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Prednisone vs hydrocortisone. Different Steroid Replacement Medications
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❿- A Different Look at Corticosteroids | AAFP
Corticosteroids were first used in clinical practice in for the treatment of rheumatoid arthritis. Indications since then have spanned multiple specialties and organ systems, including dermatology, rheumatology, immunology and oncology. This review covers practical uses of steroids as well as current and frequently overlooked clinical applications that may be helpful to family physicians. If physicians understand the composition and physiologic effects of corticosteroid agents, appropriate drug selection can be made and inappropriate or problematic uses can be avoided.
Corticosteroid agents mimic the endogenous steroid hormones produced in the adrenal cortex—mineralocorticoid aldosterone and glucocorticoid cortisol. Mineralocorticoids are primarily regulated by the renin-angiotensin system and possess salt-retaining properties.
Glucocorticoids are primarily regulated by corticotropin ACTH and can have anti-inflammatory effects, as well as several metabolic and immunogenic effects, on the body. While several corticosteroid agents possess properties of both hormones, fludrocortisone is most commonly used for its mineralocorticoid activity and hydrocortisone, cortisone, prednisone and prednisolone are used for their glucocorticoid effects. Table 1 summarizes the relative potencies of the hormonal effects in addition to providing equivalent doses.
Therapeutic effects of steroids can often parallel undesirable side effects, especially when high doses and long-term therapy are required. By anticipating the potential side effects and implementing preventive measures where possible Table 21 — 4 patients can obtain maximum benefits with minimum adverse effects.
The dosage range for steroids is wide, and patient response is variable. A low or maintenance dosage is approximately 0. Short-term, low-dose steroid therapy rarely results in any of the adverse effects listed in Table 2.
In long-term therapy, alternate-day administration should be considered. Some disease states, however, such as temporal arteritis and systemic lupus erythematosus, may not be adequately controlled with alternate-day therapy. Doubling the dosage and administering the drug every other day in the morning more closely mimics the endogenous corticosteroid circadian rhythm.
This form of administration enables the patient to experience the therapeutic effects while side effects are minimized. Viral croup is a common childhood disease. In fact, it is the most common form of upper airway obstruction in children six months to six years of age. Corticosteroids have been studied in the management of croup for the past 30 years, but their use in this condition is controversial. The use of steroids in children with croup is associated with significant clinical improvement at about 12 hours post-treatment and results in less endotracheal intubation.
Most current research focuses on outpatient use of corticosteroids in the treatment of moderate and severe croup. Some authors have found that routine use of steroids reduces the need for hospitalization. Although budenoside is well tolerated with minimal side effects because of limited systemic availability, it is not yet available for use in the United States except in a nasal form. A single intramuscular injection of 0. Therefore, intramuscular corticosteroid treatment should be considered in patients with moderate croup before discharge from the emergency department when outpatient therapy is entertained.
Pneumocystis carinii pneumonia PCP is a leading cause of morbidity and mortality in patients infected with human immunodeficiency virus HIV.
This clinically significant complication of HIV infection occurs in 60 to 80 percent of patients with acquired immunodeficiency syndrome not receiving prophylaxis 14 and causes death in approximately 25 percent of its victims. Since the late s, adjunctive treatment with corticosteroids has been documented in case reports and research studies with favorable clinical results, and it is currently endorsed by the National Institutes of Health as a standard therapy.
Documented benefits of corticosteroid therapy in patients with PCP include reduced morbidity and mortality, decreased need for mechanical ventilation assistance and a reduced long-term decline in pulmonary function or exercise tolerance.
Progression of other opportunistic infections associated with HIV infection as a result of the immunosuppressive effects of corticosteroids is a risk that must be considered.
While some studies report only minor complications associated with steroid therapy, such as reactivation of localized herpetic lesions, 18 others have reported an increased incidence of infection and cancer. Based on the benefits and risks of adjunctive corticosteroid therapy, the current recommendations are not intended for all patients but only for those with confirmed or suspected HIV and PCP infection who are at high risk of respiratory failure and death. Patients at risk include those with an arterial oxygen pressure of less than 70 mm Hg or an arterial-alveolar gradient of more than 35 mm Hg.
The recommended dosing regimen is oral prednisone, 40 mg twice daily for five days, then 40 mg once daily for five days, then 20 mg daily for the duration of the anti-pneumocystis therapy. Methylprednisolone, given at 75 percent of the oral prednisone dosage, can be substituted if parenteral therapy is necessary.
A confirmatory diagnosis of PCP and HIV infection should be obtained, and other diseases, such as tuberculosis and cryptococcosis, should be ruled out before steroid therapy is begun. Further investigation is required to determine the appropriate use and benefits of steroid therapy when the patient has concomitant life-threatening infections and when the patient has already received more than three days of anti-pneumocystis therapy and has developed significant hypoxia.
Hyperthyroidism is a common disease affecting around 2 percent of women and 0. The amount of benefit and the effect on patient outcome in this circumstance is not yet known. Graves' eye disease is treated by first normalizing the thyroid function and then administering diuretics and systemic glucocorticoids. Other causes of hyperthyroidism that may be treated with corticosteroids are subacute thyroiditis and thyroid storm. Hyperthyroid disease related to thyroiditis is usually mild and self-limited.
Beta blockers may be used to treat symptoms. In subacute thyroiditis, non-steroidal anti-inflammatory drugs or corticosteroids can be used to relieve thyroid pain and tenderness. Thyroid storm is a life-threatening condition of the hyperthyroid state. Corticosteroids are used as adjuvant analgesics for pain in cancer patients and patients with neuropathic pain such as herpes zoster—related neuropathy, spinal cord compression and pain following oral surgery. Prednisone, at a dosage of 7.
Patients with nerve compression pain or pain resulting from increased intracranial pressure showed a better response when compared with patients with other pain syndromes.
Perioperative use of corticosteroids has been advocated to reduce pain and decrease edema and trismus following oral surgical procedures. The most significant improvement occurs in the treatment of postoperative edema. Dosages of prednisone between 40 and 80 mg per day can be used.
Maximal benefit has been achieved after third-molar extraction, although some benefit has been reported after other surgeries. Some evidence indicates that combining corticosteroids with acyclovir Zovirax will decrease the duration of zoster-associated pain. Systemic treatment with corticosteroids such as prednisone, at 40 mg per day for three weeks, decreases the proportion of patients affected by postherpetic neuralgia, especially pain occurring six to 12 weeks after onset.
Alcoholic hepatitis is a chronic, progressive and often fatal disease. Treatment has generally been supportive. Meta-analysis of studies from to supports the finding that patients with acute severe alcoholic hepatitis and hepatic encephalopathy, without gastrointestinal bleeding, benefit from a trial of corticosteroid therapy.
Further clinical trials were recommended to clarify the role of steroids in the treatment of alcoholic hepatitis. Bacterial meningitis is a serious disease that may result in death or permanent neurologic complications such as seizures, paralysis or sensorineural hearing loss.
These produce inflammatory components such as cytokines, which lead to meningeal inflammation and increased intracranial pressure. Studies show that potent corticosteroids, such as dexamethasone, combined with appropriate antibiotics reduce the risk of acquired sensorineural deafness and the incidence of other neurologic sequelae in meningitis caused by Haemophilus influenzae. The drug was administered in a dosage of 0. Corticosteroids may also be used in the treatment of tuberculous meningitis.
In one randomized, controlled study 55 involving 47 patients in India, dexamethasone was found to be useful as an adjunct treatment in cases of tuberculous meningitis, especially in patients with severe disease. A more recent randomized trial 56 using prednisone in children with tuberculous meningitis showed that prednisone in a dosage of 2 to 4 mg per kg per day for one month improved survival rate and intellectual outcome.
Table 4 57 lists other unlabeled uses of corticosteroids. This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference.
This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Actions and Side Effects. Edema Decreased salt intake Increased potassium excretion Potassium supplements may be necessary.
Increased calcium excretion Use with caution in patients at increased risk of developing osteoporosis; calcium supplements may be necessary, especially in postmenopausal women. Gastrointestinal Gastric irritation Take with meals to prevent gastric upset. Endocrine Hypercortisolism Cushingoid statesecondary adrenal insufficiency Associated with long-term use even at lower dosages Menstrual difficulties, including amenorrhea and postmenopausal bleeding Precipitation of diabetes mellitus Glucose intolerance, hyperglycemia In patients with diabetes, increased dosages of insulin or oral hypoglycemic agent and changes in diet should be expected.
Cardiovascular Hypertension Use with extreme caution in patients with recent myocardial infarction because of an apparent association with left ventricular free-wall rupture.
Thromboembolism Use with caution in patients with thromboembolic disorders because of reports of rare increased blood coagulability. Thrombophlebitis CHF exacerbation Ocular Posterior subcapsular cataracts Prolonged use may result in increased intraocular pressure or damaged ocular nerve.
Use in patients with ocular herpes simplex may cause corneal perforation. Glaucoma May enhance secondary fungal or viral infections of the eye Musculoskeletal Muscle pain or weakness, muscle wasting, pathologic long bone or vertebral compression fractures, atrophy of protein matrix of bone, aseptic necrosis of femoral or humeral heads Use with caution in patients prone to development of osteoporosis; risk versus benefit should be reassessed if osteoporosis develops; elderly, debilitated or poorly nourished patients may be more prone to these effects.
Supplementation with calcium, 1, mg per day, and vitamin D, IU per day, is recommended. Neuropsychiatric Headache, vertigo, seizures, increased motor activity, insomnia, mood changes, psychosis Use with caution in patients with convulsive or psychiatric disorders.
Use may aggravate preexisting psychiatric conditions. Steroid-induced psychosis is dose-related, occurs within 15 to 30 days of therapy and is treatable if steroid therapy must be continued. Pseudotumor cerebri reported during withdrawal. Other Increased susceptibility to infections, masked symptoms of infections Contraindicated in patients with systemic fungal infections except to control drug reactions associated with amphotericin B [Fungizone] therapy.
Do not use live virus vaccinations during therapy. Reactions to skin tests may be suppressed. In most patients, endogenous corticosteroid secretions are equivalent to 5 to 7. Recommended tapering schedules Tapering the dosage over 2 months or more may be necessary for patients on prolonged treatment more than 1 year. Depending on dosage, duration of therapy and risk of systemic disease, decrease dosage by the equivalent of 2.
Then perform a challenge to determine the extent of HPA axis recovery. Depending on the results and patient's symptoms, therapy may be discontinued or a slower taper considered. If symptoms do not subside when steroid dosage is adjusted, other causes must be considered. In certain severe illnesses or during acute flare ups, daily dosing may be re-initiated. Pneumocystis carinii Pneumonia. Pain Management. Alcoholic Hepatitis.
❾-50%}Prednisone vs hydrocortisone.Hydrocortisone Vs Prednisolone in AI (HYPER-AID) (HYPER-AID)
Viral croup is a common childhood disease. In fact, it is the most common form of upper airway obstruction in children six months to six years of age.
Corticosteroids have been studied in the management of croup for the past 30 years, but their use in this condition is controversial. The use of steroids in children with croup is associated with significant clinical improvement at about 12 hours post-treatment and results in less endotracheal intubation.
Most current research focuses on outpatient use of corticosteroids in the treatment of moderate and severe croup. Some authors have found that routine use of steroids reduces the need for hospitalization. Although budenoside is well tolerated with minimal side effects because of limited systemic availability, it is not yet available for use in the United States except in a nasal form.
A single intramuscular injection of 0. Therefore, intramuscular corticosteroid treatment should be considered in patients with moderate croup before discharge from the emergency department when outpatient therapy is entertained. Pneumocystis carinii pneumonia PCP is a leading cause of morbidity and mortality in patients infected with human immunodeficiency virus HIV. This clinically significant complication of HIV infection occurs in 60 to 80 percent of patients with acquired immunodeficiency syndrome not receiving prophylaxis 14 and causes death in approximately 25 percent of its victims.
Since the late s, adjunctive treatment with corticosteroids has been documented in case reports and research studies with favorable clinical results, and it is currently endorsed by the National Institutes of Health as a standard therapy. Documented benefits of corticosteroid therapy in patients with PCP include reduced morbidity and mortality, decreased need for mechanical ventilation assistance and a reduced long-term decline in pulmonary function or exercise tolerance.
Progression of other opportunistic infections associated with HIV infection as a result of the immunosuppressive effects of corticosteroids is a risk that must be considered. While some studies report only minor complications associated with steroid therapy, such as reactivation of localized herpetic lesions, 18 others have reported an increased incidence of infection and cancer.
Based on the benefits and risks of adjunctive corticosteroid therapy, the current recommendations are not intended for all patients but only for those with confirmed or suspected HIV and PCP infection who are at high risk of respiratory failure and death. Patients at risk include those with an arterial oxygen pressure of less than 70 mm Hg or an arterial-alveolar gradient of more than 35 mm Hg. The recommended dosing regimen is oral prednisone, 40 mg twice daily for five days, then 40 mg once daily for five days, then 20 mg daily for the duration of the anti-pneumocystis therapy.
Methylprednisolone, given at 75 percent of the oral prednisone dosage, can be substituted if parenteral therapy is necessary. A confirmatory diagnosis of PCP and HIV infection should be obtained, and other diseases, such as tuberculosis and cryptococcosis, should be ruled out before steroid therapy is begun. Further investigation is required to determine the appropriate use and benefits of steroid therapy when the patient has concomitant life-threatening infections and when the patient has already received more than three days of anti-pneumocystis therapy and has developed significant hypoxia.
Hyperthyroidism is a common disease affecting around 2 percent of women and 0. The amount of benefit and the effect on patient outcome in this circumstance is not yet known. Graves' eye disease is treated by first normalizing the thyroid function and then administering diuretics and systemic glucocorticoids. Other causes of hyperthyroidism that may be treated with corticosteroids are subacute thyroiditis and thyroid storm.
Hyperthyroid disease related to thyroiditis is usually mild and self-limited. Beta blockers may be used to treat symptoms. In subacute thyroiditis, non-steroidal anti-inflammatory drugs or corticosteroids can be used to relieve thyroid pain and tenderness. Thyroid storm is a life-threatening condition of the hyperthyroid state.
Corticosteroids are used as adjuvant analgesics for pain in cancer patients and patients with neuropathic pain such as herpes zoster—related neuropathy, spinal cord compression and pain following oral surgery. Prednisone, at a dosage of 7. Patients with nerve compression pain or pain resulting from increased intracranial pressure showed a better response when compared with patients with other pain syndromes.
Perioperative use of corticosteroids has been advocated to reduce pain and decrease edema and trismus following oral surgical procedures. The most significant improvement occurs in the treatment of postoperative edema. Dosages of prednisone between 40 and 80 mg per day can be used.
Maximal benefit has been achieved after third-molar extraction, although some benefit has been reported after other surgeries. Some evidence indicates that combining corticosteroids with acyclovir Zovirax will decrease the duration of zoster-associated pain.
Systemic treatment with corticosteroids such as prednisone, at 40 mg per day for three weeks, decreases the proportion of patients affected by postherpetic neuralgia, especially pain occurring six to 12 weeks after onset. Alcoholic hepatitis is a chronic, progressive and often fatal disease. Treatment has generally been supportive. Meta-analysis of studies from to supports the finding that patients with acute severe alcoholic hepatitis and hepatic encephalopathy, without gastrointestinal bleeding, benefit from a trial of corticosteroid therapy.
Further clinical trials were recommended to clarify the role of steroids in the treatment of alcoholic hepatitis. Bacterial meningitis is a serious disease that may result in death or permanent neurologic complications such as seizures, paralysis or sensorineural hearing loss.
These produce inflammatory components such as cytokines, which lead to meningeal inflammation and increased intracranial pressure. Studies show that potent corticosteroids, such as dexamethasone, combined with appropriate antibiotics reduce the risk of acquired sensorineural deafness and the incidence of other neurologic sequelae in meningitis caused by Haemophilus influenzae.
The drug was administered in a dosage of 0. Corticosteroids may also be used in the treatment of tuberculous meningitis.
In one randomized, controlled study 55 involving 47 patients in India, dexamethasone was found to be useful as an adjunct treatment in cases of tuberculous meningitis, especially in patients with severe disease.
A more recent randomized trial 56 using prednisone in children with tuberculous meningitis showed that prednisone in a dosage of 2 to 4 mg per kg per day for one month improved survival rate and intellectual outcome. Table 4 57 lists other unlabeled uses of corticosteroids. This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference.
This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Actions and Side Effects. Edema Decreased salt intake Increased potassium excretion Potassium supplements may be necessary. Increased calcium excretion Use with caution in patients at increased risk of developing osteoporosis; calcium supplements may be necessary, especially in postmenopausal women.
Gastrointestinal Gastric irritation Take with meals to prevent gastric upset. Endocrine Hypercortisolism Cushingoid state , secondary adrenal insufficiency Associated with long-term use even at lower dosages Menstrual difficulties, including amenorrhea and postmenopausal bleeding Precipitation of diabetes mellitus Glucose intolerance, hyperglycemia In patients with diabetes, increased dosages of insulin or oral hypoglycemic agent and changes in diet should be expected.
Cardiovascular Hypertension Use with extreme caution in patients with recent myocardial infarction because of an apparent association with left ventricular free-wall rupture. Thromboembolism Use with caution in patients with thromboembolic disorders because of reports of rare increased blood coagulability. Thrombophlebitis CHF exacerbation Ocular Posterior subcapsular cataracts Prolonged use may result in increased intraocular pressure or damaged ocular nerve.
This can cause:. If you gargle and rinse your mouth with water — don't swallow — after each puff on your corticosteroid inhaler, you may be able to avoid mouth and throat irritation.
Some researchers have speculated that inhaled corticosteroid drugs may slow growth rates in children who use them for asthma. Injected corticosteroids can cause temporary side effects near the site of the injection, including skin thinning, loss of color in the skin, and intense pain — also known as post-injection flare.
Other signs and symptoms may include facial flushing, insomnia and high blood sugar. Doctors usually limit corticosteroid injections to three or four a year, depending on each patient's situation. Corticosteroids may cause a range of side effects. But they may also relieve the inflammation, pain and discomfort of many different diseases and conditions. Talk with your doctor to help you better understand the risks and benefits of corticosteroids and make informed choices about your health.
There is a problem with information submitted for this request. Sign up for free, and stay up to date on research advancements, health tips and current health topics, like COVID, plus expertise on managing health. To provide you with the most relevant and helpful information, and understand which information is beneficial, we may combine your email and website usage information with other information we have about you.
If you are a Mayo Clinic patient, this could include protected health information. If we combine this information with your protected health information, we will treat all of that information as protected health information and will only use or disclose that information as set forth in our notice of privacy practices.
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Mayo Clinic is a nonprofit organization and proceeds from Web advertising help support our mission. Mayo Clinic does not endorse any of the third party products and services advertised. A single copy of these materials may be reprinted for noncommercial personal use only. This content does not have an English version. This content does not have an Arabic version.
See more conditions. Request Appointment. Prednisone and other corticosteroids. Products and services. Prednisone and other corticosteroids Weigh the benefits and risks of corticosteroids, such as prednisone, when choosing a medication. By Mayo Clinic Staff. Thank you for subscribing! Sorry something went wrong with your subscription Please, try again in a couple of minutes Retry.
Show references Ritter JM, et al. The pituitary and the adrenal cortex. Elsevier; Accessed Oct. Grennan D, et al. Steroid side effects. Saag KG, et al. Major side effects of systemic glucocorticoids. Major side effects of inhaled glucocorticoids. Roberts WN, et al. Joint aspiration or injection in adults: Complications. Nieman LK. Pharmacologic use of glucocorticoids.
Long-term glucocorticoid therapy. Mayo Clinic; Wilkinson JM expert opinion.
Corticosteroid drugs — including cortisone, hydrocortisone and prednisone — are useful in treating many conditions, such as rashes, inflammatory bowel disease and asthma. But these drugs also carry a risk of various side effects. When prescribed in doses that exceed your body's usual levels, corticosteroids suppress inflammation. This can reduce the signs and symptoms of inflammatory conditions, such as arthritis, asthma or skin rashes.
Corticosteroids also suppress your immune system, which can help control conditions in which your immune system mistakenly attacks its own tissues. Corticosteroid drugs are used to treat rheumatoid arthritis, inflammatory bowel disease IBDasthma, allergies and many other conditions.
These drugs also help suppress the immune system in order to prevent organ rejection in transplant recipients. Corticosteroids also treat Addison's disease, a relatively rare condition where the adrenal glands aren't able to produce even the minimum amount of corticosteroid that the body needs.
Corticosteroids are administered in many different ways, depending on the condition being treated:. Corticosteroids carry a risk of side effects, some of which can cause serious health problems. When you know what side effects are possible, you can take steps to control their impact.
Because oral corticosteroids affect your entire body instead of just a particular area, this route of administration is the most likely to cause significant side effects. Side effects depend on the dose of medication you receive and may include:. When using an inhaled corticosteroid, some of the drug may deposit in your mouth and throat instead of making it to your lungs.
This can cause:. If you gargle and rinse your mouth with water — don't swallow — after each puff on your corticosteroid inhaler, you may be able to avoid mouth and throat irritation.
Some researchers have speculated that inhaled corticosteroid drugs may slow growth rates in children who use them for asthma. Injected corticosteroids can cause temporary side effects near the site of the injection, including skin thinning, loss of color in the skin, and intense pain — also known as post-injection flare.
Other signs and symptoms may include facial flushing, insomnia and high blood sugar. Doctors usually limit corticosteroid injections to three or four a year, depending on each patient's situation.
Corticosteroids may cause a range of side effects. But they may also relieve the inflammation, pain and discomfort of many different diseases and conditions. Talk with your doctor to help you better understand the risks and benefits of corticosteroids and make informed choices about your health. There is a problem with information submitted for this request.
Sign up for free, and stay up to date on research advancements, health tips and current health topics, like COVID, plus expertise on managing health. To provide you with the most relevant and helpful information, and understand which information is beneficial, we may combine your email and website usage information with other information we have about you. If you are a Mayo Clinic patient, this could include protected health information.
If we combine this information with your protected health information, we will treat all of that information as protected health information and will only use or disclose that information as set forth in our notice of privacy practices. You may opt-out of email communications at any time by clicking on the unsubscribe link in the e-mail. You'll soon start receiving the latest Mayo Clinic health information you requested in your inbox.
Mayo Clinic does not endorse companies or products. Advertising revenue supports our not-for-profit mission. Check out these best-sellers and special offers on books and newsletters from Mayo Clinic Press. Any use of this site constitutes your agreement to the Terms and Conditions and Privacy Policy linked below.
Mayo Clinic is a nonprofit organization and proceeds from Web advertising help support our mission. Mayo Clinic does not endorse any of the third party products and services advertised.
A single copy of these materials may be reprinted for noncommercial personal use only. This content does not have an English version. This content does not have an Arabic version. See more conditions. Request Appointment. Prednisone and other corticosteroids. Products and services. Prednisone and other corticosteroids Weigh the benefits and risks of corticosteroids, such as prednisone, when choosing a medication. By Mayo Clinic Staff. Thank you for subscribing!
Sorry something went wrong with your subscription Please, try again in a couple of minutes Retry. Show references Ritter JM, et al. The pituitary and the adrenal cortex. Elsevier; Accessed Oct. Grennan D, et al. Steroid side effects. Saag KG, et al.
Major side effects of systemic glucocorticoids. Major side effects of inhaled glucocorticoids. Roberts WN, et al. Joint aspiration or injection in adults: Complications. Nieman LK. Pharmacologic use of glucocorticoids. Long-term glucocorticoid therapy. Mayo Clinic; Wilkinson JM expert opinion. Mayo Clinic. Acetyl-L-carnitine: Can it relieve MS fatigue? Addison's disease Adrenal fatigue: What causes it?
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Hydrocortisone showed advantages over prednisone in improving liver function, and prednisone exhibited significantly lower risk of edema. Once daily prednisolone is another regimen in clinical use and now prescribed at less than 5mg daily. It has a longer duration of action and a. The data from this study indicates that the potency of prednisolone may be as high as six to eight times greater than hydrocortisone, so that 3 mg of. Prednisone and hydrocortisone are synthetic corticosteroids used for suppressing the immune system and inflammation. Both drugs are used to treat many. Weigh the benefits and risks of corticosteroids, such as prednisone, when choosing a medication. Corticosteroid drugs — including cortisone, hydrocortisone. The multiple dosing regimen can also result in incomplete dosing as patients may not always take hydrocortisone on time.The introduction of adrenocortical extract in improved the life expectancy of hyhpoadrenal patients, with further increases seen after the introduction of cortisone acetate from Most patients are now treated with synthetic hydrocortisone, and incremental advances have been made with optimisation of daily dosing and the introduction of multidose regimens. There remains a significant mortality gap between individuals with treated hypoadrenalism and the general population. It is unclear whether this gap is a result of glucocorticoid over-replacement, under-replacement or loss of the circadian and ultradian rhythm of cortisol secretion, with the risk of detrimental excess glucocorticoid exposure at later times in the day.
The way forwards will involve replacement of the diurnal cortisol rhythm with better glucocorticoid replacement regimens.
The steroid profile produced by both prednisolone and dual-release hydrocortisone Plenadren , provide a smoother glucocorticoid profile of cortisol than standard oral multidose regimens of hydrocortisone and cortisone acetate.
The individualisation of prednisolone doses and lower bioavailability of Plenadren offer reductions in total steroid exposure. Data from upcoming clinical studies on prednisolone will therefore be of key importance in informing future practice.
Patients were no longer dying from adrenal failure, and generous doses of glucocorticoids were given to guard against adrenal crises.
Whilst the era of synthetic glucocorticoids has ushered in longer life expectancies, the use of liberal doses has come at the cost of increased long-term cardiometabolic death 3. The leading cause of death was cardiovascular disease, and specifically ischaemic heart disease. This was followed by malignancy, endocrine causes, respiratory causes and infectious diseases. There was an overall increased standardised mortality ratio SMR of 2. Again, cardiovascular disease was the commonest cause of death with malignancy coming second.
Within malignancy, gastrointestinal tract cancers were the most prevalent followed by male genital cancers and non-melanoma skin cancers. Cardiovascular disease, adrenal failure and cancer emerged as the top three causes. The study did not, however, report the range of glucocorticoid doses used. In an exclusively hypopituitary population in the USA, Mills and colleagues described a seven-fold increase in mortality when associated with adrenal insufficiency 8.
Taken together, these data suggest that the mortality gap in hypoadrenalism is not just limited to primary disease. The cause of the aforementioned mortality gap has not been fully elucidated. Studies suggest the causes may include excess exposure to glucocorticoid replacement, under-replacement and risk of acute adrenal failure, failure to replicate the diurnal and ultradian rhythm of cortisol leading to steroid exposure at detrimental times in the day and finally, differences in the biological actions of oral synthetic glucocorticoids versus endogenous cortisol.
In the secondary disease cohort, it was clear that those who died were in fact receiving higher doses of glucocorticoid replacement treatment, These findings suggest that even very small excesses of glucocorticoid replacement may contribute towards poorer mortality outcomes. Sherlock and colleagues interrogated a regionally held UK database containing information on patients with acromegaly, which included patients receiving hydrocortisone for hypoadrenalism 9.
Patients with acromegaly had an increased SMR of 1. Patients receiving greater than 30 mg of hydrocortisone daily and between 25 and 30 mg daily, had a relative risk of mortality of 2. Even regimens greater than 20 mg of hydrocortisone may be detrimental. Evidence from Swedish populations showed that secondary hypoadrenal patients receiving such doses had a 1. Crucially, this was not the case for those taking daily doses of 20 mg or less Escalating doses of glucocorticoid replacement are associated with worsening cardiovascular risk factors.
In a three-arm crossover study, ten patients with secondary hypoadrenalism took 15 , 20 and 30 mg of hydrocortisone for 6 weeks Ambulatory arterial stiffness index scores were significantly lower when participants received 15 mg of daily hydrocortisone compared to 20 and 30 mg.
When secondary hypoadrenal patients were treated with 0. These surrogate endpoints suggest that higher doses of glucocorticoid replacement induce a metabolic syndrome which likely drives an excess risk of cardiovascular disease. Additional evidence suggests, however, that the mortality gap is not directly linked to excess glucocorticoid replacement. Despite being well matched and the apparent lower glucocorticoid exposure, the South African cohort had a significantly higher total cholesterol, triglycerides, and LDL, indicating a worse cardiovascular risk phenotype.
Although it is possible that the observations may be due to the two sample cohorts being taken from two distinctly homogenoeus populations with their own potential genetic and environmental differences, it is important to note that the timing of doses was not considered in the study. Both autonomous cortisol secretion and oral glucocorticoid replacement therapy result in a mild excess of glucocorticoids and an altered diurnal cortisol rhythm, with supraphysiological levels particularly in the latter half of the day.
Autonomous adrenal cortisol secretion is a pathological state analogous to the proposed cause of the described mortality gap. The autonomous secretion is difficult to diagnose and detect as the excess cortisol is only slightly and not overtly raised Cortisol profiles are flat, with obliteration of the physiological diurnal rhythm and morning cortisol levels may be normal. From individuals followed up over 4. Cardiovascular disease and infectious causes were the top two causes of death.
In an Italian population, patients with adrenal masses suspicious of autonomous secretion were compared to individuals with non-secreting adrenal incidentalomas A similarly designed Swedish study, reported greater mortality in patients with autonomous cortisol secretion The normal cortisol profile has been well established and is conserved between individuals Cortisol levels in humans peak at awakening, with a second peak at lunch time, and a gradual decline in levels to an overnight nadir that rises again 2—4 h before waking.
Disassociation of the cortisol concentration from the expected pattern for the time of day is detrimental Three individuals demonstrated impaired glucose tolerance in relation to meals, despite being normoglycaemic prior to the study suggesting acute insulin resistance. Mean arterial pressure was also elevated.
The disconnect between serum cortisol levels and the circadian clock maintained by all cells may be central to the adverse outcomes of shift work. It is well characterised that during shift work, there is a reversal of the diurnal cortisol rhythm, such that peak levels are seen at night, whilst individuals are awake 21 , 22 , Charmandari et al.
PBMCs are easily obtainable cells that are representative of peripheral tissue. They showed a 2. With acetylation of the GR attenuating the transcriptional response of the cells to glucocorticoids, sensitivity to glucocorticoids is in inverse phase to the circadian cortisol profile.
The lowest sensitivity was seen in the morning when cortisol peaks, and the highest in the evening, when cortisol wanes Marked differences have already been observed in healthy individuals between glucocorticoid exposure in the morning vs the afternoon Administration of 50 mg oral hydrocortisone was compared at h and h. The cortisol drug profiles and glucose handling parameters within the first 4 h were identical at both clock times. Between h and h, the peak glucose excursion, insulin secretory rates and serum insulin levels were significantly higher with the h hydrocortisone dose as compared to the h dose, indicating greater sensitivity to glucocorticoids later in the day.
Acetylation of the GR can be influenced by clock genes. Clock genes represent the time keeping mechanism that exists in all human cells. The intracellular equipment responsible for cellular timekeeping involves a number of feedback and transcriptional loops. In the hypothalamic-pituitary-adrenal HPA axis, the influence of the master clock is exerted by canonical endocrine signalling via arginine vasopressin AVP modification of pulsatile ACTH secretion, but there also exist non-endocrine pathways with neural signalling via the splanchnic innervation of the adrenals and a local circadian clock within the adrenal glands.
Apart from measurable rhythms in cortisol, GR activity is influenced by its own rhythm. Model of glucocorticoid sensitivity in peripheral tissue as it fluctuates during the day 24 , Nadir sensitivity peak resistance is seen at h, when cortisol secretion peaks.
Citation: Endocrine Connections 10, 2; In addition, glucocorticoids can also affect and manipulate the timekeeping machinery of peripheral cells.
Cuesta et al. Further, after 6 days, PER2 levels were found to be reduced in those who responded and to have phase shifted forwards, meaning the peak levels were 9 h later than baseline. PER3 demonstrated a single pre-awakening peak at baseline, but after 6 days, a new second peak in the evening was present.
Taken together, these results indicate that a single dose of hydrocortisone 20 mg in the evening can alter the expression of clock genes in peripheral cells and may in turn modify the glucocorticoid sensitivity of these cells as a result. The evidence presented suggests that the excess mortality seen in treated patients with adrenal insufficiency may be driven by glucocorticoid over-replacement, especially at times of increased sensitivity, such as the evening.
The failure to mimic the circadian cortisol profile is central to these mechanisms. Standard-release hydrocortisone is the most common treatment used in the UK and Europe 30 , Its short half-life of 1. The final dose exposes patients to the risk of having excess glucocorticoid in their blood at times in the day when it is potentially detrimental. As a result of its pharmacokinetic profile, oral hydrocortisone is inherently unable to mirror the circadian cortisol rhythm. The multiple dosing regimen can also result in incomplete dosing as patients may not always take hydrocortisone on time.
Continuous subcutaneous hydrocortisone infusion CSHI pumps, may offer a more physiological alternative cortisol replacement therapy 34 , particularly for those unable to tolerate or absorb oral replacement. In an unblinded open-label feasibility study, an improvement in the vitality and physical functioning domains of the short form health survey SF measuring health related quality of life, was noted when patients were converted from oral hydrocortisone to CSHI However, in a double-blind, placebo-controlled, randomised crossover trial comparing oral hydrocortisone and CSHI, there was no additional benefit seen with CSHI in subjective health scores The use of CSHI requires patient training and engagement, necessitating education on pump use and maintenance.
There is also a risk of local site infections and dislodgement with interruption of steroid delivery The subjective health benefits of CSHI have not been conserved between studies and cardiovascular risk as assessed by anthropometric and biochemical markers, has not been adequately explored.
As such, there are currently insufficient data from CSHI studies to conclude that the more physiological replacement offered translates into better long-term outcomes. Dual-release hydrocortisone herein referred to as Plenadren , and prednisolone both offer a once-daily solution to glucocorticoid replacement therapy.
Apart from the convenience and improved adherence to treatment with once-daily dosing, both drugs produce a smoother plasma profile Fig. As a result, Plenadren and prednisolone may offer better alternatives to standard-release multidose hydrocortisone, which in turn may improve the mortality outcomes.
Serum glucocorticoid profiles of: 1-endogenous circadian cortisol green dashed ; 2-standard thrice daily hydrocortisone regimen HC grey dotted ; 3-prednisolone 4 mg once daily red solid ; 4-Plenadren 20 mg once daily blue solid. Thrice daily hydrocortisone generates a peak and trough profile that both over- and under-shoot the normal cortisol profile. Plenadren and prednisolone generate a similar curve that is closer in morphology to the diurnal cortisol rhythm.
Plenadren is a dual-release formulation of hydrocortisone containing both immediate release and sustained release hydrocortisone in a single tablet. Therefore it is designed to give a smoother glucocorticoid profile than standard- release hydrocortisone It is available as 5 and 20 mg tablets. Data from a salivary cortisol study has shown that although morning peaks in hypoadrenal patients are equivalent to the overshoot associated with thrice daily cortisone acetate or standard hydrocortisone, Plenadren is able to generate afternoon cortisol levels that tend towards the levels seen in healthy controls In an open-label study, 64 primary hypoadrenalism patients took 3 months of thrice-daily hydrocortisone and once-daily Plenadren in a randomised crossover protocol.
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