Endocrine Physiology (PHS 327)

Physiology Program

College of Health Sciences

Bowen University, Iwo, Nigeria

Dr Michael Olugbenga S

Adrenal glands and

hormones

Introduction

• The two adrenal glands, each weighing about 4 g, lie at the superior poles of the two kidneys.

• There are two endocrine organs in the adrenal gland ; adrenal medulla and adrenal cortex

• The adrenal medulla, the central 20 % of the gland, is functionally related to the sympathetic nervous system; it secretes the catecholamines; epinephrine, norepinephrine and dopamine in response to sympathetic stimulation.

• The adrenal cortex secretes an entirely different group of hormones, called corticosteroids; Mineralocorticoids, Glucocorticoids, and Androgens

• Adrenal medullary hormones work mostly to prepare the body for emergencies, the so-called “fight-or flight” responses.

• The adrenal cortex secretes – glucocorticoids, steroids with widespread effects on the

metabolism of carbohydrate, fat and protein; and

– a mineralocorticoid which essential for the maintenance of Na+ balance and extracellular fluid (ECF) volume.

– It is also a secondary site of androgen synthesis, secreting sex hormones such as testosterone, which can exert effects on reproductive function.

• Mineralocorticoids and the glucocorticoids are necessary for survival.

• The Adrenal Cortex Has Three Distinct Layers;• Zona glomerulosa (15 % of the adrenal cortex)• secretes significant amounts of aldosterone because they contain

aldosterone synthase, which is necessary for synthesis of aldosterone.The secretion of these cells is controlled mainly by the extracellularfluid concentrations of angiotensin II and potassium, both of whichstimulate aldosterone secretion.

• Zona fasciculata (75 % of the adrenal cortex)• secretes the glucocorticoids cortisol and corticosterone, as well as

small amounts of adrenal androgens and estrogens. The secretion ofthese cells is controlled in large part by the hypothalamic-pituitaryaxis via adrenocorticotropic hormone (ACTH).

• Zona reticularis; secretes the adrenal androgensdehydroepiandrosterone (DHEA) and androstenedione, as well assmall amounts of estrogens and some glucocorticoids. ACTH alsoregulates secretion of these cells, although other factors such ascortical androgen-stimulating hormone, released from the pituitary,may also be involved.

Adrenals

Zona ReticularisSex steroids (androgens)

Zona FasciculataGlucocorticoids (Cortisol)

Glucose homeostasis and many others

Zona Glomerulosa

Mineralocorticoids (Aldosterone)

Na+, K+ and water homeostasis

Medulla: “Catecholamines”Epinephrine, Norepinephrine, dopamine

CORTEX

Section through an adrenalgland showing both the medulla and the zones

Adrenal gland section McGraw-Hill, 2008.

Fetal Adrenal Gland• During fetal life, the human adrenal is large and under

pituitary control, but the three zones of the permanent cortex represent only 20% of the gland.

• The remaining 80% is the large fetal adrenal cortex, which undergoes rapid degeneration at the time of birth.

• A major function of this fetal adrenal is synthesis and secretion of sulfate conjugates of androgens that are

• converted in the placenta to estrogens.

• No structure is comparable to the human fetal adrenal in laboratory animals.

Adrenal cortical cells regenerates• An important function of the zona glomerulosa, in addition to aldosterone

synthesis, is the formation of new cortical cells. – The adrenal medulla does not regenerate.

– When the inner two zones of the cortex are removed, a new zona fasciculata and zona reticularis regenerate from glomerular cells attached to the capsule.

– Small capsular remnants regrow large pieces of adreno-cortical tissue.

– Immediately after hypophysectomy, the zona fasciculata and zona reticularis begin to atrophy, whereas the zona glomerulosa is unchanged because of the action of angiotensin II on this zone.

– The ability to secrete aldosterone and conserve Na + is normal for some time after hypophysectomy, but in long-standing hypopituitarism, aldosterone deficiency may develop, apparently because of the absence of a pituitary factor that maintains the responsiveness of the zona glomerulosa.

• Injections of ACTH and stimuli that cause endogenous ACTH secretion produce hypertrophy of the zona fasciculata and zona reticularis but actually decrease, rather than increase, the size of the zona glomerulosa.

Glucocorticoids are necessary for adrenal medulla development

• After hypophysectomy, the glucocorticoidconcentration of the blood falls and epinephrine synthesis is decreased.

• In addition, glucocorticoids are apparently necessary for the normal development of the adrenal medulla;

• In 21β-hydroxylase deficiency, glucocorticoid secretion is reduced during fetal life and the adrenal medulla is dysplastic.

• In untreated 21β-hydroxylase deficiency, circulating catecholamines are low after birth.

Adrenal medulla• Norepinephrine, epinephrine, and small amounts

of dopamine are synthesized by the adrenal medulla.

– Norepinephrine is formed by hydroxylation and decarboxylation of tyrosine, and epinephrine by methylation of norepinephrine.

• The catecholamines have a half-life of about 2 min in the circulation.

• In the medulla, norepinephrine and epinephrine are stored in granules with ATP

• Stimulates glycogenolysis in liver and skeletal muscle

• Mobilization of free fatty acids

• Increased plasma lactate

• Stimulation of the metabolic rate.

• Increase the force and rate of contraction of the isolated heart.

• Increase myocardial excitability

• Norepinephrine produces vasoconstriction in most if not all organs via α 1 receptors, but epinephrine dilates the blood vessels in skeletal muscle and the liver via β 2 receptors.

• Catecholamines increase alertness

• In humans epinephrine usually evokes more anxiety

• and fear.

• Catecholamines also produce a prompt rise in the metabolic rate

• Cateccholamines increase cardiac output, blood pressure and oxygen consumption.

• They cause smooth muscle relaxation in bronchi, GIT and blood vessels supplying skeletal muscle.

Functions of Adrenal Medullary Hormones

Adrenal Cortex• The hormones of the adrenal cortex are derivatives of

cholesterol.

• Although the cells of the adrenal cortex can synthesize denovo small amounts of cholesterol from acetate,approximately 80 % of the cholesterol used for steroidsynthesis is provided by low-density lipoproteins (LDL)in the circulating plasma.

• The only steroids normally secreted in physiologicallysignificant amounts are the mineralocorticoidaldosterone, the glucocorticoids cortisol andcorticosterone, and the androgensdehydroepiandrosterone (DHEA) and

androstenedione.

Aldosterone's mineralocorticoid activity is about 3000 times greaterthan that of cortisol, but the plasma concentration of cortisol isnearly 2000 times that of aldosterone.

Steroids having glucocorticoid or mineralocorticoidactivities or both

Ganong 12th edition

CAH (congenital adrenal hyperplasia): For P450c21 is deficiency,

cortisol synthesis decreases, leading to overproduction of ACTH. When

this occurs adrenal steroid synthesis is stimulated and 17-

hydroxyprogesterone is converted to androstenedione and further to

testosterone, leading to severe virilization of the female fetus. This

disorder is known as CAH which disrupts the synthesis of all adrenal

and gonadal steroids. Affected genetic males are born with normal

female external genitalia.

Glucocorticoid treatment is indicated in all of the virilizing forms of

congenital adrenal hyperplasia because it repairs the glucocorticoid

deficit and inhibits ACTH secretion, reducing the abnormal secretion of

androgens and other steroids.

Some autosomal recessive mutations in biosynthetic enzymes

responsible for converting cholesterol to androgens generally lead to

partial male-to-female sex reversal.

Enzyme Deficiency

Functions of Glucocorticoids

• They include increased protein catabolism and increased hepatic glycogenesis

and gluconeogenesis.

• Glucocorticoids exert an anti-insulin action in peripheral tissues and make

diabetes worse.

• Glucocorticoids inhibit ACTH secretion.

• Glucocorticoids restore vascular reactivity.

• Glucocorticoids increase ability to concentrate, reduces irritability and

apprehension.

• Obesity is Caused by Excess Cortisol

• Cortisol Is Important in Resisting Stress and Inflammation

• The secretory rates of CRF, ACTH, and cortisol are high in the early morning

but low in the late evening.

• Glucocorticoids decrease the number of circulating eosinophils and basophils

but increase the number of neutrophils, platelets, and red blood cells.

• Glucocorticoids decrease the circulating lymphocyte count and the size of the

lymph nodes and thymus by inhibiting lymphocyte mitotic activity.

Biochemical actions of adrenocorticosteroids

A. Mineralocorticoids: aldosterone

It promotes Na+ reabsorption at the distal

convoluted tubules of kidney. Na+ retention

is accompanied by corresponding excretion

of K+,H+ and NH4+ ions.

Biochemical actions of adrenocorticosteroidsB. Glucocorticoids: Cortisol

Biochemical actions of adrenocorticosteroids

1. Effects on glucose metabolism: They promote gluconeogenesis.

They work in tandem with insulin from the pancreas to maintain blood

glucose levels in the proper balance.

2. Effects on lipid metabolism: They increase lipolysis in adipose

tissue and reduce synthesis of TAG.

3. Effects on protein and nucleic acid metabolism: They promote

transcription and protein synthesis in liver. They also cause catabolic

effects in extrahepatic tissues results in enhanced degradation of protein.

B. Glucocorticoids: Cortisol

4. Effects on water and electrolyte metabolism: Deficiency of them

cause increased production of ADH which can decrease glomerular

filtration rate causing water retention in the body.

5. Effects on immune system: Cortisol suppress the immune response

directly and indirectly by affecting most cells that participate in immune

reactions and inflammatory reactions. It is a powerful anti-inflammatory

agent even when secreted at normal levels. It also reduces the rate at

which lymphocytes multiply and accelerates their programmed cell

death to further protect the body from this overreaction. This is one of

the reasons why strong corticosteroids (prednisone, prednisolone, etc.)

are used with all diseases involving inflammatory processes, including

auto-immune diseases.

6. Effects on cardiovascular system: Cortisol could control the

contraction of the walls of the mid-sized arteries in increasing blood

pressure, but this hypertensive effect is moderated by calcium and

magnesium. It also directly affects the heart by regulating sodium and

potassium in the heart cells and increasing the strength of contraction of

the heart muscle.

7. Effects on central nervous system: The changes of behavior, mood,

excitability and even the electrical activity of neurons in the brain

frequently occur in cases of excess and deficient cortisol levels. Many

signs and symptoms of adrenal fatigue involve moodiness, decreased

tolerance, decreased clarity of thought and decreased memory. These

occur because the brain is affected by both too little and too much

cortisol.

There are four major categories of stress:

1. Physical stress: such as overwork, lack of sleep, athletic overtraining. 2.Chemical

stress: environmental pollutants, allergies to foods, diets high in refined carbohydrates,

endocrine gland imbalances.

3. Thermal stress: over-heating or over-chilling of the body

4. Emotional and mental stress

Stress

•Adrenal glands are the anti-stress glands of the body.

•Physiological Stress Increases ACTH and Adrenocortical Secretion

•Almost any type of physical or mental stress can lead withinminutes to greatly enhanced secretion of ACTH and consequently

cortisol as well, often increasing cortisol secretion as much as 20-fold.

Stress: During stress cortisol must

simultaneously provide more blood glucose,

mobilize fats and proteins for a back-up

supply of glucose, modify immune reactions,

heartbeat, blood pressure, brain alertness and

nervous system responsiveness. If cortisol

level cannot rise in response to these needs,

maintaining your body under stress is nearly

impossible.

Adrenals

Kidney

PosteriorPituitary Gland

Hypothalamus

AnteriorPituitary Gland

ACTH

StressCircadian

rhythm

CRH

(-)

Glucocorticoids, Catecholamines, etc..

Glucocorticoids, Catecholamines, etc..

Muscle:Net loss of aminoAcids (glucose)

Liver:Deamination of

proteins into amino acids,

gluconeogenesis (glucose)

Fat Cells:Free fatty

acid mobilization

Heart rate:Increased

Immune system:altered

Hypothalamopituitary adrenal (HPA) axis

Regulation of glucocorticoids

• The Secretion of glucocorticoids from the adrenal cortex is regulated

by negative feedback mechanism involving the CRH secretion by the

hypothalamus.

• CRH then acts on the anterior pituitary to stimulate ACTH secretion,

which then stimulates the adrenal cortex to secrete cortisol .

•

• About 70% of blood cortisol is bound to a carrier protein called

corticosteroid-binding globulin.

•Another 15% is bound to albumin, the remaining 15% exists free in

solution.

Regulation of glucocorticoid secretion Guyton and Hall 2011 12th edition

Abnormalities of Adrenocortical Secretion• Hypoadrenalism (Adrenal Insufficiency)-Addison's Disease• Addison's disease results from an inability of the adrenal cortices to

produce sufficient adrenocortical hormones, and this in turn is mostly caused by primary atrophy or injury of the adrenal cortices.

– In about 80 percent of the cases, the atrophy is caused by autoimmunity against the cortices.

– Adrenal gland hypofunction is also frequently caused by tuberculousdestruction of the adrenal glands or invasion of the adrenal cortices by cancer.

– In some cases, adrenal insufficiency is secondary to impaired function of the pituitary gland, which fails to produce sufficient ACTH.

• When ACTH output is too low, cortisol and aldosterone production decrease and eventually, the adrenal glands may atrophy due to lack of ACTH stimulation.

• An untreated person with total adrenal destruction dies within a few days to a few weeks because of weakness and usually circulatory shock. Yet such a person can live for years if small quantities of mineralocorticoids and glucocorticoids are administered daily.

• Hyperadrenalism-Cushing's Syndrome• The clinical picture produced by prolonged increases in plasma glucocorticoids

was described by Harvey Cushing and is called Cushing syndrome.• Hypercortisolism can occur from multiple causes which may be

ACTH-independent or ACTH-dependent.

• The causes of ACTH-independent Cushing syndrome include

glucocorticoid-secreting adrenal tumors, adrenal hyperplasia, and prolonged administration of exogenous glucocorticoids for diseases such as rheumatoid arthritis.

• ACTH-independent Cushing syndrome occur when adrenocortical cells abnormally express receptors for gastric inhibitory polypeptide (GIP) (see Chapter 25 ), vasopressin (see Chapter 38 ), β-adrenergic agonists, IL-1, or gonadotropin-releasing hormone (GnRH), causing these peptides to increase glucocorticoidsecretion.

• The causes of ACTH-dependent Cushing syndrome include ACTH-secreting tumors of the anterior pituitary gland and tumors of other organs, usually the lungs, that secrete ACTH (ectopic ACTH syndrome) or corticotropin releasing hormone (CRH).

• Cushing syndrome due to anterior pituitary tumors is oft en called Cushing disease

Typical findings in Cushing syndrome Ganong 12th edition

• Patients with Cushing syndrome are protein-depleted as a result of excess protein catabolism.

• The skin and subcutaneous tissues are therefore thin and the muscles are poorly developed.

• Wounds heal poorly, and minor injuries cause bruises and ecchymoses.

• The hair is thin and scraggly.

• Increase in facial hair and acne, but this is caused by the increased secretion of adrenal androgens and often accompanies the increase in glucocorticoid secretion.

• Body fat is redistributed in a characteristic way. The extremities are thin, but fat collects in the abdominal wall, face, and upper back, where it produces a “buffalo hump.”

• The subdermal tissues rupture to form prominent reddish purple striae

• Hyperglycemia and decreased peripheral utilization of glucose may be sufficient to precipitate insulin-resistant diabetes mellitus

• Hyperlipidemia and ketosis are associated with the diabetes, but acidosis is usually not severe.

• The glucocorticoids are present in such large amounts in Cushing syndrome that they may exert a significant mineralocorticoidaction.

• The salt and water retention plus the facial obesity cause the characteristic plethoric, rounded “moon-faced” appearance, and there may be signifi cant K + depletion and weakness.

• About 85% of patients with Cushing syndrome are hypertensive. – The hypertension may be due to increased

deoxycorticosterone secretion, increased angiotensinogensecretion, or a direct glucocorticoid effect on blood vessels.

• Glucocorticoid excess leads to bone dissolution by decreasing bone formation and increasing bone resorption.

– This leads to osteoporosis, a loss of bone mass that leads eventually to collapse of vertebral bodies and other fractures

• Glucocorticoids in excess accelerate the basic electroencephalographic rhythms and produce mental aberrations ranging from increased appetite, insomnia, and euphoria to frank toxic psychoses.

Treatment of Cushing's Syndrome

• Removal of an adrenal tumor if this is the cause ordecreasing the secretion of ACTH, if this is possible.

• Hypertrophied pituitary glands or even small tumors in the pituitary that oversecrete ACTH can sometimes be surgically removed or destroyed by radiation.

• Drugs that block steroidogenesis, such as metyrapone, ketoconazole, and aminoglutethimide, or that inhibit ACTH secretion, such as serotonin antagonists and GABAtransaminase inhibitors, can also be used when surgery is not feasible.

• If ACTH secretion cannot easily be decreased, the only satisfactory treatment is usually bilateral partial (or even total) adrenalectomy, followed by administration of adrenal steroids to make up for any insufficiency that develops.

Regulation of Secretion

Feedback control of the secretion of cortisol and other glucocorticoids via the hypothalamic-pituitary-adrenal axis. Ganong 12th edition