Adrenal Glands Part 3 - PowerPoint Presentation

Slide1

Adrenal Glands

Part 3Slide2

Adrenal Medulla

The

adrenal medulla accounts for about 10% of the mass

of the

adrenal gland Distinct embryologically and physiologically from the cortex, although cortical and medullary hormones often act in a complementary manner

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Cells of the adrenal medulla have an affinity for chromium salts in histological preparations and hence are called

chromaffin

cells

Chromaffin

cells are innervated

by neurons

from

the spinal cordSlide3

Secretory ProductsThe principal secretory products:

epinephrine

and norepinephrine,

are derivatives of the amino acid tyrosine

and belong to a class of compounds called catecholaminesare stored in membrane-bound granules within chromaffin cellsThe adrenal medulla also produces and secretes several neuropeptides but their physiological role is incompletely understood

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Biosynthesis of Medullary Catecholamines

Hydroxylation of

tyrosine

to form dihydroxyphenylalanine

(DOPA) is the rate determining reaction and is catalyzed by the enzyme tyrosine hydroxylaseActivity of this enzyme is inhibited by catecholamines (product inhibition) and stimulated by phosphorylationThe enzyme phenylethanolamine-N-methyltransferase

(PNMT) is at least partly inducible by cortisol

determine

the ratio of epinephrine to norepinephrine production

4Slide5

Storage, Release, and Metabolism of Medullary Hormones

All the epinephrine in blood originates in the adrenal

glands

However, norepinephrine may reach the blood

either by adrenal secretion or by diffusion from sympathetic synapsesCatecholamines are stored in secretory granules Acetylcholine released during neuronal stimulation increases the influx of sodium ions which depolarizes the plasma membraneThis leads to an influx of calcium through voltage-sensitive channels

triggering the secretion of catecholamines

5Slide6

Storage, Release, and Metabolism of Medullary Hormones

The

half-lives of medullary hormones in

the peripheral circulation have been estimated to be less than 10 seconds for epinephrine and less than 15 seconds for

norepinephrineEpinephrine and norepinephrine that are cleared from the circulation are either stored or degraded6Slide7

Physiological Actions of Medullary Hormones

The

sympathetic nervous system and adrenal medullary hormones, like the cortical hormones, act on a wide variety of

tissues

to maintain the integrity of the internal environment Catecholamines enable us to cope with emergencies and equip us for “fright, fight, or flight”7Slide8

Physiological Actions of Medullary Hormones

Cells in virtually all tissues of the body

express G-protein

coupled receptors for epinephrine and norepinephrine on their surface

membranesThey are called adrenergic receptors originally were divided into two categories, α and β

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Epinephrine

Norepinephrine Slide9

Physiological Actions of Medullary Hormones

Cardiovascular effects:

maximize

cardiac output and ensure perfusion of the brain and working muscles

Metabolic effects:ensure an adequate supply of energy-rich substrateRespiratory System:Relaxation of bronchial muscles facilitates pulmonary ventilation. Ocular effects:increase visual acuityEffects on skeletal muscle:

increase muscular performance,

and

quiescence of the gut permits diversion of

blood

flow, oxygen, and fuel to reinforce these effects

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Regulation of Adrenal Medullary Function

The

sympathetic nervous system, including its adrenal medullary component, is activated by any actual or threatened

change in the internal or external

environmentInput reaches the adrenal medulla through its sympathetic innervationSignals arising in the hypothalamus and other integrating centers activate both the neural and hormonal components of the sympathetic nervous system10Slide11

Regulation of Adrenal Medullary Function

Norepinephrine- or

epinephrine-secreting cells

can be preferentially and independently stimulatedIn response to hypoglycemia detected

by glucose monitoring cells in the central nervous system:the concentration of norepinephrine in blood may increase threefoldwhereas that of epinephrine, which tends to be a more effective hyperglycemic agent, may increase 50-fold11Slide12

Disorders of Adrenocortical Insufficiency

12Slide13

Adrenocortical Insufficiency13

Decreased

hormonal secretion is indicated

by a

dotted line

and

increased

secretion by a

dark solid

line

Slide14

Adrenocortical InsufficiencyDeficient adrenal production of glucocorticoids or mineralocorticoids results in adrenocortical

insufficiency which

is either the consequence

of:Primary adrenocortical insufficiency

Destruction or dysfunction of the cortex (Addison’s disease )Autoimmune diseasedeficiency in both cortisol and aldosterone productionAs a consequence of metastatic infiltration InfectiousCongenital unresponsiveness to ACTH A rare defect in the adrenal ACTH receptor protein

Congenital adrenal hyperplasia

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Adrenocortical Insufficiency

Congenital

(virilizing) adrenal hyperplasia

,

 Inherited enzymatic defects in cortisol biosynthesisany of the steroidogenic enzymes may be affectedDeficiency of 21β-hydroxylase, one of the key enzymes in the cortisol (and aldosterone) synthetic pathway, leads to:

a reduction in cortisol secretion with a compensatory rise in plasma

ACTH

and

a build up of adrenal androgenic steroid precursors

(

androstenedione

 and ultimately 

testosterone)

The

excess production of ACTH leads to an excessive growth (hyperplasia) of the adrenal cortex

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There are general symptoms of glucocorticoid/

mineralo

-corticoid deficiency

Female infants may show symptoms of:

abnormal sexual organs

or later in life (precocious puberty, hirsutism or

amenorrhoea

in adulthood)Slide17

Disorders of Adrenocortical InsufficiencySecondary adrenocortical insufficiency

Secondary to deficient pituitary ACTH secretion

Glucocorticoid therapy is the most common cause of secondary adrenocortical insufficiency

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Evaluation of suspected primary or secondary adrenocortical insufficiency.

Boxes

enclose clinical decisions,

Circles enclose diagnostic tests Metyrapone blocks

the synthesis of cortisol & rapid fall of cortisolSlide19

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Thus, in healthy individuals, the fall in serum cortisol

conc.

leads sequentially to decreased negative feedback at hypothalamic and pituitary levels,

This

increases CRH and ACTH secretion and adrenal steroidogenesis; the resultant secretion of cortisol precursors, in particular,

11-deoxycortisol

, can be measured by different techniques in blood or its metabolites in urine

Metyrapone

 Slide20

TreatmentIn patients with chronic adrenal

insufficiency combination

replacement therapy with both glucocorticoid and mineralocorticoid compounds is

necessaryA combination of

 hydrocortisone  and fludrocortisone (a synthetic mineralocorticoid) administered by mouth, is recommended 20Slide21

Hypersecretion

21Slide22

Hypersecretion of GlucocorticoidsThe resultant condition of hypercortisolism is called Cushing’s syndrome

More prevalent in women

Its symptoms may also be induced after long-term therapy with glucocorticoids

(e.g. for asthma, rheumatoid arthritis or inflammatory bowel disease)

The condition of excess pituitary ACTH secretion is traditionally referred to as Cushing’s disease22Slide23

Cushing’s SyndromeACTH-dependent

Pituitary adenoma (Cushing’s disease)

Nonpituitary

neoplasmACTH-independent

Adrenal neoplasm (adenoma, carcinoma)Nodular adrenal hyperplasia23Slide24

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Cushing’s SyndromeThe classical features of Cushing’s syndrome are:Muscle

weakness and 

wasting

thin arms and legs- due to increased protein

breakdownBack pain (due to osteoporosis)Excess cortisol (or glucocorticoid treatment) interferes with bone metabolismRedistribution of body fat tissuerounded (moon) face25Slide26

TreatmentThis is usually by removal of the pituitary, ectopic (usually in lung) or adrenal

tumor

if possible, coupled with corticosteroid replacement

therapyWhen tumors

are not easily located or inoperable, patients may undergo therapy with a steroid synthesis inhibitor Metyrapone is a competitive inhibitor of the enzyme involved in the final step of cortisol synthesis in the adrenal cortex; this drug may also be used in the treatment of Cushing’s syndrome arising from an ectopic ACTH-secreting tumor

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Mineralocorticoid HyposecretionIsolated deficiency in aldosterone production (

hypoaldosteronism

) 

may be due to adrenal enzyme defects (very rare)

It may occur for example, as a consequence of renal disease due to diabetes mellitus The general symptoms of mineralocorticoid deficiency:i.e. increased Na+/H2O excretion, hyperkalaemia (high plasma K

+), hypotension and metabolic acidosis would also be seen in conjunction with those of glucocorticoid lack in cases of adrenal insufficiency (e.g. Addison’s disease

)

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Mineralocorticoid Hypersecretion

Aldosterone

excess (

hyperaldosteronism) may be divided into two types:

Primary Hyperaldosteronism (Conn’s Syndrome): caused by a bilateral adrenal hyperplasia (abnormal enlargement) or small tumour (adenoma) of the adrenal zona

glomerulosa. 

Patients

exhibit 

hypertension (

due to Na

+

 and H

2

O

retention

)

and

a low plasma K

+

level

Plasma

renin levels are characteristically low in this

condition

Diagnosis is made by demonstration

of:

a

 high plasma or urine aldosterone level, 

in

conjunction with a low level of plasma

renin

blood

volume expansion by saline loading, would fail to suppress the high aldosterone

level

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Mineralocorticoid Hypersecretion29

Secondary

Hyperaldosteronism

:

This is caused by an abnormally increased 

renin release, and therefore raised levels of angiotensin

II

Some

possible causes

include:

Poor

renal perfusion e.g. in renal artery stenosis;

Malignant hypertension (i.e. hypertension associated with progressive renal failure due to renal arteriolar necrosis);

Renal

tumour

of the juxtaglomerular cells;

Excessive Na

+

 and H

2

O loss during diuretic therapy (most common cause) or dietary Na

+

 deprivation;

Congestive heart

failureSlide30

TreatmentHypoaldosteronism

treated

by replacement

therapyHyperaldosteronism should involve the treatment of the underlying cause of the abnormal renin/angiotensin system activationThis is coupled with administration of Spironolactone (antagonist 

of the mineralocorticoid , aldosterone, and androgen receptors ) for long-term management

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DISORDERS OF ADRENAL MEDULLARY FUNCTION

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Adrenal Medullary Hypofunction (Epinephrine Deficiency)

Epinephrine is the major catecholamine secreted by

the normal

adrenal medulla and its secretion is unique to the adrenal

medullaEpinephrine deficiency is caused by:bilateral adrenalectomies, tuberculosis, Hemorrhageautonomic insufficiencyautonomic nervous system (ANS) malfunctionsOr Cortisol deficiency

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Adrenal Medullary HyperfunctionThe adrenal medulla is not known to play a

significant role

in essential

hypertensionNorepinephrine can increase blood pressure

by increasing:increasing cardiac output, increasing peripheral resistance through their vasoconstrictive action on the arteriole, and increasing renin release from the kidney leading to increased circulating levels of angiotensin II

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PheochromocytomaR

are,

usually noncancerous (benign) tumor that develops in cells in the center of an adrenal gland

Are usually unilateral

Symptoms include:HeadachesPalpitationsDiaphoresisSevere hypertensionTreatment of malignant tumors consists of surgery, chemotherapy, external beam radiation to skeletal metastases, and high-dose 131I-MIBG (metaiodobenzylguanidine

) therapy for patients with MIBG-avid tumors

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