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Adrenal  The adrenal glands comprise three separate hormone systems: o The zona glomerulosa, which secretes aldosterone

o The zona fasciculata and reticularis, which secrete cortisol and the adrenal androgens o The adrenal medulla, which secretes adrenaline. Glucocorticoid: Steroid w/cortisol-like activity; potent meta regulator and immunosuppressants Mineralocorticoid: Steroids with aldosterone-like activity; promote renal sodium retention. Adrenal steroid concentrations in serum fluctuate widely. Single measurements are of limited value in clinical investigations, and dynamic tests are widely used in diagnosis. Congenital adrenal hyperplasia: inherited enzyme defect in corticosteroid biosynthesis that can prove fatal unless diagnosed early. 21-Hydroxylase deficiencies: most commonly encountered form of CAH. Raised plasma 17hydroxyprogesterone confirms diagnosis. Glucocorticoid production and release is under ACTH regulation. Mineralocorticoid release is under angiotensin II and K+ regulation. Steroid hormone receptors produce their effects by binding to hormone-responsive elements in DNA and modulating (increase or decrease) gene transcription. Specificity of the mineralocorticoid receptor is conferred by specificity in tissue distribution and localized conversion of glucocorticoids to cortisone by 11-hydroxysteroid dehydrogenase. Glucocorticoids facilitate fuel mobilization, decrease glucose utilization, and produce immunosuppression. Aldosterone increases renal sodium reabsorption and in exchange stimulates potassium excretion. Catecholamine release is under sympathetic nervous system control. The response to stress by the host relies on close interaction between the cortisol and catecholamines to ensure adequate fuel mobilization and hemodynamic control.

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Table 9–2 The Main Targets and Actions of Glucocorticoids and the Consequences of Cushing Disease and Addison Disease.
Target System Intermediary metabolism Specific Target Liver Physiologic Function Increased expression of gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, glucose-6phosphatase, and fructose-2,6bisphosphatase Permissive for lipolytic signals (catecholamines, GH) leading to elevated plasma FFA to fuel gluconeogenesis Degradation of fibrillar muscle proteins by activating the ubiquitin pathway, thereby providing amino acid substrates for gluconeogenesis Maintains plasma glucose during fasting (antihypoglycemic action); increases plasma glucose during stress (hyperglycemic action) Decreased reabsorption of calcium Cushing Disease Addison Disease Increased hepatic glucose output; together Diminished hepatic glucose with insulin, increased hepatic glycogen output and glycogen stores stores

Adipose tissue

Overall effect (together with insulin): central obesity (truncal obesity, moon facies, and buffalo hump) Muscle weakness and wasting mainly in proximal muscles; increased urinary nitrogen excretion (urea from amino acids) Impaired glucose tolerance, insulinresistant diabetes mellitus; increased plasma glucose is due to decreased peripheral glucose utilization and increased hepatic glucose output Hypercalciuria without hypercalcemia leading to secondary hyperparathyroidism

Decreased adiposity and decreased lipolysis

Skeletal muscle

Muscle weakness, decreased muscle glycogen stores; decreased urinary nitrogen excretion Hypoglycemia, increased insulin sensitivity

Plasma glucose

Calcium homeostasis

Kidney

Retardation of bone growth mainly through decreased GH; hypercalcemia possible

Target System

Specific Target Bone, cartilage

Physiologic Function Inhibition of collagen synthesis and bone deposition Inhibition of calcium, magnesium, and phosphate absorption by antagonizing calcitriol actions Decreases endogenous opioid production; depresses gonadotroph responsiveness to GnRH; stimulates GH gene expression by the pituitary; inhibits GH secretion via the hypothalamus Inhibits insulin secretion by decreasing the efficacy of cytoplasmic Ca2+ on the exocytotic process Increases PNMT expression and activity (epinephrine synthesis) Decreases all major hormonebinding proteins Causes age-related involution of the thymus; induces thymic atrophy

Cushing Disease Retardation of bone growth and bone age by direct action and by decreasing GH; osteoporosis in adults

Addison Disease

Gastrointestinal tract

Other endocrine systems

Hypothalamus, pituitary

Scanty menses due to suppressed gonadotroph sensitivity to GnRH; suppressed GH secretion by hypothalamic action; minimal suppression of the TRHTSH axis

Scanty menses by upregulated CRH-endogenous opioid pathway-mediated suppression of GnRH; suppressed GH secretion; hypothyroidism (if present) is due to autoimmune mechanism Absolute hypoinsulinemia with relative hyperinsulinemia

Pancreas

Absolute hyperinsulinemia with relative hypoinsulinemia (lower plasma insulin than expected for the degree of hyperglycemia) Increased responses to sympathoadrenal activation Decrease in total T4, free T4 remains normal Immunocompromised state; lymphocytopenia

Adrenal medulla Carrier proteins (CBG, SHBG, TBG) Immune system Thymus, lymphocytes Monocytes

Decreased responses to sympathoadrenal activation

Relative lymphocytosis in peripheral blood Monocytosis in peripheral blood

Inhibits monocyte proliferation Monocytopenia in peripheral blood and antigen presentation; decreased production of IL-1, IL6, and TNF

Granulocytes

Demargination of neutrophils by suppressing the expression of adhesion molecules Inhibition of inflammation by inhibiting PLA2, thereby inhibiting production of leukotrienes and prostaglandins; suppresses COX-2 expression No significant effect

Peripheral blood: granulocytosis, eosinopenia

Peripheral blood: granulocytopenia, eosinophilia

Inflammatory response

Erythrocytes

Increased hemoglobin and hematocrit are Anemia is more pronounced in due to ACTH-mediated overproduction of women and is due to loss of androgens adrenal androgens; anemia may be related to direct autoimmune targeting of gastric parietal cells Easy bruisability due to dermal atrophy; striae or sites of increased tension, especially sites of adipose tissue accumulation; poor wound healing; hirsutism and acne are due to ACTHmediated increase of adrenal androgens; hyperpigmentation is a direct effect of ACTH on melanocortin 1 receptors Cushing disease may be associated with galactorrhea Darkening of the skin is due to ACTH-mediated stimulation of epidermal melanocortin 1 receptors; vitiligo may occur due to direct autoimmune destruction of melanocytes in circumscribed areas Addison disease is not associated with galactorrhea

Skin and connective tissue

Antiproliferative for fibroblasts and keratinocytes

Breast Lung

Mammary epithelium Type II alveolar cell

Mandatory requirement for lactation Stimulation of surfactant production

Target System Cardiovascular system

Specific Target Heart

Physiologic Function Increased contractility

Cushing Disease Hypertension

Addison Disease Lower peripheral resistance; hypertension with further postural decrease in blood pressure (orthostatic hypotension); low-voltage ECG

Vasculature

Increased vascular reactivity to vasoconstrictors (catecholamines, angiotensin II) Increased GFR and nonphysiologic actions on mineralocorticoid receptors Hypokalemic alkalosis, increased ECF volume due to mineralocorticoid activity (increased DOC, saturation of type 2 11Bhydroxysteroid dehydrogenase by high levels of cortisol) Hyponatremia due to SIADH Hyponatremia, hyperkalemic acidosis, and decreased ECF volume are mainly due to loss of mineralocorticoid activity Increased ADH mainly via hypovolemia-related baroreceptor mechanism Depression

Na+, K+, and ECF volume

Kidney

Posterior pituitary Psychiatric parameters of CNS function Mood Eucortisolemia maintains emotional balance Increases appetite Suppression of REM sleep Sensitizes hippocampal glutamate receptors, induces atrophy of dendrites Increasing intraocular pressure

Initially, euphoria; long-term, depression, psychosis Hyperphagia Sleep disturbances Impaired memory, bilateral hippocampal atrophy Cataract formation; increased intraocular pressure

Appetite Sleep Memory

Decreased appetite in spite of improved taste and smell

Eye

Decreased intraocular pressure

Table 6–3. Adrenergic Receptors and Signaling Pathways Adrenergic receptor β -Adrenergic receptors β1, β2, β3 α1-Adrenergic receptors α1A, α 1B, α 1D α 2-Adrenergic receptors α 2A, α2B, α2C G protein Gα s G protein Mostly Gq/11 family of G proteins Mostly varied Gαi and G0 proteins Second messenger Activate adenylate cyclase

Usually activate PLC α (thereby activating PKC via DAG and increasing intracellular Ca2+ via IP3) or PLA2  May decrease activity of adenylate cyclase (opposing effects of β -adrenergic receptors)  Activate K channels Inhibit Ca2+ channels and activate PLC β or PLA2 (an effect similar α 1-adrenergic receptors)
Physiologic function Converts progesterone to 11deoxycorticosterone and 17α hydroxyprogesterone to 11-deoxycortisol Consequence of deficiency  Decreased cortisol and aldosterone  Hypoglycemia because of low cortisol  Loss of sodium because of mineralocorticoid deficiency

Table 6–2. Key Enzymes Involved in Steroid Hormone Synthesis and Metabolism
Enzyme and relevance 21 – Hydroxylase: Accounts for 95% of genetic abnormalities in adrenal steroid hormone synthesis

 11B- Hydroxylase: second most frequent abnormality in adrenal steroid hormone synthesis Converts 11-deoxycorticosterone to corticosterone; 11-deoxycortisol to cortisol

11B Hydroxysteroid dehydrogenase type II: Inhibited by glycyrrhetinic acid, a compound of licorice

Converts cortisol into corticosterone, which has less affinity for mineralocorticoid receptor

Virilization because of excess androgen production  Excess 11-deoxycortisol and 11deoxycorticosterone  Excess mineralocorticoid activity  Hypoglycemia because of low cortisol  Salt and water retention Decrease in glucocorticoid inactivation in mineralocorticoid-sensitive cells leading to excess mineralocorticoid activity

Table 6–4. Catecholamine Physiologic Effect Alpha-Adrenergic mediated Vasoconstriction Iris dilation Intestinal relaxation Intestinal sphincter contraction Pilomotor contraction Bladder sphincter contraction Bronchoconstriction Cardiac contractility Hepatic glucose production Decreased insulin release B-Adrenergic mediated Vasodilation Cardio acceleration Increased myocardial strength Intestinal and bladder wall relaxation Uterus relaxation Bronchodilation Calorigenesis Lipolysis Increased renin release Increased glucagon release

Uterine smooth muscle contraction Glycogenolysis