hormones of the adrenal cortex 1-13

8/14/2019 Hormones of the Adrenal Cortex 1-13

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HORMONES OF THE

ADRENAL CORTEX


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INTRODUCTION

The adrenal cortex synthesizesglucocorticoids, mineralocorticoids, and

androgens It initiates its action by combining with

specific intracellular receptors

The hormone-receptor complex then bindsto specific DNA regions to regulate geneexpression


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IMPORTANCE

Glucocorticoids are essential for

adapatation to stress

Mineralocorticoids regulate sodium and

potassium balance


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LAYERS OF THE ADRENAL CORTEX

Zona glomerulosa

produces

mineralocorticoids Zona Fasciculata and

zona reticularis

produce

glucocorticoids andandrogens
http://en.wikipedia.org/wiki/Image:Gray1185.pnghttp://en.wikipedia.org/wiki/Image:Gray1185.png


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All glucocorticoids have mineralocorticoid

activity and vice-versa


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GLUCOCORTICOIDS

21-carbon steroids that regulate

gluconeogenesis

Cortisol produced by the zona fasciculata

predominates in humans

Corticosterone produced by the zona

fasciculata and glomerulosa is lessdominant in humans


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MINERALOCORTICOIDS

21-carbon steroids that promote sodium

retention and excretion of potassium and

hydrogen ions The most potent, aldosterone, is produced

by the zona glomerulosa


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The zona fasciculata and reticularis

produce dehydroepinandrosterone and

the weak precursor androstenedione,which are converted to more potent

androgens in extra-adrenal tissues

Estrogens are not made in the normaladrenal gland in significant amounts


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NOMENCLATURE

All steroids have

cyclopentanoperhydrophenanthrene ring


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Steroid hormones and their precursors

and metabolites differ in number and type

of substituted groups, number and type ofdouble bonds, and stereochemical

configuration

Asymmetric carbons allow forstereoisomerism


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Most adrenal cholesterol is esterified and

stored in the cytoplasm

Upon stimulation by ACTH or cAMP, anesterase is activated and free cholesterol

is transported to mitochondria where

CytP450 side chain cleavage enzymeconverts cholesterol to pregnenolone


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An ACTH-dependent steroidogenic

acute regulatory (StAR) protein is

essential for the transport of cholesterol toP450scc in the inner mitochondrial

membrane

Aminoglutethimide inhibits P450scc
http://en.wikipedia.org/wiki/Image:Aminoglutethimide.pnghttp://en.wikipedia.org/wiki/Image:Aminoglutethimide.png


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3 -OHSD and 5,4-isomerase are

found in the

SER

They convert

pregnenolone to

progesterone


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17-Hydroxylase and 21-

hydroxylase are SER

enzymes

11 hydroxylase is inthe mitochondria


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Progesterone ishydroxylated at C21 to form

11-DOC which is a sodium-

retaining mineralocorticoid


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Hydroxylation at C11

forms corticosterone,

which has glucocorticoid

activity but is only 5% aspotent as aldosterone in

man


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C21 hydroxylation isnecessary for both

glucocorticoid and

mineralocorticoid activity


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Found only in glomerulosa cells, so

aldosterone can only be synthesized

in the zona glomerulosa


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Glucocorticoid synthesis requires 3 hydroxylases

acting on C17, C21, and C11 (C11 is the slowest

reaction)


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DHEA

DHEA is the majorandrogen produced by the

adrenal gland

Adrenal androgen

production increases if

glucocorticoid biosynthesisis impeded


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DHEA

Most DHEA is rapidlymodified by adding sulfate

in the adrenal gland and

liver

DHEA sulfate is inactive;

sulfate removal reactivatesDHEA


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DHEA

Reduction ofandrostenedione at C17

forms testosterone, the

most potent adrenal

androgen


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SECRETION OF STEROID

HORMONES There is little storage of steroids in the

adrenal gland; most are released in

plasma after synthesis Cortisol levels are highest in AM after

awakening and lowest in late afternoon

(diurnal rhythm)


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HORMONE TRANSPORT IN

PLASMA The main carrier is transcortin or

corticosteroid-binding globulin (CBG)

produced by the liver, whose synthesis isincreased by estrogen

Small amounts of cortisol are bound to

albumin


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CBG-bound cortisol has a half-life of 1.5-2

hours while corticosterone, which binds

less tightly, has a half-life of less than 1hour

Deoxycorticosterone and progesterone

compete with cortisol for binding withCBG


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Aldosterone does not have a specific

transport protein, but it forms a weak

association with albumin


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METABOLISM AND EXCRETION

Glucocorticoids are reduced and

conjugated at C3 by glucuronide, or to a

lesser extent with sulfate, making it water-soluble

70% of conjugated steroids are urinated,

20% are defecated, and 10% exit the skin


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Aldosterone is cleared by the liver and

excreted through urine again via

glucuronidation Androgens are excreted as 17-keto

compounds

Testosterone is converted by the liver toless active metabolites


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THE BIOLOGIC ACTIVITY OF A

STEROID DEPENDS ON:1. Its ability to bind to a receptor

2. Concentration of free hormone in the

plasma Cortisol, corticosterone, and aldosterone

all bind with high affinity to theglucocorticoid receptor

However, cortisol is dominant because ofits high plasma concentration


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Cortisol synthesis is regulated by ACTH,

which is regulated via negative feedback

by CRH


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THE RENIN-ANGIOTENSIN

SYSTEM (RAS) Also called renin-angiotensin-

aldosterone system (RAAS)

Regulates electrolytes and blood pressure Primary hormone is angiotensin II
http://upload.wikimedia.org/wikipedia/commons/a/a2/Renin-angiotensin-aldosterone_system.png


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(produced by the juxtaglomerular cells

of the renal afferent arteriole)

- low bloodpressure

- blood loss
http://upload.wikimedia.org/wikipedia/commons/a/a2/Renin-angiotensin-aldosterone_system.pnghttp://upload.wikimedia.org/wikipedia/commons/a/a2/Renin-angiotensin-aldosterone_system.pnghttp://upload.wikimedia.org/wikipedia/commons/a/a2/Renin-angiotensin-aldosterone_system.pnghttp://upload.wikimedia.org/wikipedia/commons/a/a2/Renin-angiotensin-aldosterone_system.pnghttp://upload.wikimedia.org/wikipedia/commons/a/a2/Renin-angiotensin-aldosterone_system.pnghttp://upload.wikimedia.org/wikipedia/commons/a/a2/Renin-angiotensin-aldosterone_system.pnghttp://upload.wikimedia.org/wikipedia/commons/a/a2/Renin-angiotensin-aldosterone_system.pnghttp://upload.wikimedia.org/wikipedia/commons/a/a2/Renin-angiotensin-aldosterone_system.png


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Formation of angiotensin peptides. The solid arrows show the classic pathways, and thedashed arrows indicate minor alternative pathways


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Juxtaglomerular cells are sensitive to

sodium and chloride levels in the blood

Renin release is stimulated by low water,sodium, and chloride levels


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FACTORS THAT INFLUENCE

RENIN RELEASESTIMULATORS

Decreased BP

Supine Erect Low salt levels

-adrenergics

Prostaglandins

INHIBITORS

High BP

Erect Supine High salt levels

-adrenergic antagonists

PG inhibitors

K+, ADH, angiotensin II


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EFFECTS OF GLUCOCORTICOIDS

Increase glucose production by increasing

delivery of amino acids from peripheral

tissues and increasing gluconeogenesis Increase hepatic glycogen deposition by

stimulating glycogen synthase

Increase lipolysis in extremities Increase lipogenesis in face and trunk


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EFFECTS OF GLUCOCORTICOIDS

Increase protein and RNA metabolism Suppress immune response (lysis of

lymphocytes) Suppress inflammation by :

- Decreased leukocyte activity

- Decreased fibroblast

- Increased lipocortins which inhibit phospholipaseA2


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OTHER EFFECTS OF

GLUCOCORTICOIDS Maintain normal BP and cardiac output

Maintain water and electrolyte equilibrium

Mediate response to stress


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EFFECTS OF

MINERALOCORTICOIDS Stimulate sodium transport by the distal convoluted

and collecting tubules

Promote potassium, hydrogen, and ammonium ion

secretion by the kidney

In terms of mineralocorticoid effect, cortisol is less

potent than aldosterone, but because of its high

serum concentration, it also has significantmineralocorticoid activity


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ADDISONS DISEASE

Primary adrenal insufficiency

Hypoglycemia, extreme sensitivity to

insulin, stress intolerance, anorexia, wtloss, nausea, weakness

Low BP, low GFR, Low ability to excrete

excess water Salt craving


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ADDISONS DISEASE

Low sodium, high potassium in serum

Increased skin pigmentation because of

increased POMC activation


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CUSHINGS SYNDROME

Glucocorticoid excess

May also be due to increased pharmacologic

use or pituitary adenoma Diurnal pattern of ACTH secretion is lost

Thinning of skin, muscle wasting, osteoporosis

Truncal obesity, buffalo hump Impaired resistance to infection


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CONNS SYNDROME

Primary aldosteronism due to adenomas inthe zona glomerulosa

Hypertension, hypokalemia,hypernatremia, alkalosis

Renal artery stenosis can lead to JG cellhyperactivity and elevate renin andangiotensin II, resulting in secondaryaldosteronism


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CONGENITAL ADRENAL

HYPERPLASIA Included in newborn screening

Decreased cortisol, increased ACTH

Increased adrenal androgens causing

virilization and ambiguous genitalia

(Adrenogenital syndrome)

hormones of the adrenal cortex 1-13

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