Hormones of the Adrenal Gland

Bio 328, Spring, 2013

R. Clark, P.T., Ph.D.

Adrenal Gland Hormones Physiology of Cortisol: the Major Glucocorticoid in Humans

Adrenal Gland Hormones The cortex of the Adrenal Gland synthesizes three different classes of adrenocortical hormones (also called corticoids). Cholesterol is the precursor for the synthesis of all of the adrenocortical hormones. The adrenal cortical cells actively endocytose LDL via plasma membrane receptors. Free cholesterol is transferred to the mitochondria where it is converted to pregnenolone. The pregnenolone moves into the Endoplasmic Reticulum; synthetic intermediates are shuttled between the endoplasmic reticulum and the mitochondria. The synthesis of each of the adrenocortical hormones shares some synthetic steps therefore genetic defects in one pathway may cause the overproduction of one of the other adrenocortical hormones. Overview of Synthetic steps: The Cortex is divided into three zones: Zona Glomerulosa secretes mineralocorticoids; Aldosterone, the major mineralocorticoid in humans

Angiotensin II and elevated plasma K+ levels stimulate secretion of Aldosterone.

Zona Fasciculata secretes glucocorticoids; Cortisol, is the major glucocorticoid in humans. This zone also secretes small amounts of androgenic hormones.

Zona Reticularis primarily secretes androgenic hormones; dehydroepiandrosterone sulfate (DHEA-S) and androstenedione plus small amounts of glucocorticoids are secreted.

DHEA-S is converted into testosterone or estradiol in the peripheral tissues

Recall: the Adrenal Medulla, the innermost portion, secretes the catecholamines epinephrine and norepinephrine. Tyrosine is the precursor for the synthesis of these neuroendocrine hormones. Introduction Glucocorticoids are synthesized and secreted by the Adrenal Glands. The chief glucocorticoid secreted in humans is cortisol, which is a life essential hormone. Cortisol plays a key role in maintaining blood glucose during fasting and stimulates fat metabolism. Cortisol also helps to maintain vascular responsiveness and modulate central nervous system function. In addition, cortisol has a powerful anti-inflammatory role by suppressing almost all functions of the immune system. Normal levels of cortisol effects the actions of many other hormones and is thus said to have a permissive effect on endocrine action. Physiological stress causes activation of the Hypothalamus-Pituitary-Adrenal axis; therefore, secretion of Cortisol plays an important role in the body’s response to stress. Secretion of Cortisol is exclusively controlled by the hypothalamus-pituitary axis. Hypothalamic CRF Anterior Pituitary ACTH ACTH is a fragment of a larger molecule, preproopiomelanocortin. Secretion of

ACTH includes the secretion of other products, namely endorphins and melanocyte-stimulating hormone (MSH).

Cortisol Secretion of ACTH is complex. ACTH secretion fluctuates in the circadian rhythm and responds to a number of stimuli including: CRF, transition between sleep and waking, physiologic stress, anxiety, depression, and other hormones. Negative feedback of cortisol decreases secretion. ACTH primarily affects secretions of the zona fasciculata and the zona reticularis.

Hormones of the Adrenal Cortex

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Cortisol Action on Target Tissues 70-80% of the circulating Cortisol travels bound to a specific corticosteroid-binding protein called transcortin. Another 15% of cortisol is bound to plasma albumin leaving only 5-10% of cortisol “free”. Plasma cortisol is in equilibrium with a biologically inactive analog called cortisone. Enzymes in peripheral tissues can convert cortisone and thus provide more cortisol when needed. “Free” cortisol easily transverses the lipid bilayer of cells and binds with an intracellular glucocorticoid receptor. The concentration of glucocorticoid receptors (GR) varies in different tissues; skeletal muscle has a high density of GR. Once cortisol is bound with GR the cortisol•GR complex moves into the nucleus and binds to specific glucocorticoid regulatory elements (GREs). Once Cortisol•GR•GREs forms, gene transcription is initiated or repressed. Metabolic effects occur over a wide time scale of minutes-hours-days. Figure

Cortisol Effects on Metabolism Cortisol plays a complex and permissive role in the mobilization of fuels and thus substrate flow. Cortisol is a diabetogenic anti-insulin agent. Nocturnal surges in secretion support gluconeogenesis, lipolysis, & ketogenesis during the

overnight fast. Cortisol mobilizes muscle protein to support gluconeogenesis by inhibiting protein synthesis and

stimulating protein catabolism. Excess glucocorticoids can deplete protein stores in muscle, skin, connective tissue and bone.

Cortisol is critical in maintaining blood glucose during situations of fasting or starvation. Cortisol stimulates muscle glycogenolysis and gluconeogenesis. Without cortisol, once liver glycogen is depleted plasma levels of glucose become very low.

Cortisol is antagonistic to insulin actions. Cortisol induces insulin resistance. Cortisol increases appetite, induces adiposity and stimulates lipogenesis. The increased lipogenesis

occurs in specific regions of the body, i.e. abdomen, buffalo hump. Cortisol’s permissive effects on glucagon, growth hormone, and epinephrine & norepinephrine

augments the loss of body protein and hyperglycemia. Normal cortisol levels are necessary for normal skeletal and cardiac muscle function however

excess cortisol diminishes protein synthesis and facilitates protein degradation. Type IIB muscle fibers are effected the greatest and type I the least. Inactivity predisposes muscle to the deleterious effects of cortisol.

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Cortisol Effects on other Body Tissues Cortisol inhibits bone formation in part by inhibiting synthesis of collagen and inhibiting the

absorption of calcium. Additionally, Cortisol increases the rate of bone resorption (bone degradation). Excess cortisol causes a marked decrease in bone mass and osteoporosis develops.

Cortisol inhibits collagen synthesis leading to fragile vessels and thinning of the skin. The vasculature becomes susceptible to rupture, therefore hemorrhage and easy bruising may occur.

Normal levels of Cortisol are necessary to maintain normal blood pressure. Cortisol exerts a permissive role on the action of hormones responsible for maintaining vascular responsiveness.

Cortisol stimulates glomerular filtration rate and is needed for rapid excretion of a water load. Normal Cortisol levels are necessary for proper function of the nervous system. GR are especially

found in high density in the limbic and hypothalamic areas of the brain. Excess cortisol can cause insomnia, depression, disturbed memory function, and seizures.

Cortisol plays a pivot role in fetal development of the central nervous system, retina, skin, gastrointestinal tract, and lungs.

Cortisol Has Profound Effects on Inflammatory and Immune Responses Almost all components of leukocyte function are suppressed. The anti-inflammatory effects and immunosuppressive effects of glucocorticoids are used in a variety of medical disorders to decrease the deleterious effects of inflammation and autoimmunity. Synthetic glucocorticoids are used in organ transplantation as an immunosuppressant. Hormone Response to Physiologic Stress Goal: Mobilize fuels, Maintain cardiovascular parameters (e.g. blood pressure, cardiac output), and Repairset the stage for repair

ADH

Aldosterone

Cortisol

GH

Glucagon

SNS Pathology Associated with the Adrenal Gland Adrenal Insufficiency; hypofunction of the Adrenal Gland: Addison’s Disease

Please note: Individuals should be wearing and ID bracelet or similar Med alert. Why is it important to monitor vital signs in individuals with Adrenal insufficiency (hyposecretion)?