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Chapter 35 Corticotropin and Adrenal Corticosteroids

Adrenal Glands • Adrenal cortex: – Does not receive neural innervation – Must be stimulated hormonally (ACTH)

• Consists of 3 zones: – Zona glomerulosa – Zona fasciculata – Zona reticularis

• Secretes corticosteroids

Adrenocortical Hormone Agent Adrenal gland

zona glomerulosa mineralocorticoids

zona glomerulosa zona fasciculata zona reticularis

zona fasciculata adrenal glucocorticoids

cortex

medulla zona reticularis sex hormones

zona glomerulosa ----mineralocorticoids aldosterone ----regulating salt and water metabolism ----regulated by the rennin-angiotensin system zona fasciculata ----glucocorticoids cortisol----concerning with normal metabolism and resistance to stress ---- regulated by Adrenocorticotropic Hormone(ACTH) zona reticularis ----adrenal androgens ----dehydroepiandrosterone

Secretion by the two inner zones, and to some extent, the outer zone, is controlled by pituitary corticotropin-releasing hormone (CRH). Glucocorticoids serve as feedback inhibitors on corticotropin (ACTH) and corticotropin- releasing factor (CRF) secretion. Cells of the outer zone have receptors for angiotensinⅡ and express aldosterone synthase, an enzyme that catalyzes the terminal reactions in mineralocoricoid biosynthesis. In contrast, cells of the inner zone lack receptors for angiotensin Ⅱ, but they express two enzymes, steroid 17αhydroxylase (P45017α ) and 11β-hydroxylase(P45011β ), which catalyze the production of glucocorticoids.

Hypothalamus

Short feedback Anterior pituitary

CRF

long feedback ACTH

Glucocorticoids

Adrenal gland

effect

【 Structure-activity relationships 】 21 CH2OH

2 3

O

1

A 4

20 C O 18 R 12 17 13 16 11 C 14 D 15 19 9 8 10 B 7 5 6

The double bond at C4-5 , the keto group at C3 and the carbonyl at C20 are essential for both glucocorticoid and mineralocorticoid activity.

Basic chemical structure of adrenal corticosteroids

21 CH2OH

【 Structure-activity relationships 】 chemical structure of mineralocorticoid

R

20 C 18 11

19 2 3

O

1

A 4

10 5

9

12

C 14

8

B 7

6

Without a hydroxyl group at C17, and without an oxygen group at C11(for example, Desoxycortone ) or an oxygen group connecting with C18 (for example, Aldosterone )

13

17

D

O 16 15

21 CH2OH

【 Structure-activity relationships 】

R 19 2

chemical structure of glucocorticoid A hydroxyl group at C17, and a hydroxyl group or an oxygen group at C11 , and a double bond at C1-2 enhance antiinflammatory and lower salt and water metabolism

3

O

1

A 4

10 5

20 C O 18 12 17 13 16 11 D C 14 15 9

8

B 7

6

Fluorination at C9 and a methyl or a hydroxyl group at C16 has somewhat greater glucocorticoid activity and somewhat less mineralocorticoid activity

Glucocorticoids 【 Pharmacokinetics 】 adrenal corticosteroid and their derivatives are readily Naturally occurring absorbed from the tract. Selected compounds can also be administered intravenously, intramuscularly, topically, or as an aerosol. Greater than 90% of the absorbed glucocorticoids are bound to plasma proteins: most (80%) to corticosteroid-binding globulin (CBG; also called transcortin), and the remainder (10%) to 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 adrenal steroids may increase dramatically in individuals with hepatic dysfunction.

GC bound to CBG

Free GC diffusion into cell GC receptor

GC-receptor complex

CYTOPLASM

metabolic response Nucleus

Induced gene

translation transcription protein mRNA mRNA

Model of glucocorticoid (GC) action

【 Pharmacologic effects 】 Corticosteroid effects were viewed as physiological effects (reflecting actions of corticosteroids at doses corresponding to normal daily production levels) pharmacological effects (representing effects seen only at doses exceeding the normal daily production of corticosteroids).

【 Pharmacologic effects 】 1. Metabolic effects (1) Carbohydrate and Protein metabolism ----to increase blood glucose levels ----to lead to negative nitrogen balance Glucocorticoids increase serum glucose levels and glycogen stores. This is achieved by stimulating the liver to form glucose from amino acids and glycerol and by stimulating the deposition of glucose as liver glycogen. In the periphery, glucocorticoids diminish glucose utilization, increase protein breakdown, and activate lipolysis, thereby providing amino acids and glycerol for gluconeogenesis.

【 Pharmacologic effects 】 1. Metabolic effects (2) Lipid metabolism ----to increase fat breakdown and inhibit fat synthesis ----to lead to fat redistribution Two effects of corticosteroids on lipid metabolism are firmly established. The first is the dramatic redistribution of body fat that occurs in settings of hypercorticism, such as Cushing’s syndrome. The other is the permissive facilitation of the effects of other agents, such as growth hormone and βadrenergic receptor agonists, in inducing lipolysis in adipocytes, with a resultant increase in free fatty acids following glucocorticoid administration. With respect to fat distribution, there is increased fat in the back of the neck (“buffalo hump”), face (“moon faces”), and supraclavicular area, coupled with a loss of fat in the extremities.

【 Pharmacologic effects 】 1. Metabolic effects (3) Electrolyte and water balance ----to produce sodium retention and diuresis ----to produce hypocalcemia Glucocorticoids exert effects on fluid and electrolyte balance, largely due to permissive effects on tubular function and actions that maintain glomerular filtration rate. Glucocorticoids play a permissive role in the renal excretion of free water. Furthermore, glucocorticoids also exert multiple effects on Ca2+ metabolism, and these effects collectively lead to decreased total body Ca2+ stores.

【 Pharmacologic effects 】 2. Permissive action “Permissive” effects—in the absence of which many normal functions become deficient. The actions of corticosteroids are related in complex ways to those of other hormones. For example, in the absence of lipolytic hormones, cortisol has virtually no effect on the rate of lipolysis by adipocytes. Likewise, in the absence of glucocorticoids, epinephrine and norepinephrine have only minor effects on lipolysis. Administration of a small dose of a glucocorticoid, however, markedly potentiates the lipolytic action of these amines. These effects of corticosteroids that involve concerted actions with other hormonal regulators are termed as permissive action and most likely reflect steroid-induced changes in protein synthesis that, in turn, modify tissue responsiveness.

【 Pharmacologic effects 】 3. Anti-inflammatory and Immunosuppressive action The immunosuppressive and anti-inflammatory actions of glucocorticoids are inextricably linked, perhaps because they both involve inhibition of leukocyte functions. Glucocorticoids can prevent or suppress inflammation in response to multiple inciting events, including radiant, mechanical, chemical, infectious, and immunological stimuli. This is due to their profound effects on the concentration, distribution, and function of peripheral leukocytes and due to their suppressive effects on the inflammatory cytokines and chemokines and on other lipid and glucolipid mediators of inflammation.

【 Pharmacologic effects 】 Inflammation, regardless of its cause, is characterized by the extravasation and infiltration of leukocytes into the affected tissue. These events are mediated by a complex series of interactions with cell adhesion molecules, particularly those on endothelial cells, and are inhibited by glucocorticoids. Under the action of glucocorticoid, the concentration of neutrophils increases while the lymphocytes (T and B cells), monocytes, eosinophils, and basophils in the circulation decrease in number. Glucocorticoids also inhibit the functions of tissue macrophages and other antigen-presenting cells. So the ability of these cells to respond to antigens and mitogens is reduced. The effect on macrophages is particularly marked and limits their ability to phagocytose and kill microorganisms and to produce tumor necrosis factor-α, interleukin-1, metalloproteinase, and plasminogen activator.

【 Pharmacologic effects 】 In addition to their effects on leukocyte function, glucocorticoids influence the inflammatory response by reducing the prostaglandin, leukotriene, and plateletactivating factor synthesis that results from activation of phospholipase A2. Finally, glucocorticoids reduce expression of cyclooxygenaseⅡ, the inducible form of this enzyme, in inflammatory cells, thus reducing the amount of enzyme available to produce prostaglandins.

【 Pharmacologic effects 】 4. Other effects Glucocorticoids have important effects on the central nervous system. Increased amounts of glucocorticoids often produce behavioral disturbances in humans—initially insomnia and euphoria and subsequently depression. Large doses of glucocorticoids may increase intracranial pressure. Glucocorticoids given chronically suppress the pituitary release of ACTH (adrenocorticotropin) , GH (growth hormone), TSH (thyroid-stimulating hormone), and LH (luteinizing hormone).

【 Pharmacologic effects 】 4. Other effects Large doses of glucocorticoids have been associated with the development of peptic ulcer, possibly by suppressing the immune response against Helicobacter pylori. They also appear to antagonize the effect of vitamin D on calcium absorption, and lead to osteoporosis, vertebral fractures (since glucocorticoids inhibit osteoblast formation as well as intestinal Ca2+ absorption, and it can increase parathyroid hormone level). The glucocorticoids also have important effects on the hematopoietic system, increasing the number of platelets and red blood cells.

【 Therapeutic uses 】 1. Replacement therapy (1)Treatment of chronic adrenal insufficiency: Addison’s disease Addison’s disease is caused by adrenal cortex dysfunction (as diagnosed by the lack of patient response to corticotropin, ACTH, administration). The disease is characterized by hyperpigmentation, weakness, fatigue, weight loss, hypotension, and inability to maintain the blood glucose level during fasting. In such individual, minor noxious, traumatic, or infectious stimuli may produce acute adrenal insufficiency with circulatory shock and even death. Hydrocortisone is given to correct the deficiency. Administration of fludrocortisone, a synthetic mineralocorticoid with some glucocorticoid activity, may also be necessary to raise the mineralocorticoid activity to normal levels.

【 Therapeutic uses 】 1. Replacement therapy (2)Treatment of acute adrenocortical insufficiency: This life-threatening disease is characterized by gastrointestinal symptoms (nausea, vomiting, and abdominal pain), dehydration, hyponatremia, hyperkalemia, weakness, lethargy, and hypotension. It usually is associated with disorders of the adrenal rather than the pituitary or hypothalamus, and it frequently follows abrupt withdrawal of glucocorticoids used at high doses or for prolonged periods. When acute adrenocortical insufficiency is suspected, treatment must be instituted immediately. Therapy consists of correction of fluid and electrolyte abnormalities and treatment of precipitating factors in addition to large amounts of parenteral hydrocortisone.

【 Therapeutic uses 】 1. Replacement therapy (3)Treatment of adrenocortical hypo- and hyperfunction: Congenital adrenal hyperplasia, Cushing’s syndrome. Congenital adrenal hyperplasia is a group of disease resulting from an enzyme defect in the synthesis of one or more adrenal steroid hormones. Treatment of this condition requires administration of sufficient corticosteroids to normalize the patient’s hormone levels. Cushing’s syndrome is caused by a hypersecretion of glucocorticoid that is due to either excessive release of ACTH by the anterior pituitary or to an adrenal tumor. The manifestation are those associated with the chronic presence of excessive glucocorticoids. This disorder is treated by surgical removal of the tumor producing ACTH or cortisol, irradiation of the pituitary tumor, or resection of one or both adrenals. These patients must receive large doses of cortisol during and following the surgical procedure.

CONGENITAL ADRENAL HYPERPLASIA (CAH)

CRH

cAMP Corticotrophs ACTH

cAMP

Adrenal hyperplasia Adrenal

Corticosteroids

【 Therapeutic uses 】 2. Treatment of autoimmunity diseases and allergic diseases (1) Autoimmunity diseases: including rheumatic disease (such as rheumatic fever, rheumatoid arthritis, rheumatic myocarditis), nephritic syndrome, autoimmune hemolytic anemia, lupus erythematosus, etc.----the goal of administering glucocorticoids is to release symptom (2) Allergic reactions: include angioneurotic edema, contact dermatitis, allergic rhinitis, urticaria, bronchial asthma, acute allergic purpura, etc.----to be assistant treatment, and the goal is to inhibit tissue impaire and inflammation produced by antigenantibody response

【 Therapeutic uses 】 3. Therapeutic uses in infections or inflammation Glucocorticoids were used to treat gram-negative septicemia, severity bacteroidal diarrhea, acute miliary tuberculosis, fulminant epidemic meningitis, etc. Glucocorticoids dramatically reduce the manifestations of inflammations, including the redness, swelling, heat, and tenderness that are commonly present at the inflammatory site. The effect of glucocorticoids on the inflammatory process is the result of their effects on the distribution, concentration, and function of leukocytes. In the presence of known infections of some consequence, glucocorticoids should be administered only if absolutely necessary and concomitantly with appropriate and effective antimicrobial or antifungal therapy.

【 Therapeutic uses 】 4. Hematologic disorders Acute lymphoblastic leukemia, leukopenia, aplastic anemia, thrombocytopenia, etc. But recrudescence is easy after withdrawal of glucocorticoids.

5. Use of local therapy Such as topical preparations for skin disease (atopic dermatitis, eczema, psoriasis, pemphigus, etc), ophthalmic forms for eye disease (conjunctivitis ， keratitis ， iritis), intra-articular injections for joint disease (arthritis, bursitis, tenosynovitis), inhaled steroids for asthma, and hydrocortisone enemas for ulcerative colitis.

6.Other effects Large doses of dexamethasone are given to patients following brain surgery to minimize cerebral edema in the postoperative period, and in organ transplants, glucocorticoids can prevention and treatment of rejection (immunosuppression).

【 Dosage 】 In determining the dosage of adrenocortical steroids, many factors need to be taken into consideration, including glucocorticoid versus mineralocorticoid activity, duration of action, type of preparation, and the time of day that a steroid is administered. For example, when large doses of the hormone are required over an extended period of time (more than 2 weeks), suppression of the hypothalamic-pituitary-adrenal (HPA) axis occurs. To prevent this adverse effect, a regimen of alternate-day administration of the adrenocortical steroid may be useful. This schedule allows the HPA axis to recover on the days the hormone is not taken.

【 Adverse effects 】 1.Continued use of supraphysiological glucocorticoids doses (1) Iatrogenic adrenocortical hyperfunction Also called Cushing’s syndrome. It is caused by using excessive glucocorticoid resulting in metabolism turbulence of carbohydrate, protein, lipid, salt and water. Cushing’s syndrome is manifested as “moon faces”, “buffalo hump”, hirsutism, edema, poor wound healing, hypopotassaemia, hypertension, diabetes, et al. Steroid-induced punctate acne may appear, and insomnia and increased appetite are noted. In the treatment of dangerous or disabling disorders, these changes may not require cessation of therapy.

【 Adverse effects 】 (2) Gastrointestinal Glucocorticoids can increase stomach acid and pepsin secretion, restrain stomach mucus secretion, and reduce the resistibility of gastrointestinal mucous membrane, resulting in causing or aggravating on peptic ulcers, even haemorrhage or perforation of enteron.

(3) Musculoskeletal Proximal myopathy and tendon rupture may occur. Osteoporosis develops insidiously leading to fractures of vertebrae, rib, femora and feet. Pain and restriction of movement may occur months in advance of radiographic changes. Growth in children is impaired.

【 Adverse effects 】 (4) Immune Suppression of the inflammatory response to infection and immunosuppression caused some patients with atypical symptoms and sign and quickly to deteriorate. The incidence of infection can be more severe when it occurs.

(5) Central nervous system Depression and psychosis can occur during the first few days of high dose administration, especially in those with a history of metal disorder. Other effects including euphoria, insomnia, and aggravation of schizophrenia and epilepsy.

【 Adverse effects 】 2. Withdrawal of therapy The most severe complication of steroid cessation, acute adrenal insufficiency, results from too rapid withdrawal of corticosteroids after prolonged therapy, while the HPA ( hypothalamic-pituitaryadrenal ) axis has been suppresses. In addition to this most severe form of withdrawal, a characteristic glucocorticoid withdrawal syndrome consists of fever, myalgias, arthralgias, anorexia, nausea or vomiting, weight loss, lethargy, headache, and postural hypotension.

Mineralocorticoids Mineralocorticoids help control the body’s water volume and concentration of electrolytes, especially sodium and potassium. The most important mineralocorticoid in humans is aldosterone. Although the amounts are normally insignificant, deoxycorticosterone (DOC) was of some importance therapeutically in the past. Its actions, effects, and metabolism are similar to those described below for aldosterone. Fludrocortisone, a synthetic corticosteroid, is the most commonly prescribed salt-retaining hormone.

Aldosterone Aldosterone is synthesized mainly in the adrenal zona glomerulosa under the dual regulation of angiotensin Ⅱ and ACTH. Angiotensin Ⅱ, controlled by the renin system of the kidney, is the primary regulator of mineralocorticoid synthesis; ACTH appears to play a permissive role only. The half-life of aldosterone injected in tracer quantities is 15-20 minutes, and it does not appear to be firmly bound to serum proteins. The metabolism of aldosterone is similar to that of cortisol.

【 Physiologic & Pharmacologic Effects 】 Mineralocorticoids act by binding to the mineralocorticoid receptor in the cytoplasm of target cells, especially principal cells of the distal convoluted and proximal collecting tubules of the kidney. Aldosterone and other steroids promote the reabsorption of sodium from the distal convoluted and proximal collecting renal tubules, loosely coupled to the excretion of potassium and hydrogen ion. Sodium reabsorption in the sweat and salivary glands, gastrointestinal mucosa, and across cell membrane in general is also increased.

【 Therapeutic uses 】 Treatment of mineralocorticoid deficiency Primary mineralocorticoid deficiency occurs in the Addison disease, destructive neoplasms, and other adrenal disease. Secondary mineralocorticoid deficiency is commonly seen in the older patients and results from reduced renin release due to age-relate renal insufficiency. Aldosterone is rapidly metabolized by the liver and is not used for mineralocorticoid replacement. Fludrocortisone is the most commonly used synthesis mineralocorticoid because of its long half-life and selective for mineralocorticoid effects.

【 Adverse effects 】 Elevated aldosterone levels may cause hypernatremia, hypokalemia, metabolic alkalosis, whereas retention of sodium and water leads to an increased plasma volume, and hypertension.

Adrenocorticotropic Hormone (ACTH; Corticotropin) ACTH (Corticotropin) is a 39-amino-acids polypeptide secreted by the anterior pituitary gland. Its primary endocrine function is to stimulate the synthesis and release of adrenocortical hormones. ACTH is given parenterally and cannot be administered orally because of gastrointestinal proteolysis. Its half-life in plasma is about 15 minutes. The release of ACTH by the pituitary is controlled by the hypothalamus via corticotropin-releasing hormone (CRH), production of which is influenced by environmental stresses as well as by the level of circulating hydrocortisone. High plasma concentration of any steroid with glucocorticoid effect prevents release of CRH and so of ACTH, lack of which in turn results in adrenocortical hypofunction.

Adrenocorticotropic Hormone (ACTH; Corticotropin) ACTH is used diagnostically as a test of the capacity of the adrenal cortex to produce cortisol. However, this therapeutic use is seldom appropriate because the peptide hormone has to be injected; selective glucocorticois action (without mineralocorticoid effect) cannot be obtained, and clinical results are irregular. Aside from rare hypersensitivity reactions, the toxicity of ACTH is primarily attributable to the increased secretion of corticosteroids.

Adrenal Steroid Inhibitors Metyrapone Metyrapone is a relatively selective inhibitor of 11β-hydroxylase, which interferes with corticosteroid synthesis by blocking the final step (11hydroxylation) in the glucocorticoid synthesis, leading to an increase in 11deoxycortisol as well as adrenal androgens and the potent mineralocorticoid, 11-deoxycorticosterone. Metyrapone is used for the treatment of Cushing’s syndrome and can be used for tests of adrenal function. (NOTE: Dexamethasone suppression is now used more commonly for diagnosis.) The adverse effects encountered with metyrapone include salt and water retention, hirsutism, transient dizziness, and gastrointestinal disturbances.