4. Adrenocorticoid Function

Appetite

________ is severely increased- raids garbage in the house or out; pulls foods down off kitchen counters.

Adrenal gland

________ is enriched in receptors that internalize HDL and LDL.

Glucocorticoids

________ modulate the mediators of immune system as the different lymphokines and mediators of inflammatory reactions: prostaglandins, leukotrienes, kinins, serotonin, histamine.

lactation

Factors: housing, ________, exercise, surgery, anaesthesia, heat, emotional strain, anticipation of feeding.

nocturnal animal

Cat (________): circadian rhythm- the highest levels in the evening and the lowest in the morning.

Feedback circuit

________: immunoregulatory cytokines act as afferent and ACTH and glucocorticoids as efferent hormonal signals.

Cortisol

________ is cleared from the plasma with a half- life of 60min.

glucuronic acid

Conjugation with ________ to form glucuronidates.

Conventional treatment

________: Lysodren which limits the glands ability to produce excess cortisol.

Medulla

________- neuroectodermal origin- epinephrine and norepinephrine.

ACTH

________: steroidogenic activity of the 2 inner zones of the adrenal cortex.

11β hydroxylation

________: cortisol → cortisone.

Cushings disease

________ in dogs, if not treated can cause diabetes, nervous system disorders, pancreatitis, eye infections, ear infections, or heart disease.

Medication

________- caused Cushings: Allergy ________ can cause Cushings disease in dogs and this condition can be fully reversed.

Pathologic excess of adrenal androgens

________ might induce virilization= development of masculine secondary sex characteristics in the female or immature male.

Primary hypoadrenocorticism

________ (Addison´s disease)- deficiency of both glucocorticoid and mineralocorticoid secretion.

Cortisol production rate

________- radiolabelled cortisol.

Adrenal glands

________ are bilateral structures located craniomedial to the kidneys.

Cortex

mesodermal origin

zona glomerulosa (arcuata)

mineralcorticoids

zona fasciculata

glucocorticoids

zona reticularis

androgens

microsomal cytochrome P-45017α (17

hydroxylase/lyase)

11β-hydroxylation

cortisol → cortisone

ACTH

steroidogenic activity of the 2 inner zones of the adrenal cortex

Rapid stimulation of steroidogenesis via adenylate cyclase → activation of PK A → phosphorylation of enzyme

conversion of cholesterol to pregnenolone

Na+,K+

production of aldosterone by zona glomerulosa

K+

direct regulation

Na+

renin-angiotensin

cortisol

most potent

As steroid hormones

transcription factors

In humans (monophasic sleep)

secretory bursts between midnight and early morning

Non-primate mammals (polyphasic sleep)

circadian variations

Factors

housing, lactation, exercise, surgery, anaesthesia, heat, emotional strain, anticipation of feeding

Glucocorticoids modulate the mediators of immune system as the different lymphokines and mediators of inflammatory reactions

prostaglandins, leukotrienes, kinins, serotonin, histamine

Feedback circuit

immunoregulatory cytokines act as afferent and ACTH and glucocorticoids as efferent hormonal signals

Primary hypoadrenocorticism (Addison´s disease)

deficiency of both glucocorticoid and mineralocorticoid secretion

Secondary hypoadrenocorticism

pituitary ACTH deficiency causing decreased glucocorticoid secretion

Animals receiving long-term corticosteroid treatment despite hyperadrenocorticoid changes, develop adrenocortical insufficiency because of prolonged hypothalamo-pituitry suppression

atrophy of the two inner zones of the adrenal cortex

Mineralocorticoid excess (Conn´s syndrome)

human

Glucocorticoid excess (Cushing´s syndrome)

human, dog, cat, horse

Cushing´s disease in dogs

two forms

certain changes in dogs behavioir

eating and scavenging for anything to eat, excessive water drinking, changes in skin and fur, frequent urination (especially in the house)

Medication-caused Cushings

Allergy medications can cause Cushings disease in dogs and this condition can be fully reversed

Appetite is severely increased

raids garbage in the house or out; pulls foods down off kitchen counters

Sores or lesions developing on body

you will notice if your dog requires frequent grooming

Conventional treatment

Lysodren which limits the glands ability to produce excess cortisol

Managing a diet

raw chicken with cooked white rice, boiled chicken with the cooked rice, cooked carrots

Androgen excess (adrenogenital syndrome)

human

Hyperadrenocorticism

eosinopenia, lymphopenia, leucocytosis, erythrocytosis, alkaline phosphatase, ALT, hyperglycaemia, hyperlipidaemia, low T4, glycosuria

Describe the structure of the adrenal glands

medulla and cortex

What are examples of hormones synthesised in the adrenal medulla?

epinephrine, norepinephrine

What are the zones found in the adrenal cortex?

zona glomerulosa, zona fasiculata, zona reticularis

What types of hormones are produced in the zona glomerulosa? Give examples

mineralcorticoids; aldosterone, deoxycorticosterone

What types of hormones are produced in the zona fasiculata? Give examples

glucocorticoids; cortisol, corticosterone

What types of hormones are produced in the zona reticularis? Give examples

androgens; androstenedione

What is the substrate for biosynthesis of steroids? (steroidogenesis)

exogenous and endogenous cholesterol

How are cortisol and corticosterone transported in the blood?

10% in free form;
70% bound to transcortin;
20% bound to albumin

How is aldosterone transported in the blood?

bound to albumin

Describe the metabolic breakdown and excretion of cortisol

only unbound cortisol is filterable in the glomerulus.
80% is reabsorbed, while 20% is excreted.
Cortisol has a half-life of 60 minutes.
11β-HSD1 converts cortisol to cortisone.
Reduction of ring A to tetrahydro- derivatives.
Reduction of the 20-keto group to a hydroxyl.
Conjugation with glucuronic acid to form glucuronidates

What is aldosterone converted to for excretion?

tetrahydroaldosterone-3-glucuronide
aldosterone-18-glucuronide

What are the steps of the biotransformation of cortisol?

cortisol, dihydrocortisol, tetrahydrocortisol, tetrahydrocortisol-glucuronide, urine

Describe the regulation of secretion from the adrenal gland

hypothalamus releases corticotropin-releasing hormone, stimulating the anterior pituitary gland to release ACTH, stimulating the adrenal gland to synthesise cortisol.
cortisol inhibits the release of ACTH by inhibiting the hypothalamus.

What are examples of synthetic analogues of cortisol?

prednisone, prednisolone, dexamethasone, triamcinolone

What are the naturally occurring glucocorticoids?

cortisol, cortisone, corticosterone

What are the functions of glucocorticoids?

stimulate gluconeogenesis;
anti-inflammatory action

How do glucocorticoids stimulate gluconeogenesis?

act as transcription factors for the synthesis of key enzymes; fructose-1,6-biphosphatase, glucose-6-phosphatase, pyruvate carboxylase

What pathological effect can androgens have?

development of masculine secondary sex characteristics in the female or immature male;
clitoral enlargement in horses

What is actions do mineralcorticoids have on the body?

control the volume and cationic composition of extracellular fluid by regulating Na+:K+ balance;
act on tubular apparatus of the kidneys, gut, salivary glands, sweat glands;
excretion of Mg2+ and NH4+

Describe the interaction of the neuroendocrine system and the immune system

bidirectional communication;
injury leads to production of cytokines, causing the activation of the pituitary-adrenal axis stimulating glucocorticoid production, which inhibits immune mediators

Describe hypoadrenocorticism

primary: Addison's disease caused by deficiency of both glucocorticoid and mineralcorticoid secretion;
secondary: pituitary ACTH deficiency causing decreased glucocorticoid secretion;
animals receiving long-term corticosteroid treatment despite hyperadrenocorticoid changes, develop adrenocortical
insufficiency because of prolonged hypothalamo-pituitary suppression – atrophy of the two inner zones of the adrenal cortex

What are the clinical syndromes of hyperadrenocorticism?

mineralcorticoid excess (Conn's syndrome);
glucocorticoid excess (Cushing's syndrome);
androgen excess (adrenogenital syndrome)

What are the two forms of Cushing's disease in dogs?

pituitary dependent, adrenal-based

What are the causes of Cushing's disease?

pituitary gland tumour;
adrenal gland tumours;
medication-induced Cushing's

Why does a pituitary gland tumour cause Cushing's?

the tumour causes overproduction of ACTH, which will stimulate the adrenal cortex and causes excess production of cortisol

How is medication-induced Cushing's reversed?

corticosteroid allergy medications will be tapered off and the dog should recover in a few months

What diagnostics are used for Cushing's?

complete blood count;
urinalysis and bacterial culture of urine;
urine cortisol-creatinine ratio;
abdominal ultrasound exam and x-rays;
MRI of the brain;
ACTH stimulation test

What are the clinical signs of Cushing's disease in dogs?

extreme water consumption followed by excessive urination;
appetite is severely increased;
abdominal enlargement;
sores or lesions;
hair loss or thin skin

What can occur if Cushing's is not treated?

diabetes, nervous system disorders, pancreatitis, eye infections, ear infections, heart disease

What is the conventional treatment for Cushing's?

Lysodren; limits the ability of the adrenal glands to produce excess cortisol

What are the clinical signs of Cushing's in horses?

long, thick and curly coat;
abnormal shedding;
lethargy;
narcolepsy;
laminitis;
excessive drinking;
excessive urinating;
weight loss;
increased appetite;
recurrent infections

What would be seen in lab results for primary hypoadrenocorticism?

hyponatraemia, hypokalaemia, hypovolaemia

What would be seen in lab results for hyperadrenocorticism?

eosinopenia, lymphopenia, leucocytosis, erythrocytosis, alkaline phosphatase, ALT, hyperglycaemia, hyperlipidaemia, low T4, glycosuria

What are the tests for basal function of the adrenal cortex?

RIA, cortisol production rate, plasma corticoids, urinary corticoids, salivary cortisol, cortisol in milk, plasma ACTH

What are the dynamic tests for testing the function of the adrenal cortex?

ACTH stimulation test (Addison´s disease);
Low-dose dexamethasone suppression test;
High-dose dexamethasone suppression test;
corticoids creatinine ratio