at every visit: polyuria, polydipsia, weight loss.
Monitor glucose parameters for at least 48 hours after glucocorticoids initiation, then every 3 to 6 months for the first
year and annually afterward. In children, an annual oral glucose tolerance test merits consideration if the child is
obese or has risk factors for diabetes.

Assessment of Ophthalmological Complications

An annual ophthalmological examination shall be considered, especially for those with symptoms of cataracts, and
early referral for intraocular pressure assessment should occur if there is a personal or family history of open-angle
glaucoma, diabetes mellitus, or high myopia.

Prevention of Adverse Effects

Although some adverse effects of glucocorticoids are unavoidable, some can be prevented by:

Use of the lowest dose of glucocorticoids for the shortest period needed to achieve the treatment goals

Management of preexisting comorbid conditions

Monitoring of patients under treatment for adverse effects

Patients who also require concomitant treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or
anticoagulants shall receive therapy with proton pump inhibitors (PPI). There is no consensus on PPI treatment of
patients on glucocorticoids alone without NSAIDs and no other risk factors for peptic complications.

Patients who require an extended course of glucocorticoids, especially high doses, shall receive
appropriate immunizations before the institution of therapy. Prophylaxis for opportunistic infection with
Pneumocystis jirovecii pneumonia (PCP) is also recommended in patients receiving prednisone at a dose of 20 mg or
more for more than two weeks. The prophylaxis can stop once the dose of prednisone is below 20 mg daily dose.
Symptoms of and/or exposure to serious infections should also be assessed as corticosteroids are relatively
contraindicated in patients with untreated systemic infections. Concomitant use of other medications also merits
attention before initiating therapy as significant drug interactions exist between glucocorticoids and several drug
classes.

Withdrawal of Glucocorticoid Therapy

Abrupt cessation of chronic glucocorticoid therapy can be dangerous as there is a risk of HPA axis suppression.
Withdrawal of glucocorticoid therapy needs tapering over the period. In general, patients who are given acute
corticosteroid therapy for less than 14 to 21 days do not develop HPA axis suppression, and treatment can stop with
no need for any tapering regime in them. If the therapy has been ongoing for greater than three weeks, tapering is
needed (e.g., over two months), but there is no universally accepted optimal regimen.[30]

Toxicity
Acute psychosis can develop in patients receiving high-dose glucocorticoids. Immediate cessation of the drug on the
appearance of symptoms is the first step. Although many drugs, including antipsychotics, antidepressants,
benzodiazepines, and hydrocortisone, have been tried with variable success, currently, there is no consensus on the
ideal therapeutic remedy to stop and reverse the corticosteroid-induced neuropsychiatric adverse effects in adults or
children. Their specific adverse effects further limit the use of the medications mentioned above.[24][25] The
outcome of limited interventional trials has shown decreased corticosteroid-induced neuropsychiatric symptoms with
chlorpromazine and lorazepam, albeit at the cost of drowsiness, orthostatic hypotension, and paradoxical agitation.
[31]

Physiologic doses of hydrocortisone have shown to improve mild to moderate psychosocial disturbances and
insomnia experienced by children who developed severe behavioral problems with dexamethasone-based treatment
regime administered to treat ALL.[32] Recently, oral potassium chloride (KCl) administered at a median dose of 0.5
mEq/kg/ day in two divided doses per day reportedly was to be moderately effective in reducing corticosteroid-
induced psychiatric events in the majority of children with ALL. No adverse effects were found with oral KCl
supplementation.[33]

Enhancing Healthcare Team Outcomes

Glucocorticoids are widely used to manage many acute and chronic inflammatory disorders. The adverse effects of
glucocorticoids are extensive and can involve many organ systems. While short-term use of corticosteroids is
associated with mild side effects, long-term use can result in several severe adverse effects, some of which are
irreversible. This is why an interprofessional team approach to corticosteroid therapy and subsequent monitoring is
necessary. Clinicians shall consider adverse effects and patients' underlying comorbidities before prescribing
glucocorticoids and use glucocorticoids judiciously. The clinician should use the lowest possible dose for the shortest
possible. Patient education is vital in recognizing the adverse effects early. Children are particularly vulnerable to the
side effects of corticosteroids, and parents need to understand the benefits and adverse effects of glucocorticoids.
Pharmacists shall alert physicians about possible drug interactions, check dosing and duration, and answer patient
questions. The nursing team can play a crucial role in communication with the patient, early detection of adverse
effects, and regular monitoring.

Close communication with other health professionals is necessary to ensure that the patient is not left unmonitored.
[34] This kind of interprofessional team methodology to corticosteroid therapy will yield improved patient results
while mitigating the numerous and potentially serious adverse effects of such therapy, especially when these agents
are used long term. [Level 5]

Review Questions

Access free multiple choice questions on this topic.

Comment on this article.

References
1. HENCH PS, KENDALL EC. The effect of a hormone of the adrenal cortex (17-hydroxy-11-
dehydrocorticosterone; compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc
Staff Meet Mayo Clin. 1949 Apr 13;24(8):181-97. [PubMed: 18118071]
2. Chikanza IC. Mechanisms of corticosteroid resistance in rheumatoid arthritis: a putative role for the corticosteroid
receptor beta isoform. Ann N Y Acad Sci. 2002 Jun;966:39-48. [PubMed: 12114257]
3. Schäcke H, Döcke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol
Ther. 2002 Oct;96(1):23-43. [PubMed: 12441176]
4. Saag KG, Koehnke R, Caldwell JR, Brasington R, Burmeister LF, Zimmerman B, Kohler JA, Furst DE. Low dose
long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events. Am J Med. 1994
Feb;96(2):115-23. [PubMed: 8109596]
5. Da Silva JA, Jacobs JW, Kirwan JR, Boers M, Saag KG, Inês LB, de Koning EJ, Buttgereit F, Cutolo M, Capell
H, Rau R, Bijlsma JW. Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence
and prospective trial data. Ann Rheum Dis. 2006 Mar;65(3):285-93. [PMC free article: PMC1798053] [PubMed:
16107513]
6. Huscher D, Thiele K, Gromnica-Ihle E, Hein G, Demary W, Dreher R, Zink A, Buttgereit F. Dose-related patterns
of glucocorticoid-induced side effects. Ann Rheum Dis. 2009 Jul;68(7):1119-24. [PubMed: 18684744]
7. Dykman TR, Gluck OS, Murphy WA, Hahn TJ, Hahn BH. Evaluation of factors associated with glucocorticoid-
induced osteopenia in patients with rheumatic diseases. Arthritis Rheum. 1985 Apr;28(4):361-8. [PubMed:
3872664]
8. Hoes JN, van der Goes MC, van Raalte DH, van der Zijl NJ, den Uyl D, Lems WF, Lafeber FP, Jacobs JW,
Welsing PM, Diamant M, Bijlsma JW. Glucose tolerance, insulin sensitivity and β-cell function in patients with
rheumatoid arthritis treated with or without low-to-medium dose glucocorticoids. Ann Rheum Dis. 2011
Nov;70(11):1887-94. [PubMed: 21908880]
9. Curtis JR, Patkar N, Xie A, Martin C, Allison JJ, Saag M, Shatin D, Saag KG. Risk of serious bacterial infections
among rheumatoid arthritis patients exposed to tumor necrosis factor alpha antagonists. Arthritis Rheum. 2007
Apr;56(4):1125-33. [PubMed: 17393394]
10. Widdifield J, Bernatsky S, Paterson JM, Gunraj N, Thorne JC, Pope J, Cividino A, Bombardier C. Serious
infections in a population-based cohort of 86,039 seniors with rheumatoid arthritis. Arthritis Care Res
(Hoboken). 2013 Mar;65(3):353-61. [PubMed: 22833532]
11. Panoulas VF, Douglas KM, Stavropoulos-Kalinoglou A, Metsios GS, Nightingale P, Kita MD, Elisaf MS, Kitas
GD. Long-term exposure to medium-dose glucocorticoid therapy associates with hypertension in patients with
rheumatoid arthritis. Rheumatology (Oxford). 2008 Jan;47(1):72-5. [PubMed: 18077493]
12. Whitworth JA. Mechanisms of glucocorticoid-induced hypertension. Kidney Int. 1987 May;31(5):1213-24.
[PubMed: 3298796]
13. van der Goes MC, Jacobs JW, Boers M, Andrews T, Blom-Bakkers MA, Buttgereit F, Caeyers N, Choy EH,
Cutolo M, Da Silva JA, Guillevin L, Holland M, Kirwan JR, Rovensky J, Saag KG, Severijns G, Webber S,
Westhovens R, Bijlsma JW. Patient and rheumatologist perspectives on glucocorticoids: an exercise to improve
the implementation of the European League Against Rheumatism (EULAR) recommendations on the
management of systemic glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis. 2010 Jun;69(6):1015-
21. [PubMed: 19762359]
14. Thiele K, Buttgereit F, Huscher D, Zink A., German Collaborative Arthritis Centres. Current use of
glucocorticoids in patients with rheumatoid arthritis in Germany. Arthritis Rheum. 2005 Oct 15;53(5):740-7.
[PubMed: 16208641]
15. Skalka HW, Prchal JT. Effect of corticosteroids on cataract formation. Arch Ophthalmol. 1980 Oct;98(10):1773-
7. [PubMed: 7425901]
16. Tripathi RC, Parapuram SK, Tripathi BJ, Zhong Y, Chalam KV. Corticosteroids and glaucoma risk. Drugs Aging.
1999 Dec;15(6):439-50. [PubMed: 10641955]
17. Long WF. A case of elevated intraocular pressure associated with systemic steroid therapy. Am J Optom Physiol
Opt. 1977 Apr;54(4):248-52. [PubMed: 143890]
18. Akingbehin AO. Corticosteroid-induced ocular hypertension. I. Prevalence in closed-angle glaucoma. Br J
Ophthalmol. 1982 Aug;66(8):536-40. [PMC free article: PMC1039844] [PubMed: 7104271]
19. Piper JM, Ray WA, Daugherty JR, Griffin MR. Corticosteroid use and peptic ulcer disease: role of nonsteroidal
anti-inflammatory drugs. Ann Intern Med. 1991 May 01;114(9):735-40. [PubMed: 2012355]
20. Brown ES, Chandler PA. Mood and Cognitive Changes During Systemic Corticosteroid Therapy. Prim Care
Companion J Clin Psychiatry. 2001 Feb;3(1):17-21. [PMC free article: PMC181154] [PubMed: 15014624]
21. McGrath P, Rawson-Huff N. Corticosteroids during continuation therapy for acute lymphoblastic leukemia: the
psycho-social impact. Issues Compr Pediatr Nurs. 2010;33(1):5-19. [PubMed: 20121577]
22. Mrakotsky CM, Silverman LB, Dahlberg SE, Alyman MC, Sands SA, Queally JT, Miller TP, Cranston A,
Neuberg DS, Sallan SE, Waber DP. Neurobehavioral side effects of corticosteroids during active treatment for
acute lymphoblastic leukemia in children are age-dependent: report from Dana-Farber Cancer Institute ALL
Consortium Protocol 00-01. Pediatr Blood Cancer. 2011 Sep;57(3):492-8. [PMC free article: PMC3354622]
[PubMed: 21560226]
23. Tavassoli N, Montastruc-Fournier J, Montastruc JL., French Association of Regional Pharmacovigilance Centres.
Psychiatric adverse drug reactions to glucocorticoids in children and adolescents: a much higher risk with
elevated doses. Br J Clin Pharmacol. 2008 Oct;66(4):566-7. [PMC free article: PMC2561106] [PubMed:
18537961]
24. Drozdowicz LB, Bostwick JM. Psychiatric adverse effects of pediatric corticosteroid use. Mayo Clin Proc. 2014
Jun;89(6):817-34. [PubMed: 24943696]
25. Stuart FA, Segal TY, Keady S. Adverse psychological effects of corticosteroids in children and adolescents. Arch
Dis Child. 2005 May;90(5):500-6. [PMC free article: PMC1720409] [PubMed: 15851433]
26. Hill MR, Szefler SJ, Ball BD, Bartoszek M, Brenner AM. Monitoring glucocorticoid therapy: a pharmacokinetic
approach. Clin Pharmacol Ther. 1990 Oct;48(4):390-8. [PubMed: 2225699]
27. MILLER SE, NEILSON JM. CLINICAL FEATURES OF THE DIABETIC SYNDROME APPEARING
AFTER STEROID THERAPY. Postgrad Med J. 1964 Nov;40(469):660-9. [PMC free article: PMC2482796]
[PubMed: 14230307]
28. Buckley L, Guyatt G, Fink HA, Cannon M, Grossman J, Hansen KE, Humphrey MB, Lane NE, Magrey M,
Miller M, Morrison L, Rao M, Robinson AB, Saha S, Wolver S, Bannuru RR, Vaysbrot E, Osani M, Turgunbaev
M, Miller AS, McAlindon T. 2017 American College of Rheumatology Guideline for the Prevention and
Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Rheumatol. 2017 Aug;69(8):1521-1537. [PubMed:
28585373]
29. Kanis JA, Johansson H, Oden A, McCloskey EV. Guidance for the adjustment of FRAX according to the dose of
glucocorticoids. Osteoporos Int. 2011 Mar;22(3):809-16. [PubMed: 21229233]
30. Richter B, Neises G, Clar C. Glucocorticoid withdrawal schemes in chronic medical disorders. A systematic
review. Endocrinol Metab Clin North Am. 2002 Sep;31(3):751-78. [PubMed: 12227130]
31. Pelletier G, Lacroix Y, Moghrabi A, Robaey P. Double-blind crossover study of chlorpromazine and lorazepam
in the treatment of behavioral problems during treatment of children with acute lymphoblastic leukaemia
receiving glucocorticoids. Med Pediatr Oncol. 2000 Apr;34(4):276-7. [PubMed: 10742070]
32. Warris LT, van den Heuvel-Eibrink MM, Aarsen FK, Pluijm SM, Bierings MB, van den Bos C, Zwaan CM,
Thygesen HH, Tissing WJ, Veening MA, Pieters R, van den Akker EL. Hydrocortisone as an Intervention for
Dexamethasone-Induced Adverse Effects in Pediatric Patients With Acute Lymphoblastic Leukemia: Results of a
Double-Blind, Randomized Controlled Trial. J Clin Oncol. 2016 Jul 01;34(19):2287-93. [PubMed: 27161966]
33. Pariury H, Willhoite J, Michlitsch J, Agrawal A. Potassium supplementation mitigates corticosteroid-induced
neuropsychiatric effects in pediatric oncology patients. Pediatr Hematol Oncol. 2019 Oct;36(7):445-450.
[PubMed: 31538841]
34. Strehl C, Buttgereit F. [Long-term glucocorticoid therapy : Is there a safe dosage?]. Internist (Berl). 2016
Sep;57(9):934-9. [PubMed: 27351788]
Disclosure: Muhammad Yasir declares no relevant financial relationships with ineligible companies.

Disclosure: Amandeep Goyal declares no relevant financial relationships with ineligible companies.

Disclosure: Sidharth Sonthalia declares no relevant financial relationships with ineligible companies.

Copyright © 2023, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) (
http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used
commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

Bookshelf ID: NBK531462 PMID: 30285357