This is a 14-year-old female who presents with a chief complaint of constant fatigue and weakness. She appears agitated and restless. She was diagnosed with asthma at the age 5 and started taking low-dose inhaled corticosteroids at the age 7. She has been using medium doses of inhaled corticosteroids with formoterol for the last 3 years. Within the recent 9 months, she was hospitalized for status asthmaticus and received IV and oral corticosteroids. Since her last hospital stay, she has been taking daily oral corticosteroids for the last 6 months. She has gained 12 kg of weight in 3 months since the start of his daily steroids and noticed increasing facial hair growth and easy bruising. Her menses became irregular with 45 day intervals. She also reports becoming increasingly moody and depressed than usual.
Exam: VS T 37.5, P 80, RR 16, BP 143/95. Height: 10th percentile. Weight: 50th percentile. She has truncal obesity and a puffy/round face with severe acne. Her legs have several small bruises without any signs of hyperpigmentation.
Labs: Sodium 147 mEq/L, potassium 3.1 mEq/L, chloride 95 mEq/L, bicarbonate 26 mEq/L, calcium 9.4 mg/dL, creatinine 1.0 mg/dL, glucose 105 mg/dL. Cortisol levels were slightly elevated with no diurnal variation.
These findings plus her history suggest the diagnosis of iatrogenic Cushing syndrome. She is gradually tapered off her corticosteroid treatment over a period of 5 weeks. Her Cushinoid symptoms resolve and her height eventually reaches the 50th percentile.
The adrenal glands are composed of two parts: the adrenal cortex and the adrenal medulla. The adrenal cortex produces two classes of steroids, the corticosteroids and the androgens. Corticosteroids are four-ringed steroid hormones which all share the same precursor, cholesterol. The corticosteroids are comprised of two major physiological groups: the glucocorticoids and the mineralocorticoids. Androgens contribute to growth and reproduction.
Glucocorticoids (corticosteroids) are named for their regulation of carbohydrate metabolism, but they also have many other clinically important effects including intermediary metabolism, growth, reproduction, and suppression of inflammation and the immune system. Glucocorticoids are also involved in leukocyte recruitment by regulating cytokine release (1). Cortisol is the main physiologic glucocorticoid, and it is called hydrocortisone when used pharmacologically. It has a wide range of physiological actions and is primarily involved in maintaining blood glucose levels in response to stress. Some glucocorticoids also have mineralocorticoid effects. In addition, glucocorticoids are widely used for treating various autoimmune and inflammatory disorders.
Mineralocorticoids, with aldosterone being the main physiologic mineralocorticoid, influence electrolyte balance, intravascular volume, and blood pressure. They increase sodium reabsorption and the urinary excretion of potassium and hydrogen ions by acting on the distal tubules and cortical collecting ducts of the kidney. These actions on electrolyte transport, in the kidney and in other tissues (e.g., colon, salivary glands, and sweat glands), appear to account for the physiological and pharmacological activities that are characteristic of mineralocorticoids (2).
This chapter will primarily focus on glucocorticoids (corticosteroids). Corticotropin-releasing factor (CRF), also known as corticotropin-releasing hormone (CRH), is released from the hypothalamus to stimulate the release of ACTH (adrenocorticotropic homrone) a hypothalamic hormone that regulates physiological responses to stress. CRF stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH), which in turn stimulates the adrenal gland to release cortisol, which then provides negative feedback on the hypothalamus to maintain cortisol levels in the optimal range (2).
The fetal adrenal cortex is divided into two zones: the outer definitive zone and the inner fetal zone. The outer definitive zone is mainly responsible for the synthesis of glucocorticoid and mineralocorticoid. The fetal zone produces androgenic precursors to be used by the placenta. After birth, the adrenal glands weigh 8 to 9 grams, and the fetal zone regresses by 6 to 12 months of life while the outer definite zone continues to enlarge (2).
Before birth, cortisol is essential for normal development of the central nervous system (CNS), retina, skin, and GI system. Glucocorticoids also prepare the fetal lung for respiratory function by promoting maturation of type II alveolar cells and increasing pulmonary surfactant production. If mothers are in premature labor between 26 and 34 weeks of gestation, betamethasone or dexamethasone is given clinically to accelerate fetal lung maturation and minimize the risk of intraventricular hemorrhage, respiratory distress syndrome, and death (3).
The definitive zone and remnants of the fetal zone eventually evolve into the adult adrenal cortex, which is composed of three layers (GFR): the zona glomerulosa, the zona fasciculata, and the zona reticularis. They are responsible for the production of mineralocorticoids, glucocorticoids, and androgenic steroids, respectively. Cortisol is produced in both the zona fasciculata and the zona reticularis. Glucocorticoids, including cortisol, are secreted following a diurnal pattern and reach their peak concentrations in the morning and lowest concentrations at night. Once cortisol is released from the adrenal cortex or absorbed in the body, 90% or more are reversibly bound to plasma proteins, primarily corticosteroid-binding globulin (CBG) (4). Albumin also binds a small amount of cortisol with less affinity.
Once the glucocorticoid is released from its binding, it takes an active form and crosses the cell membrane into the cytoplasm by passive diffusion to bind to the intracellular glucocorticoid receptor. A glucocorticoid receptor remains inactive bound to various heat-shock proteins and cyclophilins. These chaperone proteins dissociate once cortisol binds its glucocorticoid receptor, which then leads to the entry of the glucocorticoid-receptor dimer into the cell nucleus. Glucocorticoid response elements (GREs), found at regulatory regions of target genes, interact with the glucocorticoid-receptor complex at promoter regions. This interaction can increase or decrease gene transcription activity via coactivator proteins and associated transcription factors, such as the proinflammatory nuclear factor (nuclear factor-kappa B) and RNA polymerase II.
Cortisol increases enzyme activity that promotes hepatic gluconeogenesis and glycogenolysis. Glucocorticoids also play an important role in providing carbon precursors for hepatic gluconeogenesis by decreasing protein synthesis and increasing proteolysis. It also helps with the sparing of glucose by promoting lipolysis in adipose tissue through the action of growth hormone on adipocytes, which stimulates hormone-sensitive lipase (1).
Cortisol stimulates growth hormone secretion in small concentrations by increasing gene expression and growth hormone mRNA levels. However, chronic hypercortisolism can lead to the decreased secretion of growth hormone and other growth factors including insulin-like growth factor I. Pediatric patients with Cushing syndrome, for example, suffer from delayed growth and lower-than-average height as an adult. Iatrogenic corticosteroid administration is the most common cause of Cushing syndrome in adults, but adrenal tumors are the primary cause in preschool children (2). Administration of small doses of glucocorticoids may also cause growth retardation in children (3). Therefore, it is important to use the lowest effective dose for each patient.
The effects of glucocorticoids on the thyroid axis and reproductive function are mostly inhibitory. These hormones suppress thyroid-stimulating hormone secretion and 5-deiodinase activity, which converts T4 to T3. They also inhibit gonadotropin-releasing hormone pulsatility and secretion of luteinizing hormone and follicle-stimulating hormone.
Glucocorticoids have a significant impact on bone metabolism and catabolism of muscle, skin, and connective tissue. Patients with prolonged high levels of cortisol can undergo wasting of lymphoid tissue, muscle, fat, bone, and skin. One of the complications is Cushing syndrome, which is known to cause the redistribution of fat in the neck (buffalo hump) or face (moon facies). Glucocorticoids also increase bone resorption and inhibit osteoblast activity, causing osteopenia and osteoporosis in patients with chronic use. The corticosteroid hormones decrease intestinal calcium absorption and renal calcium reabsorption. They also result in insulin resistance in the muscle and cause muscle weakness and pain. Cortisol inhibits fibroblast activity and can cause skin thinning, capillary injury, and bruising (4).
Cortisol is associated with increased gastrointestinal motility and the production of GI acid and enzymes. Increased gastric acid and pepsin production with glucocorticoid excess can increase the risk of developing peptic ulcer disease. Glucocorticoids also stimulate appetite and is therefore associated with weight gain.
Glucocorticoids have both indirect and direct effects on the central nervous system. They exert influence on the CNS via their role in maintaining blood pressure, electrolyte balance, and blood glucose concentrations. Glucocorticoids have a profound impact on cognition, mood, behavior, and memory. The imbalance in glucocorticoid concentrations can lead to an increased incidence of mania, depression, psychoses, and neuroses. These issues can be corrected with appropriate glucocorticoid replacement therapy (3).
Cortisol can have mineralocorticoid activity in the kidney and increase glomerular filtration rate. Cortisol has a high affinity to the mineralocorticoid receptor, but the presence of the enzyme 11beta-HSD2 inhibits this activity. The mineralocorticoid activity of cortisol is therefore dependent on the activity of 11beta-HSD2 (4). It acts on the distal portion of the nephron to retain sodium and excrete potassium. Blood pressure is maintained due to increased responsiveness to catecholamines and angiotensin II by glucocorticoids. Mineralocorticoid-related side effects are mostly seen in patients using fludrocortisone as well as some glucocorticoids, such as hydrocortisone. These side effects include hypertension, sodium and water retention, and potassium excretion (4).
The glucocorticoid hormones have significant effects on the immune system and inflammatory response to stress. Cortisol increases the production of anti-inflammatory cytokines and decreases the availability of arachidonic acid. Glucocorticoids also reduce the expression of pro-inflammatory cytokines to cause a decrease in the immune response. Arachidonic acid is a precursor to many immune mediators, such as leukotrienes, thromboxanes, and prostaglandins. Cortisol decreases the production of these inflammatory immune mediators by facilitating lipocortin synthesis and leading to the inhibition of phospholipase A2 activity (4). Decreased levels of phospholipase A2 downregulate phosphatidylcholine synthesis and limit the availability of arachidonic acid. Cortisol also inhibits cyclooxygenase 2 gene expression and decreases production of leukotrienes and thromboxanes. Nitric oxide synthase is also inhibited, leading to decreased nitric oxide production and reduced vasodilation. Decreased availability of inflammatory immune mediators suppresses capillary dilation and capillary permeability. It inhibits the extravasation of leukocytes such as monocytes, eosinophils, neutrophils, and T lymphocytes, and diminishes the secretion of lipolytic and proteolytic enzymes to reduce fibrosis (5). These anti-inflammatory and immunosuppressive effects protect the body from unregulated and potentially harmful inflammatory responses, supporting the pharmacological use of corticosteroids (i.e., higher than physiologic levels) in organ transplants and the treatment of allergic, autoimmune, and inflammatory disorders. However, continued use of pharmacological doses can have severe immunologic adverse effects, such as a higher risk of opportunistic infections. Corticosteroid use is associated with reactivation of latent tuberculosis (1).
Glucocorticoids are also known to induce an immunologic phenomenon called a Th2 shift. Cellular and humoral immunities are controlled by different types of helper T cells. Th1 cells and antigen-presenting cells (APCs) stimulate the production of IL-12, IFN-gamma, IFN-alpha, and TNF-alpha. Th2 cells induce the production of IL-4, IL-10, and IL-23. Glucocorticoids inhibit the stated function of Th1 cells but upregulate the production of cytokines by Th2 cells. In other words, physiologic levels of glucocorticoids selectively suppress the Th1-cellular immunity and cause a shift towards the Th2-humoral immunity response (6). Clinically, reducing the Th1 response has many important effects. Stress and the subsequent increase in glucocorticoids result in the Th2 shift, altering an individual's response to infection and autoimmune diseases. Because Th1 response is vital in mycobacterial infections and HIV, these diseases can be exacerbated with stress and increased corticosteroid activity. Rheumatoid arthritis, multiple sclerosis, or many chronic inflammatory diseases are thought to be due to an elevated Th1 response, excess IL-12 and TNF-alpha production. Conditions associated with notable changes in the levels of glucocorticoid, such as chronic stress, pregnancy, and postpartum, can alter the prognosis of infections and autoimmune diseases (6). For instance, Th2-predominant diseases, such as systemic lupus erythematous, can be exacerbated by stress or pregnancy.
Pharmacological corticosteroid compounds have differing glucocorticoid and mineralocorticoid activity. These differences are rooted in their chemical structures with varying affinities for the mineralocorticoid and glucocorticoid receptors. The dissimilarity can also be seen in hormone metabolism, solubility, affinity to plasma proteins, absorption, and excretion. Clinically, these structural and chemical differences make several treatment options possible with differing potency and duration. For example, prednisone and prednisolone have an additional double bond which increases anti-inflammatory potency and carbohydrate activity by 4 to 5 times but decreases water and sodium retention compared to cortisol (5). Halogenated derivatives such as betamethasone and dexamethasone have 25 to 40 times greater glucocorticoid activity but minimal mineralocorticoid effect compared to cortisol.
Corticosteroids can also be classified by their potency and duration of action. Short-acting glucocorticoids with low potency include cortisol (hydrocortisone) and cortisone. Intermediate-duration glucocorticoids with moderate potency include prednisone, prednisolone, triamcinolone, and methylprednisolone. Long-acting glucocorticoids with high potency include dexamethasone and betamethasone, which have minimal mineralocorticoid activity.
Hydrocortisone can be administered topically, orally, or parenterally. It has moderate anti-inflammatory potency and is therefore useful for treating mild inflammatory skin conditions without significant side effects. Corticosteroids are suitable for topical use when treating dermatitis, vitiligo, and psoriasis, and its effects become greater when used with occlusive dressings (3). Prednisolone is commonly used for long-term disease suppression due to its predominant glucocorticoid potency. Betamethasone and dexamethasone have almost exclusive glucocorticoid activity, which makes them useful for treating conditions, such as cerebral edema, that benefit from less fluid retention (3).
The table below classifies glucocorticoids based on duration and potency. Dose equivalencies can be made based on these values.
Glucocorticoid potency equivalance (3):
In clinical practice, glucocorticoids are used to treat both endocrine and nonendocrine disorders. Glucocorticoid therapies require careful consideration of their risks and benefits due to many associated side effects. The optimal dose for treating any disease should be determined based on repeated patient evaluation and patient clinical response. It should be noted, however, that a single dose of glucocorticoid does not generally have any significant adverse effects, and even a short course of glucocorticoid therapy (about 1 week) in patients without specific contraindications is unlikely to cause any harm (3).
Patients with primary adrenal insufficiency (Addison's disease) receive glucocorticoid replacement therapy that involves both hydrocortisone and fludrocortisone. Hydrocortisone is usually given orally in 2-3 doses. Fludrocortisone (mineralocorticoid) is added since hydrocortisone alone does not produce a sufficient mineralocorticoid effect (1).
Newborns with congenital adrenal hyperplasia (CAH) have impaired enzymatic conversion of precursors to cortisol and the consequent increased release of corticotrophin from the anterior pituitary causing an imbalance in androgens and mineralocorticoid activity. Unrecognized/untreated CAH results in an acute adrenal deficiency crisis. This condition results in the overproduction of precursors in the androgenic pathway before the enzymatic block. Patients with CAH require replacement therapy with hydrocortisone as well as mineralocorticoid (fludrocortisone) therapy if they experience salt wasting (3). Treatment is aimed at suppressing the secretion of corticotrophin and restoring levels of physiological steroid hormones to normal. Plasma levels of 17-hydroxyprogesterone (17-OHP), renin, blood pressure, and growth should be monitored as therapy progresses. If 17-OHP levels are elevated, hydrocortisone dosing should be increased. If levels of plasma renin are elevated, mineralocorticoid dosing should be increased. Growth slowing suggests that patient's glucocorticoid dosing is too high (3).
Repeated or prolonged corticosteroid use during pregnancy may be associated with fetal developmental abnormalities, leading to behavioral disorders and adrenal insufficiency. An in vivo experiment has also elucidated the connection between prenatal glucocorticoid exposure and cleft palate, as well as altered neuronal development. Therefore, neonates with significant prenatal exposure to corticosteroids should be monitored carefully for signs of anatomic, behavioral, or adrenal abnormalities (3).
All forms of adrenal insufficiency (e.g., Addison's disease, Waterhouse-Friderichsen syndrome, congenital adrenal hyperplasia) can result in adrenal crisis (also sometimes called Addisonian crisis) which is characterized as a shock-like state with vomiting, hypoglycemia, hyponatremia, and hyperkalemia. The hyperkalemia can be severe resulting in lethal dysrhythmias. IV calcium is administered to restore a perfusing rhythm and measures to lower the serum potassium (IV bicarbonate, insulin/glucose, furosemide, albuterol aerosols, fludrocortisone, and sodium/potassium exchange resins) must be administered immediately. Pharmacologic stress doses of glucocorticoids are required to restore corticosteroid balance (7).
Sepsis can sometimes cause bilateral adrenal hemorrhage known as Waterhouse-Friderichsen syndrome. This is classically, but not always associated with meningococcemia. In addition to septic shock, these patients have acute adrenal insufficiency, requiring glucocorticoid replacement in addition to the treatment for shock (fluids, inotropes, antibiotics) (5).
Acute adrenal insufficiency (crisis) can also result from discontinuing long term corticosteroid therapy. Patients on long-term exogenous corticosteroids have diminished capacity to produce corticosteroids sufficiently by adrenal glands. Adrenal atrophy may persist for many years after the cessation. Withdrawal syndrome can also ensue, leading to diminished cardiovascular tone, hypotension, shock, and death. Other symptoms of this syndrome include malaise, anorexia, arthralgia, myalgia, nausea, conjunctivitis, weight loss, diarrhea, psychiatric manifestations, and fever. Adrenal insufficiency should be considered in patients who have been given pharmacologic doses of corticosteroids in the previous year and in patients abruptly discontinuing glucocorticoid therapy after more than 7 days of administration (3). Patients on chronic glucocorticoid administration need to be tapered off gradually, with a 25% reduction from the previous week, and should be regularly monitored for any signs of withdrawal syndrome (2). Most patients recover within several weeks but may take up to 6-12 months (2). These patients may require further evaluation of the hypothalamic pituitary axis (HPA) with an ACTH stimulation test and potentially need stress dose replacement depending on the course of patient recovery. Decreased adrenocortical function after corticosteroid withdrawal may also necessitate stress doses of glucocorticoids in cases of physiologically stressful events, including infection, trauma, surgery, and sometimes even minor viral infections.
Questions
1. Which of the following flucocorticoids have intermediate potency and duration?
a. prednisone
b. hydrocortisone
c. triamcinolone
d. dexamethasone
e. a and c
2. Which of the following accurately describes the mechanism of immunosuppression by glucocorticoids?
a. Glucocorticoids upregulate phospholipase A2 activity via lipocortin synthesis and decrease the availability of arachidonic acids.
b. Glucocorticoids inhibit cyclooxygenase 2 gene expression and decrease the production of inflammatory immune modulators, such as leukotrienes and thromboxanes.
c. Glucocorticoids stimulate nitric oxide synthesis and subsequently decrease vasodilation.
d. Glucocorticoids increase the levels of neutrophils and other leukocytes in the peripheral blood.
3. A patient has been taking prednisone for 10 days to treat his flares of eczema. What is the next step in management to wean off his steroid therapy?
a. replace prednisone with hydrocortisone
b. discontinue glucocorticoid administration all at once
c. tapered off gradually (15% reduction from the previous week) with no clinical follow-up
d. tapered off gradually (25% reduction from the previous week) with clinical follow-up
4. A 6 year old boy with a history of chronic arthritis visiting from another country is hospitalized with multiple fractures. He was riding in a car which was struck head-on by a truck. His parents were killed in the accident. He doesn't speak English but a translator identifies his history of chronic arthritis. He is small for his age. On day 6 of hospitalization, he develops vomiting, hypotension, hypoglycemia, hyponatremia, and hyperkalemia. The mostly likely cause of this is which of the following:
a. blood loss from femur fractures
b. hemolysis from previous transfusions
c. congenital adrenal hyperplasia
d. acute adrenal crisis
e. Waterhouse-Friderichsen syndrome
References
1. Garg R, Adler GK. Chapter 29. Pharmacology of the Adrenal Cortex. In: Golan DE, Armstrong EJ, Armstrong AW (eds). Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, fourth edition. 2016. Lippincott Williams & Wilkins, Pennsylvania Furnace. pp: 524-540
2. Hughes CR, Man E, Achermann JC. Chapter 9. The Adrenal Cortex and Its Disorders. In: Dattani MT, Brook CGD (eds). Brook's Clinical Pediatric Endocrinology, seventh edition. 2019. John Wiley & Sons, Incorporated, Hoboken. pp: 335-407.
3. Hupfeld CJ, Iñiguez-Lluhí JA. Chapter 50. Adrenocorticotropic Hormone, Adrenal Steroids, and the Adrenal Cortex. In: Brunton LL, Knollmann BC (eds). Goodman & Gilman's: The Pharmacological Basis of Therapeutics, fourteenth edition. 2022. McGraw-Hill, New York City. pp: 1003-1022.
4. Koeppen BM. Chapter 43. The Adrenal Gland. In: Koeppen BM, Stanton BA, Hall JM, Swiatecka-Urban A (eds). Berne and Levy Physiology, eighth edition. 2023. Elsevier, Amsterdam. pp: 756-775.
5. White PC. Chapter 592. Physiology of the Adrenal Gland. In: Kliegman RM, St Geme III JW, Blum NJ, et al (eds). Nelson Textbook of Pediatrics, 21st edition. 2020, Elsevier, Philadelphia. pp: 2954-2959.
6. Elenkov IJ. Glucocorticoids and the Th1/Th2 balance. Ann N Y Acad Sci. 2004;1024:138-146. doi:10.1196/annals.1321.010
7. White PC. Chapter 615. Adrenocortical Insufficiency and Altered Sensitivity to Corticosteroids. In: Kliegman R, St. Geme III JW, Blum NJ, et al (eds). Nelson Textbook of Pediatrics, 22nd edition. 2025, Elsevier, Philadelphia, PA. pp:3450-3461
Answers to questions
1.d. Hydrocortisone is a short-acting glucocorticoid with low potency. Dexamethasone is a high-potency, long-acting glucocorticoid. Prednisone and triamcinolone are moderate-potency glucocorticoids with intermediate duration.
2.b. Glucocorticoids inhibit cyclooxygenase 2 gene expression and decrease the production of inflammatory immune modulators, such as leukotrienes and thromboxanes. The other choices are not correct: Glucocorticoids inhibit phospholipase A2 activity via lipocortin synthesis and decrease the availability of arachidonic acids. Glucocorticoids suppress nitric oxide synthase activity to decrease nitric oxide synthesis and decrease vasodilation. Glucocoriticoids can temporarily increase circulating leukocyte counts but this does not result in significant immunosuppression.
3.d. Patients on glucocorticoid therapy for more than 7 days can potentially develop adrenal insufficiency if they abruptly discontinue their steroid administration. It is safest to taper the dose with a 25% reduction from the previous week and should be monitored for any signs of withdrawal syndrome.
4.d. Since the patient has a history of chronic arthritis, it's possible that he is on chronic medication(s) for this. A high probability is that he is on chronic corticosteroid treatment with a drug such as prednisolone. A history should have revealed this, but since he is young, he doesn't speak English, and his parents died in the accident, this history wasn't revealed. Abrupt discontinuation of his chronic corticosteroid treatment with the additional stress of trauma and surgery results in the acute adrenal crisis. Patients with chronic inflammatory diseases (e.g., Crohn disease, systemic lupus erythematosus, rheumatoid arthritis) who chronically require corticosteroid and/or immunomodulating therapy can arrive at a hospital unconscious. Electronic medical records, medical bracelets, contact with the patient's primary care provider, and other means are available to inform medical providers of this so that important chronic medications can be continued or modified accordingly.