NCLEX: Adrenal Hormones

The adrenal gland consists of the cortex and the medulla. The medulla secretes catecholamines, whereas the cortex, the subject of this chapter, secretes two types of corticosteroids (glucocorticoids and mineralocorticoids; The adrenal cortex has three zones, and each zone synthesizes a different type of steroid hormone from cholesterol. The outer zona glomerulosa produces mineralocorticoids (for example, aldosterone) that are responsible for regulating salt and water metabolism. Production of aldosterone is regulated primarily by the renin–angiotensin system. The middle zona fasciculata synthesizes glucocorticoids (for example, cortisol) that are involved with metabolism and response to stress. The inner zona reticularis secretes adrenal androgen a discussion of androgens). Secretion by the two inner zones and, to a lesser extent, the outer zone is controlled by pituitary adrenocorticotropic hormone (ACTH; also called corticotropin), which is released in response to hypothalamic corticotropin-releasing hormone (CRH). Glucocorticoids serve as feedback inhibitors of ACTH and CRH secretion.

Adrenal Hormones

Adrenal Hormones

Adrenal Hormones: CORTICOSTEROIDS

Focus topic: Adrenal Hormones

The corticosteroids bind to specific intracellular cytoplasmic receptors in target tissues. Glucocorticoid receptors are widely distributed throughout the body, whereas mineralocorticoid receptors are confined mainly to excretory organs, such as the kidney, colon, salivary glands and sweat glands. Both types of receptors are found in the brain. After dimerizing, the receptor–hormone complex recruits coactivator (or corepressor) proteins and translocates into the nucleus, where it attaches to gene promoter elements. There it acts as a transcription factor to turn genes on (when complexed with coactivators) or off (when complexed with corepressors), depending on the tissue. This mechanism requires time to produce an effect. However, other glucocorticoid effects are immediate, such as the interaction with catecholamines to mediate relaxation of bronchial musculature. This section describes normal actions and therapeutic uses of corticosteroids.

A. Glucocorticoids

Focus topic: Adrenal Hormones

Cortisol is the principal human glucocorticoid. Normally, its production is diurnal, with a peak early in the morning followed by a decline and then a secondary, smaller peak in the late afternoon. Factors such as stress and levels of the circulating steroid influence secretion. The effects of cortisol are many and diverse. In general, all glucocorticoids:

  • Promote normal intermediary metabolism: Glucocorticoids favor gluconeogenesis through increasing amino acid uptake by the liver and kidney and elevating activities of gluconeogenic enzymes. They stimulate protein catabolism (except in the liver) and lipolysis, thereby providing the building blocks and energy that are needed for glucose synthesis. [Note: Glucocorticoid insufficiency may result in hypoglycemia (for example, during stressful periods or fasting).]
  • Increase resistance to stress: By raising plasma glucose levels,
    glucocorticoids provide the body with energy to combat stress
    caused by trauma, fright, infection, bleeding, or debilitating disease.
  • Alter blood cell levels in plasma: Glucocorticoids cause a decrease in eosinophils, basophils, monocytes, and lymphocytes by redistributing them from the circulation to lymphoid tissue. Glucocorticoids also increase hemoglobin, erythrocytes, platelets, and polymorphonuclear leukocytes.
  • Have anti-inflammatory action: The most important therapeutic properties of the glucocorticoids are their potent anti-inflammatory and immunosuppressive activities. These therapeutic effects of glucocorticoids are the result of a number of actions. The lowering of circulating lymphocytes is known to play a role. In addition, these agents inhibit the ability of leukocytes and macrophages to respond to mitogens and antigens. Glucocorticoids also decrease the production and release of proinflammatory cytokines. They inhibit phospholipase A2, which blocks the release of arachidonic acid (the precursor of the prostaglandins and leukotrienes) from membrane-bound phospholipid. The decreased production of prostaglandins and leukotrienes is believed to be central to the anti-inflammatory action. Lastly, these agents influence the inflammatory response by stabilizing mast cell and basophil membranes, resulting in decreased histamine release.
  • Affect other systems: High levels of glucocorticoids serve as feedback inhibitors of ACTH production and affect the endocrine system by suppressing further synthesis of glucocorticoids and thyroid-stimulating hormone. In addition, adequate cortisol levels are essential for normal glomerular filtration. The effects of corticosteroids on other systems are mostly associated with adverse effects of the hormones (see Adverse Effects below).

Adrenal Hormones

B. Mineralocorticoids

Focus topic: Adrenal Hormones

Mineralocorticoids help to control fluid status and concentration of electrolytes, especially sodium and potassium. Aldosterone acts on distal tubules and collecting ducts in the kidney, causing reabsorption of sodium, bicarbonate, and water. Conversely, aldosterone decreases reabsorption of potassium, which, with H+, is then lost in the urine. Enhancement of sodium reabsorption by aldosterone also occurs in gastrointestinal mucosa and in sweat and salivary glands. [Note: Elevated aldosterone levels may cause alkalosis and hypokalemia, retention of sodium and water, and increased blood volume and blood pressure. Hyper-aldosteronism is treated with spironolactone.] Target cells for aldosterone contain mineralocorticoid receptors that interact with the hormone in a manner analogous to that of glucocorticoid receptors.

C. Therapeutic uses of the corticosteroids

Focus topic: Adrenal Hormones

Several semisynthetic derivatives of corticosteroids are available. These agents vary in anti-inflammatory potency, mineralocorticoid activity, and duration of action. Corticosteroids are used in replacement therapy and in the treatment of severe allergic reactions, asthma, rheumatoid arthritis, other inflammatory disorders, and some cancers.

  • Replacement therapy for primary adrenocortical insufficiency (Addison disease): Addison disease is caused by adrenal cortex dysfunction (as diagnosed by the lack of response to ACTH administration). Hydrocortisone [hye-droe-KOR-tih-sone], which is identical to natural cortisol, is given to correct the deficiency. Failure to do so results in death. The dosage of hydrocortisone is divided so that two-thirds of the daily dose is given in the morning and one-third is given in the afternoon. [Note: The goal of this regimen is to mimic the normal diurnal variation in cortisol levels.] Administration of fludrocortisone [floo-droe-KOR-tih-sone], a potent synthetic mineralocorticoid with some glucocorticoid activity, may also be necessary to supplement mineralocorticoid deficiency.
  • Replacement therapy for secondary or tertiary adrenocortical insufficiency: These disorders are caused by a defect in CRH production by the hypothalamus or in ACTH production by the pituitary.[Note: Under these conditions, the synthesis of mineralocorticoids in the adrenal cortex is less impaired than that of glucocorticoids.] Hydrocortisone is used for treatment of these deficiencies.
  • Diagnosis of Cushing syndrome: Cushing syndrome is caused by hypersecretion of glucocorticoids (hypercortisolism) that results from excessive release of ACTH by the anterior pituitary or an adrenal tumor. [Note: Chronic treatment with high doses of glucocorticoids is a frequent cause of iatrogenic Cushing syndrome.] Cortisol levels (urine, plasma, and saliva) and the dexamethasone [dex-a-METH-a-sone] suppression test are used to diagnose Cushing syndrome. The synthetic glucocorticoid dexamethasone suppresses cortisol release in normal individuals, but not those with Cushing syndrome.
  • Replacement therapy for congenital adrenal hyperplasia (CAH): CAH is a group of diseases resulting from an enzyme defect in the synthesis of one or more of the adrenal steroid hormones. CAH may lead to virilization in females due to overproduction of adrenal androgens. Treatment of the condition requires administration of sufficient corticosteroids to normalize hormone levels by suppressing release of CRH and ACTH. This decreases production of adrenal androgens. The choice of replacement hormone depends on the specific enzyme defect.
  • Relief of inflammatory symptoms: Corticosteroids significantly reduce the manifestations of inflammation associated with rheumatoid arthritis and inflammatory skin conditions, including redness, swelling, heat, and tenderness that may be present at the site of inflammation. These agents are also important for maintenance of symptom control in persistent asthma, as well as management of asthma exacerbations and active inflammatory bowel disease. In noninflammatory disorders such as osteoarthritis, intra-articular corticosteroids may be used for treatment of a disease flare. Corticosteroids are not curative in these disorders.
  • Treatment of allergies: Corticosteroids are beneficial in the treatment of allergic rhinitis, as well as drug, serum, and transfusion allergic reactions. [Note: In the treatment of allergic rhinitis and asthma, fluticasone [floo-TIK-a-sone] and others are applied topically to the respiratory tract through inhalation from a metered dose dispenser. This minimizes systemic effects and allows the patient to reduce or eliminate the use of oral corticosteroids.]
  • Acceleration of lung maturation: Respiratory distress syndrome is a problem in premature infants. Fetal cortisol is a regulator of lung maturation. Consequently, a regimen of betamethasone ordexamethasone  administered intramuscularly to the mother within the 48 hours proceeding premature delivery can accelerate lung maturation in the fetus.

Adrenal Hormones

D. Pharmacokinetics

Focus topic: Adrenal Hormones

  • Absorption and fate: Orally administered corticosteroid preparations are readily absorbed. Selected compounds can also be administered intravenously, intramuscularly, intra-articularly (for example, into arthritic joints), topically, or via inhalation or intranasal delivery. All topical and inhaled glucocorticoids are absorbed to some extent and, therefore, have the potential to cause hypothalamic–pituitary–adrenal (HPA) axis suppression. Greater than 90% of absorbed glucocorticoids are bound to plasma proteins, mostly corticosteroid-binding globulin or albumin. Corticosteroids are metabolized by the liver microsomal oxidizing enzymes. The metabolites are conjugated to glucuronic acid or sulfate, and the products are excreted by the kidney. [Note: The half-life of corticosteroids may increase substantially in hepatic dysfunction.] Prednisone [PRED-nih-sone] is preferred in pregnancy because it minimizes steroid effects on the fetus. It is a prodrug that is not converted to the active compound, prednisolone [pred-NIH-so-lone], in the fetal liver. Any prednisolone formed in the mother is biotransformed to prednisone by placental enzymes.
  • Dosage: Many factors should be considered in determining the dosage of corticosteroids, including glucocorticoid versus mineralocorticoid activity, duration of action, type of preparation, and time of day when the drug is administered. When large doses of the hormone are required for more than 2 weeks, suppression of the HPA axis occurs. Alternate-day administration of the corticosteroid may prevent this adverse effect by allowing the HPA axis to recover/function on days the hormone is not taken.

Adrenal Hormones

E. Adverse effects

Focus topic: Adrenal Hormones

Common side effects of long-term corticosteroid therapy. Adverse effects are often dose related. For example, in patients with rheumatoid arthritis, the daily dose of prednisone was the strongest predictor of occurrence of adverse effects. Osteoporosis is the most common adverse effect due to the ability of glucocorticoids to suppress intestinal Ca2+ absorption, inhibit bone formation, and decrease sex hormone synthesis. Patients are advised to take calcium and vitamin D supplements. Bisphosphonates may also be useful in the treatment of glucocorticoid-induced osteoporosis. [Note: Increased appetite is not necessarily an adverse effect. In fact, it is one of the reasons for the use of prednisone in cancer chemotherapy.] The classic Cushing-like syndrome (redistribution of body fat, puffy face, hirsutism, and increased appetite) is observed in excess corticosteroid replacement. Cataracts may also occur with long-term corticosteroid therapy. Hyperglycemia may develop and lead to diabetes mellitus. Diabetic patients should monitor blood glucose and adjust medications accordingly if taking corticosteroids. Coadministration of medications that induce or inhibit the hepatic mixed-function oxidases may require adjustment of the glucocorticoid dose. Topical therapy can also cause skin atrophy, ecchymosis, and purple striae.

Adrenal Hormones

Adrenal Hormones

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F. Discontinuation

Focus topic: Adrenal Hormones

Sudden discontinuation of these drugs can be a serious problem if the patient has suppression of the HPA axis. In this case, abrupt removal of corticosteroids causes acute adrenal insufficiency that can be fatal. This risk, coupled with the possibility that withdrawal might cause an exacerbation of the disease, means that the dose must be tapered slowly according to individual tolerance. The patient must be monitored carefully.

G. Inhibitors of adrenocorticoid biosynthesis or function

Focus topic: Adrenal Hormones

Several substances have proven to be useful as inhibitors of the synthesis or function of adrenal steroids: ketoconazole, spironolactone, and eplerenone.

  • Ketoconazole: Ketoconazole [kee-toe-KON-ah-zole] is an antifungal agent that strongly inhibits all gonadal and adrenal steroid hormone synthesis. It is used in the treatment of patients with Cushing syndrome.
  • Spironolactone: This antihypertensive drug competes for the mineralocorticoid receptor and, thus, inhibits sodium reabsorption in the kidney. It can also antagonize aldosterone and testosterone synthesis. It is effective for hyperaldosteronism and is used along with other standard therapies for the treatment of heart failure with reduced ejection fraction. Spironolactone [speer-oh-no-LAK-tone] is also useful in the treatment of hirsutism in women, probably due to interference at the androgen receptor of the hair follicle. Adverse effects include hyperkalemia, gynecomastia, menstrual irregularities, and skin rashes.
  • Eplerenone: Eplerenone [e-PLER-ih-none] specifically binds to the mineralocorticoid receptor, where it acts as an aldosterone antagonist. This specificity avoids the side effect of gynecomastia that is associated with the use of spironolactone. It is approved for the treatment of hypertension and also for heart failure with reduced ejection fraction.
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