Glucocorticoids (corticosteroids, steroids)

Glucose corticosteroids are a type of steroid hormone derived from cholesterol that binds to and then activates the glucocorticoid receptor, which is expressed in almost all cells.

Induce apoptosis and help control immune responses.

Reduces inflammation by entering cells and binding as agonists to cytosolic glucocorticoid receptors.

Glucocorticoid hormones, among their many functions, act as negative regulators of inflammation by suppressing, for instance, interleukin-1 and inducing the interleukin-1 decoy receptor interleukin-1R2.

Bound glucocorticoid receptors transactivate the B-2 adrenergic receptor gene, the lipocortin-1 gene, the IL-10 gene and the NF-KB inhibitor gene to produce anti-inflammatory effects.

Endogenous levels are heritable and vary in response to environmental pertubations.

Mediate most of effects via their glucocorticoid receptor, a ligand activated transcription factor of the large nuclear receptor family.

Glucocorticoid receptor signaling promotes gene expression signatures reflecting reflecting T-cell dysfunction, associated with increased expression of inhibitory checkpoint receptors such as programmed cell death protein-1 and increased Interleukin-10 production.

The induction of apoptosis depends on the levels of glucocorticoid receptor present and alterations in gene expression.

More than 10 million new prescriptions each year, with up to 0.9% of the population and as many as 7% of hospitalized patients receive corticosteroids at any one time.

In general, 5 mg of prednisone is equal to 4 mg of methylprednisolone, to 0.75 mg of dexamethasone, and to 20 mg of hydrocortisone.

Use in children include cases of prematurity, low birthweight, bronchopulmonary dysplasia, heart defects, adrenal hyperplasia acute lymphoblastic leukemia, Hodgkin’s disease, autoimmune diseases including Crohn’s disease, multiple sclerosis Duchenne muscular dystrophy, nephrotic syndrome and asthma.

Studies show that glucocorticoids increased levels of clotting factors and fibrinogen.

Cushing syndrome linked to increased VTE risk.

Steroids used to treated acute and chronic conditions.

Side effect and complications include: osteoporosis, osteonecrosis, cataracts, glaucoma, hyperglycemia, hypokalemia, hypertension, hyperlipidemia, weight gain, fluid retention, bruiseability, impaired resistance to infection, impaired healing, myopathy, adrenal insufficiency and glucocorticoid withdrawal syndrome.

Induce osteoporosis and increase risk for fracture.

Vertebral fractures are the most common fractures associated with glucocorticoids.

The risk of vertebral fracture increases within three months of the initiation of treatment with glucocorticoids and peaks at 12 months.

Fracture is the most common serious and preventable adverse event associated with glucocorticoids.

The risk of fracture increases with age and with the dose and duration of glucocorticoid therapy.

Risk of venous thromboembolism is increased among glucocorticoid users (Johannesdottir SA et al).

Glucocorticoids decrease bone formation by indirect effects on osteoblasts, and increased osteocyte apoptosis and initially increase the lifespan of mature osteoclasts.

Glucocorticoids have secondary effects that are damaging to the skeleton and include decreased intestinal calcium absorption, increased urinary calcium excretion, hypogonadism, and muscle weakness.

Glucocorticoids have direct and indirect effects on bone remodeling.

Glucocorticoid treatment decreases bone formation because of a decrease in osteoblast recruitment and accelerated apoptosis.

Indirect glucocorticoid effects predispose patients to an increased risk of fracture by reduced muscle mass leading to increased risk of falls, decrease in renal calcium resorption and levels of sex hormones, and alterations in parathyroid hormone pulsatility.

Fracture risk rapidly decreases when glucocorticoids are discontinued.

Significant improvement in bone mineral density occurs in the lumbar spine within six months after the discontinuation of google corticoids.

Glucocorticoids act to inhibit feedback of both the hypothalamus, decreasing corticotropin-releasing hormone [CRH], and corticotrophs in the anterior pituitary gland, decreasing the amount of adrenocorticotropic hormone [ACTH].

Glucocorticoid analogue drugs such as prednisone down-regulate the natural synthesis of glucocorticoids.

This mechanism leads to dependence in a short time and can be dangerous if medications are withdrawn too quickly.

The body must have time to begin synthesis of CRH and ACTH and for the adrenal glands to begin functioning normally again.

Glucocorticoids increase the risk of fracture, especially of cancellous bone such as a vertebrae.

Glucocorticoid induced osteoporosis predominantly affects cancellous bone such as the lumbar spine and proximal femur.

Glucocorticoid induced osteoporosis associated with biphasic bone mineral density loss with rapid, 6-12%, within the first year and 3% loss yearly thereafter (LoCascio V et al).

Glucocorticoid induced osteoporosis risk of fracture increases by as much as 75% within the first 3 months of treatment, before bone density significantly declines.

Glucocorticoid Induced bone disease is the most common cause of secondary osteporosis, and the leading iatrogenic cause of the disease.

The relative risk of clinically diagnosed vertebral fracture doubles and the risk of hip fracture increases by approximately 50% among patients who receive 2.5-7.5 mg of prednisolone daily.

In a study with follow up of six months-10 years, glucocorticoids taken at very high doses significantly increase the risk of vertebral fractures; among patients who receive 30 mg of prednisolone per day with a cumulative dose of at least 5 g, the risk of vertebral fracture increased by a factor of 14 and the risk of hip fracture increased by a factor of three.

Fractures occur in 30-50% of patients receiving receiving long-term glucocorticoid therapy.

The intermittent use of high dose glucocorticoids with cumulative doses of 1 g or less had less effect on the risk of fracture, whereas the use of high dose inhaled glucocorticoids for more than four years increased the risk of fracture slightly.

Reduce bone formation by decreasing number and function of osteoblasts.

Increases rate of bone resorption by stimulating formation and activity of osteoclasts.

Oral use is associated with increased risk of acute pancreatitis.

Daily doses of prednisone of 7.5 mg associated with glucocorticoid induced osteoporosis.

The risk of vertebral and hip fractures occurs rapidly after the start of treatment with small doses is 2.5 to 7.5 mg of prednisone daily.

In patients 18-64 years of age continuous treatment with prednisone 10 mg a day for more than 90 days was associated with hip fractures by a factor of seven, an increase in vertebral fractures by a factor of 17 (Steinbuch M et al).

The use of inhaled glucocorticoids is associated with an increased risk of fractures as is alternate day in alternate day and intermittent oral regimens.

Risk factors associated with glucocorticoid induced osteoporosis include advanced page, low body mass index of less than 24, underlying medical illnesses such as rheumatoid arthritis, polymyalgia rheumatica, inflammatory bowel disease, chronic obstructive pulmonary disease, status post transplantation, smoking, excessive alcohol intake, previous fractures, falls, history of hip fractures in family members, glucocorticoid sensitivity regulated by polymorphisms in the glucocorticoid receptor gene, increased 11 beta-HSD1 expression, high glucocorticoid dose with high current or cumulative dose or prolongation of therapy, and low bone mineral density.

Bisphosphonates less effective in protecting bone mineral density in patients with glucocorticoid induced osteoporosis than in patients with other forms of osteoporosis, because glucocorticoids antagonize the effects of nitrogen containing bisphosphonates in inducing apoptosis of osteoclasts and inhibiting bone resorption.

Bisphosphonates in glucocorticoid induced osteoporosis intravenous therapy may be preferable to oral treatment in patients on prolonged glucocorticoid therapy.

Bisphosphonate therapy should be continued for as long as glucocorticosteroids are prescribed.

Teriparatide a recombinant human parathyroid 1-34 is utilized for treatment of glucocorticoid induced osteoporosis.

Anticonvulsant agents accelerate the metabolism of corticosteroids other than hydrocortisone, decreasing their potency.

In a 18 month randomized trial comparing teriparatide with alendronate in patients with glucocorticoid induced osteoporosis, teriparatide increased spinal bone mineral density over a shorter period and to a greater extent than did alendronate and also reduced vertebral fractures by 90% (Saag KG et al).

The 11 beta-hydroxysteroid dehydrogenase (11β-HSD) system a pre-receptor modulate of glucocorticoid action: two

isoenzymes 11 beta-HSD1 and 11 beta-HSD2, catalyze the conversion between active glucocorticoids such as cortisol or prednisolone and in active glucocorticoids such as cortisone or prednisone.

11β-HSD1 enzyme is an activator, and the11β-HSD2 enzyme is an inactivator.

Increased risk of fracture associated with glucocorticoid administration in older individuals may be explained, in part, by the increase in 11β-HSD1 that occurs with aging.

Glucocorticoid induced osteoporosis is similar in men, women and among ethnic groups.

Histological studies of glucocorticoid induced osteoporosis shows fewer osteoblasts and an increased prevalence of osteocyte apoptosis compared to normal controls.

Increased osteocyte apoptosis is associated with decreased vascular endothelial growth factor, bone angiogenesis, bone interstitial fluid, and bone strength.

Vertebral fractures are more common with glucocorticosteroid induced osteoporosis than are hip fractures.

Glucocorticoid induced apoptosis may account for loss of bone strength that occurs before the loss of bone mineral density, and may account for the mismatch between bone mineral density and the risk of fracture in patients with glucocorticoid induced osteoporosis.

Glucocorticoids reduces osteoclast production, but increases their lifespan, while it decreases the lifespan of osteoblasts- Thus the is the number of osteoclasts is therefore in the normal range, whereas the number of osteoblast markedly decreases, reducing bone formation.

In contrast to above, increased bone formation and resorption is seen in postmenopausal osteoporosis, increased parathyroid hormone secretion, and indicate that hypogonadism and secondary hyperparathyroidism are not central to the pathogenesis of glucocorticoid induced osteoporosis.

Stimulates calciuresis and impairs intestinal calcium absorption by inhibiting vitamin D activity.

Causes a reduction of calcium and secondarily increase the release of parathyroid hormone, which leads to bone resorption.

In adults cause rapid increased risk of fracture and dose-dependent bone loss.

Decreased bone mineral density occurs in pediatric disorders that require glucocorticoid treatment including: juvenile rheumatoid arthritis, systemic lupus and inflammatory disease.

Inhibits gonadotropins and can reduce sex steroid production.

Supplementation with calcium and vitamin D can preserve bone mass in patients receiving long-term glucocorticoids.

Induced bone loss can be prevented by the use of bisphosphonates.

Can cause adverse neuropsychiatric effects that can be unpredictable and severe with mood lability, anxiety, impaired cognition, behavioral disturbances and psychosis.

Associated with hyperglycemia, a complication that may affect outcomes in the ICU setting (Umpierrez GE).

Patients on glucocorticoids should have their height measured, since loss of height suggests possible vertebral fractures.

Before therapy with glucocorticosteroids levels of 25-hydroxyvitamin D, creatinine, calcium, glucose, potassium, and lipid levels should be performed.

Measurement of bone mineral density and vertebral x-rays are often recommended tests at the time of initiation of therapy, but they are not helpful in identifying individuals at risk for glucocorticoid induced osteoporosis.

Glucocorticoids associated with osteonecrosis with an estimated incidence of 5-40%.

Higher doses and prolonged doses of glucocorticoids associated with greater risk of osteonecrosis.

Short term and intraarticular glucocorticoids may be associated with osteonecrosis.

Glucocorticoid osteonecrosis may be secondary to fat embolism, vascular thrombosis and osteocyte apoptosis.

All patients taking glucocorticoids should receive calcium supplementation of 1200 mg a day in divided doses and adequate vitamin D supplementation of 800-2000 units per day to help prevent osteoporosis.

Bisphosphonates are the first line treatment options for glucocorticoid induced osteoporosis.

Bisphosphonates reduce the relative risk of glucocorticoid induced vertebral fractures by about 40% in patients taking 10-20 mg of prednisone daily or the equivalent for at least one year before enrollment in the study.

Before commencing long-term therapy patients should be screened for tuberculosis with a skin test chest radiograph.

Before long term therapy is started patients should be screened for diabetes, and diabetics require significant monitoring of their disease.

Patients on corticosteroids should be screened for hypertension, glaucoma and cataracts.

Patients on steroids should have potassium monitoring for hypokalemia.

Bone density measurement should be performed before initiation of long-term treatment and periodically thereafter.

Patients on long-term steroids need to be monitored for yeast infections.

With drug dosage reduction the patient’s must be observed for adrenal insufficiency or corticosteroid withdrawal symptoms.

Methylprednisone has antiemetic properties.

The anti-emetic mechanism of glucocorticoids may involve reduction in prostaglandin production, direct modulation of the 5-HT3 receptor or compensation for acute adrenal hypofunction induced by chemotherapy.

Patients on corticosteroids need to be monitored for effects on mood, memory, and cognitive function.

Patients on corticosteroids need to be monitored for weight gain, osteoporosis, and aseptic necrosis of bone.

Patients on corticosteroids should be on physical exercise programs.

Patients should avoid prolonged bed rest went on corticosteroids to prevent accelerated muscle weakness and bone mineral loss.

Patients on prolonged corticosteroids should avoid elective surgery.

Dexamethasone is associated with a PSA response rate of approximately 50% and a median duration of response of approximately 12 months (Venkitaraman R et al).

Dexamethasone is superior to other corticosteroids in the setting of hormonally refractory prostate cancer.

Dexamethasone is an established agent for the prevention of chemotherapy induced nausea and vomiting, in both the acute and delayed phases.

Long-term glucocorticoid use is common in patients with: rheumatoid arthritis, COPD, , systemic lupus erythematosus, inflammatory bowel disease, and asthma.

In general, 5 mg of prednisone is equal to 4 mg of methylprednisolone, to 0.75 mg of dexamethasone, and to 20 mg of hydrocortisone.

Dexamethasone associated with insomnia, indigestion, weight gain, acne and hiccups.

Sudden withdrawal after long-term treatment with corticosteroids can lead to:

Adrenal insufficiency

Hypotension

Fever

Myalgia

Arthralgia

Rhinitis

Conjunctivitis

Painful itchy skin nodules

Weight loss

Death

Corticosteroids: Cancer Treatment or Not?

Tackling cancer is a complex undertaking in a world where the treatment options can be as diverse as its respective patient populations. The current climate of cancer treatment has reached an unprecedented level of precision, but one drug commonly used in cancer treatment challenges the concept of specificity—corticosteroids.

Corticosteroids have numerous mechanisms of actions therapeutic uses in a variety of cancer treatments.

Glucocorticoids (GCs), are routinely used to help counter some of the side effects of chemotherapy and help shield healthy tissues in the body from the deleterious effects of chemotherapy.

Glucocorticoids have the ability to alter/regulate expression of certain proteins by binding the glucocorticoid receptor (GR).

The binding of the glucocorticoid to the glucocorticoid receptor creates the GC-GR complex which is then transported to the cell’s nucleus.

In the cell’s nucleus the complex then works to alter the transcription of certain genes.

GCs ability to induce apoptosis in hematological cells makes them useful in cancers of the blood such as chronic lymphoblastic leukemia, chronic lymphoblastic leukemia, non-Hodgkin’s and Hodgkin’s lymphoma, and multiple myeloma.

GCs help fight cancer is through their angiostatic properties., by inhibiting the blood supply of cancer-associated fibroblasts and tumor-associated macrophages making them unable to replicate and spread the disease.

GC therapy is also, however, linked to mechanisms known to negate the effects of cancer therapy, which includes activities such as promoting resistance to chemotherapy and shielding cells from apoptosis.