Hormones of the Adrenal Cortex • Objectives • Name the hormones synthesized in and secreted from adrenal cortex • List the steps of synthesis of adrenal cortical hormones writing the precursors and the main enzymes involved • Describe the mechanisms of storage, transport , degradation and excretion of each of the adrenal cortical hormones. • Explain the metabolic functions of adrenocorticosteroids • References • Harper’s Biochemistry 25th and 26th eds.
The adrenal glands are located at the top of the kidneys. They have two distinct parts. The outer Cortex, and the inner Medulla, producing distinct secretions.
Adrenal Glands The outer part is called the adrenal cortex, which produces many different hormones called corticosteroids. This includes cortisol. These hormones regulate the salt and water balance in the body, prepare the body for stress, regulate metabolism, interact with the immune system, and induce sexual function. The inner part, which is called the adrenal medulla, produces catecholamines, such as epinephrine. Epinephrine also known as adrenaline, increase the blood pressure and heart rate during times of stress.
Adrenal Glands BACK
Hormones of adrenal cortex Three general classes of steroid hormones based on predominant functions Mineralocorticoids: 21 carbon containing steroids , synthesized byzonaglomerulosa, regulate water and electrolyte balance. Aldosterone is the most prominent mineralocorticoid. Glucocorticoids: Also 21 carbon steroids, produced mostly in zonafasciculataand affect glucose (hence the name), amino acid and fat metabolism. Cortisol (also known as hydrocortisone) is most important GC in humans. Androgens: The zonareticularis and fasciculataproduce significant amounts of androgen precursor DHEA (dehydroepiandrosterone) and androstenedione (both 19 carbon).
Synthesis of Adrenocortical Hormones • Made from cholesterol taken from LDLs in the blood and stored in adrenocortical cells • Adrenocortical cells stimulated by ACTH or cAMP. Cholesterol
Storage and secretion • Little (if any) storage of steroid hormones , directly go into circulation as and when they are produced • Cortisol release follows the diurnal rhythm of ACTH release. Highest levels in the morning shortly after awakening and lowest in the evening and early morning. Plasma Transport • Cortisol circulates in plasma bound to proteins or as free. • Transcortin or corticosteroid binding globulin (CBG) binds cortisol. • Most of the steroid hormones bind to CBG. • Cortisol binds CBG and has a half life of 1.5 - 2 hrs. 8-10% Cortisol is free. • Progesterone and deoxycorticosterone also bind CBG strongly. • Corticosterone binds CBG with less affinity. • Aldosterone does not have a specific protein but binds weekly with albumin
Degradation and Excretion • Glucocorticoids: Cortisol, Cortisone and 11-deoxycortosol are reduced by NADPH dependant enzymes and conjugated with either glucoronate or sulfate which render them water soluble. About 70% of the conjugated steroids are excreted in the urine , 20% in feces and rest exit through the skin. • Mineralocorticoids: Aldosterone is very rapidly cleared from the plasma by liver because it lacks a specific protein carrier. It is converted to tetrahydroaldosterone 3-glucoronide which is excreted in urine. • Androgens:are excreted as 17-keto compounds including DHEA (sulfate) as well as androstenedione and its metabolites. Small amounts of testosterone secreted by adrenals are also converted to 17-keto compounds like androsterone and etiocholanolone which are excreted in urine.
Metabolic functions of adrenal corticosteroids • Glucocorticoid hormones: the most important are Cortisol, cortisone and Corticosterone • Effects on Carbohydrate metabolism: • ↑esGluconeogenesis and glucose output • ↑esamino acid utilization • ↑esglycogen storage • ↓esglucose uptake by tissues other than liver • Effects on Lipid metabolism: • ↑eslipolysis • ↑escirculating free fatty acids (FFA) • ↓ esutilization of FFA for TG synthesis.
Metabolic functions of adrenocorticosteroids • Effects on Protein metabolism: • ↑es degradation of proteins in extra hepatic tissues • ↑es protein synthesis in liver • Effects on Nucleic acid metabolism: • promotes transcription of specific genes in liver. • Effects on water and electrolyte metabolism: • Mediated through ADH ,Deficiency causes ↑ ADH which decreases glomerular filtration and leads to water retention. • Other biochemical functions: • Suppress immune response in high doses (esp. cortisol) • Modulate response of catecholamines • Increase the production of gastric HCl and pepsinogen • Inhibit the bone formation- increases the risk of osteoporosis.
Metabolic functions of adrenocorticosteroids Androgens:DHEA and androstenedione are precursors of testosterone which is the most potent androgen. General Biochemical functions of androgens are: • Growth, development and maintenance of male reproductive organs • Effect on protein metabolism: promote protein synthesis , positive nitrogen balance and increase muscle mass. • Effect on carbohydrate and fat metabolism: increase glycolysis, lipolysis and TCA cycle • Effect on mineral metabolism: Promote mineral deposition and bone growth.
Metabolic functions of adrenocorticosteroids • Mineralocorticoid hormones: the most active and potent mineralocorticoid is Aldosterone. • ↑es reabsorption of sodium by the distal convoluted tubules of kidney. Water follows sodium , thus leads to water retention • ↑es Excretion of K+, H+ and NH+4 ions in urine. • Acts on all epithelial cells that exchange Na and water( kidney , GI tract , salivary glands etc) • Promotes synthesis of transport proteins (pumps) which facilitate Na and water movement across cell membranes.