Adrenal glands and hormones. Adrenal glands The adrenals are orange-colored glands that sit on top...

Adrenal glands and hormones

Adrenal glands

The adrenals are orange-colored

glands that sit on top of the kidneys

near the spine, just underneath the

last rib and extending down about an

inch. The right adrenal is shaped

something like a pyramid, whereas

the left is shaped more like a half

moon.

Each adrenal gland is composed of

two endocrine components: a medulla

(inner part) that constitutes 20% of

the gland and a cortex (outer part)

that constitutes the remaining 80%.

The cortex consists of three zones.

The medulla and each of the zones in

the cortex each produce different

hormones that serve a variety of

functions in your body.

Adrenal Glands

The Adrenal Cortex

The adrenal cortex is divided into

three zones which each secrete

different hormones that carry out

specific functions throughout your

body.

1. Zone of glomerulosa Aldosterone is secreted from this zone which is the major hormone

controlling the sodium and potassium levels, and thus fluid balance,

within your bloodstream, cells and interstitial fluids. It is also called

mineralocorticoids.

3

2

Medulla

Cortex

1. Zone of glomerulosa

The Adrenal Cortex

2. Zone of fasciculata Coritsol (hydrocortisone) is produced,

affects glucose, amino acid and fat

metabolism, which is called glucocorticoids.

Cells of this zone are arranged into fascicles

separated by venous sinuses.

3. Zone of reticularis

Dehydroepiandrosterone (DHEA)-precursor for androgen is

synthesized. This zona manufactures an ancillary portion of sex

hormones for each sex and also produces male hormones in women

and female hormones in men to keep the effects of the dominant sex

hormones in balance .

3

2

Medulla

Cortex

1. Zone of glomerulosa

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

Synthesis of adrenocorticosteroids

All steroid hormones have in common the 17-carbon cyclopentao-

perhydrophenanthrene nucleus. Additional carbons can be added at

positions 10 and 13 or as a side chain attached to C17.


Steroid hormones and their precursors and metabolites differ in

1. number and type of substituted groups,

2. number and location of double bonds,

3. stereochemical configuration.

3

1718

19

18

21


1. Uptake of cholesterol by the adrenal cortex is mediated by the LDL receptor. With long-term stimulation of the adrenal cortex by ACTH, the number of LDL receptors increases. Much of the cholesterol in the adrenal is esterified and stored in cytoplasmic lipid droplets.


2. Upon stimulation of the adrenal by ACTH or cAMP, an esterase is activated, and the free cholesterol formed is transported into the mitochondria.

3. In the mitochondria, a cytochrome P450 side chain cleavage enzyme (P450SCC) converts cholesterol to pregnenolone.


4. Pregnenolone may be converted by dehydrogenase/isomerase to progesterone or else by P450c17 (17-α-hydroxylase) to 17α-hydroxypregnenolone. Progesterone can also be converted to 17α-hydroxyprogesterone by P450c17.


17-α-hydroxylase

17-α-hydroxylase

dehydrogenase/isomerase

5. After the synthesis of progesterone and 17-hydroxyprogesterone, P450c21(21-hydroxylase) can hydroxylate these steroids at the 21 position, resulting in 11-deoxycorticosterone and 11-deoxycortisol, respectively.


21-hydroxylase

21-hydroxylase

6. The final step in the synthesis of adrenal mineralocorticoids and glucocorticoids is mediated by P450c11 (11-β-hydroxylase), which also mediates the final steps in the synthesis of aldosterone from deoxycorticosterone.

11-β-hydroxylase

11-β-hydroxylase

11

7. P450c17 has two activities, that of a 17α-hydroxylase and that of a C-

17,20 lyase capable of breaking up the C-17,20 carbon bond of 17α-

hydroxypregnenolone or 17α-hydroxyprogesterone, yielding

dehydroepiandrosterone (DHEA) or androstenedione, respectively.



8. 17-hydroxysteroid dehydrogenase

convert androstenedione to

testosterone. P450aro mediates the

aromatisation of androgens to

estrogens in the gonads. In peripheral

target tissues, testosterone can further

be converted to 5α-

dihydrotestosterone by 5α-reductase.

Biosynthesis

Of human

steroid

Hormones

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.

Some autosomal recessive mutations in biosynthetic enzymes

responsible for converting cholesterol to androgens generally lead to

partial male-to-female sex reversal.

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.


B. Glucocorticoids: Cortisol


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 powerful anti-inflammatory

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.

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

Posterior Pituitary Gland

Hypothalamus

AnteriorPituitary Gland

ACTH

Stress Circadian

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

(Figure 9-40)

Fasting

People have considerable difficulty when on a prolonged fasting.

They will always rationalize the problems encountered on a fasting

as being due to the body detoxifying.

During a fasting, the body will call on the adrenals to produce

glucocorticoids to maintain blood glucose level which is adequate for

normal level of activity. The glucocorticoids can elevate blood

glucose by breaking down protein into carbohydrates through the

process of gluconeogenesis.

Regulation of glucocorticoids

The Secretion of glucocorticoids from the adrenal cortex is regulated

by negative feedback involving the CRH secretion by the

hypothalamus. CRH then acts on the anterior pituitary to stimulate

ACTH secretion, which then stimulates the adrenal cortex into cortisol

secretion. 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.

The HPA axis or HPA system, a negative

feedback system, is one of the most

important elements of homeostasis, the

process that maintains a steady internal

biochemical and physiological balance in

your body. The HPA Axis adjusts cortisol

level according to the needs of the body,

under normal and stressed conditions, via

ACTH. ACTH is secreted from the pituitary

gland in response to orders form the

hypothalamus and travels in the

bloodstream to the adrenal cortex.

※ The Hypothalamus/Pituitary/Adrenal (HPA) Axis

People who suffer from adrenal fatigue almost always have some

form of irregular blood sugar pattern, of which hypoglycemia is the

most common.

When your adrenals are fatigued, their cortisol output is diminished

and you have lower levels of circulating blood cortisol, your liver has

a more difficult time converting glycogen into glucose.

Addison's Disease: Primary Chronic Adrenocortical Insufficiency

Cushing's syndrome (hyperadrenocorticism or hypercorticism) is a endocrine disorder caused by high levels of cortisol (hypercortisolism) in the blood. This can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or ACTH.

The Adrenal Medulla

The functional unit of the adrenal

medulla is the chromaffin cell, which

functions as a neuroendocrine cell. In

response to stimulation, chromaffin cells

secrete the hormones epinephrine

(adrenaline) and norepinephrine

(noradrenalin) directly into the blood.

The medulla is involved in extreme stress and, within this context,

epinephrine and norepinephrine both work with cortisol from the

adrenal cortex. Epinephrine and norepinephrine are important mainly in

crisis situations.

1

3

2

Medulla

Cortex

Catecholamines Biosynthesis

1. Tyrosine is precursor for the synthesis of catecholamines.

2. The catecholamine are produced in response to fight,

fright and flight (3F). These include emergencies like

shock, cold, fatigue, emotional condition like anger.

Biochemical function of catecholamine1. Effect on carbohydrate metabolism: Both of them can increase

glycogenolysis and gluconeogenesis and decrease glycogenesis.

①Catecholamine promote the release of glucose from liver and decrees

its utilization by muscle; Epinepherine inhibits insulin secretion ②but promote glucagon secretion.

2. Effect on lipid metabolism: Both of them enhance the breakdown of

TAG in adipose tissue. This cause increase in the free fatty acid in

the circulation which are effectively utilized by the heart and muscle

as fuel source.

3. Effect on physiological function: Cateccholamines increase cardiac

output, blood pressure and oxygen consumption. They cause smooth

muscle relaxation in bronchi, GIT and blood vessels supplying

skeletal muscle.

phaeochromocytoma (PCC) or pheochromocytoma:

a neuroendocrine tumor of the medulla of the adrenal

glands (originating in the chromaffin cells), or extra-

adrenal chromaffin tissue that failed to involute after birth

and secretes excessive amounts of catecholamines,

usually adrenaline (epinephrine) if in the adrenal gland

and not extra-adrenal, and noradrenaline

(norepinephrine).

17% of adrenal cases are bilateral (suggesting hereditary disease)

18.4% in children (also suggesting hereditary disease)

5% are extra-adrenal (located in any orthosympathetic tissue): of these 9% are in the abdomen and 1% are located elsewhere. Some extra-adrenal phaeochromocytomas are probably actually paragangliomas, but the distinction is only possible after surgical resection.

11.1% malignant, but this rises to 30% for extra-adrenal cases

26% are hereditary

3% recur after being resected

14% of affected individuals do not have arterial hypertension

1. Within the sympathetic nerve chain along the spinal cord (orange spots)

2. Overlying the distal aorta (the main artery from the heart) (green spots)

3. Within the ureter (collecting system from the kidney (yellow spot)

4. Within the urinary bladder (blue spot)

5. Remember, 90% are in the adrenal glands (red spots on the kidneys)

Here's a look at the extra-adrenal sites of pheochromocytomas

Adrenal glands and hormones. Adrenal glands The adrenals are orange-colored glands that sit on top...

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