Adrenocortical Hormones Regulation and Functions

Adrenocortical Hormones
Chapter 77
Textbook of Medical Physiology
Guyton and Hall
Dr. Yasmin Hzayyen
Orthodontic Resident
RMS

INTRODUCTION
• There are 2 adrenal glands.
• 4 grams each.
• At the superior pole of the 2 kidneys.
• Each gland is composed of 2 distinct parts:
1. Adrenal Cortex
2. Adrenal Medulla

INTRODUCTION
Adrenal medulla
• The central 20% of the gland
• Related to the sympathetic nervous system;
It secretes epinephrine and norepinephrine

INTRODUCTION
Adrenal cortex
• Secretes corticosteroids.
• These hormones are all synthesized from the steroid cholesterol
and they all have similar chemical formulas.
• Slight differences in their molecular structures.
• Different very important functions.

Corticosteroids Mineralcorticoids, Glucocorticoids
and Androgens.
• Two major types of adrenocortical hormones, secreted by adrenal
cortex:
Mineralcorticoids Glucocorticoids
Affect the electrolytes “minerals” Affects the blood glucose
of the extracellular fluids sodium & concentration
potassium; protein and fat metabolism;
Aldosterone Cortisol
• And a small amounts of sex hormones , especially:
Androgenic Hormones .

Synthesis and Secretion of Adrenocortical
Hormones

Hormones
• The adrenal cortex has three distinct layers:
(1) The zona glomerulosa:
• Thin layer of cells that lies just underneath the capsule; 15% of the cortex.
• Secrete Aldosterone; because these cells contain the enzyme aldosterone
synthase.
• The secretion is controlled mainly by the extracellular fluid
concentrations of angiotensin II and potassium.
(stimulate)

Hormones
(2) The zona fasiculata:
• The middle and widest layer; 75% of the cortex.
• Secretes the glucocorticoids cortisol and corticosterone, as well as small
amounts of adrenal androgens and estrogens.
• The secretion is controlled by the hypothalamic-pituitary axis via
adrenocorticotropic hormone (ACTH).

Hormones
(3) The zona reticularis:
• The deep layer of the cortex.
• Secretes the adrenal androgens dehydroepiandrosterone (DHEA) and
androstenedione. As well as small amounts of estrogens and some
glucocorticoids.
• The secretion is controlled by ACTH, although other factors such as cortical
androgen-stimulating hormone
(released from the pituitary) may also be
involved.
The mechanisms are not nearly as well
understood as those for glucocorticoids
and mineralocorticoids.

Adrenocortical Hormones are steroids derived from cholesterol
• The cells in the adrenal cortex can synthesize de novo small amounts of
cholesterol from acetate.
• Approximately 80% of the cholesterol used for steroid synthesis is provided by
low-density lipoproteins ( LDL) in the circulating plasma.
• Transport of cholesterol is regulated by feedback mechanisms.
• For example, ACTH increases the number of adrenocortical cell receptors for
LDL, as well as the activity of enzymes that liberate cholesterol from LDL.
Cholesterol enters cell, delivered to mitochondria, cleaved by enzyme
cholesterol desmolase to form pregnenolone.
• This initial step in steroid synthesis is stimulated by the different factors that
control secretion of the major hormone.

Synthetic Pathways for Adrenal Steroids
• Synthesis occur in two of the organelles of the cell: mitochondria
and endoplasmic reticulum.
• Each step is catalyzed by a speciﬁc enzyme system.
• Cortisol has a keto-oxygen on carbon#3 and
hydroxylated on carbon# 11 & #21.
• Aldosterone has an oxygen atom bound at carbon#18.

Mineralocorticoids
• Aldosterone (very potent, accounts for 90% of all mineralocorticoid activity)
• Desoxycorticosterone (1/30 as potent as aldosterone, but very small
quantities secreted)
• Corticosterone (slight mineralocorticoid activity)
• 9a-Fluococortisol (synthetic, slightly more potent than aldosterone)
• Cortisol (very slight mineralocorticoid activity, but large quantity secreted)
• Cortisone (synthetic, slight mineralocorticoid activity)

Glucocorticoids
• Cortisol (very potent, accounts for about 95% of all glucocorticoid activity)
• Corticosterone (provides 4% of total glucocorticoid activity, much less
potent than cortisol)
• Cortisone (synthetic, almost as potent as cortisol)
• Prednisone (synthetic, four times as potent as cortisol)
• Methylprednisone (synthetic, five times as potent as cortisol)
• Dexamethasone (synthetic, 30 times as potent as cortisol)

• It is clear from the previous list that some of these hormones have
both glucocorticoid and mineralocorticoid activities.
• The intense glucocorticoid activity of Dexamethasone, has almost
zero mineralocorticoid activity, making this an important drug for
stimulating specific glucocorticoid activity.

Adrenocortical Hormones Are Bound to Plasma
Proteins
• Approximately 90 to 95 per cent of the cortisol in the plasma binds
to plasma proteins, especially a globulin called cortisol-binding
globulin or transcorin and, to a lesser extent, albumin.
• This high degree of binding to plasma proteins slows the elimination
of cortisol from the plasma; therefore, cortisol has a relatively long
half-life of 60 to 90 minutes.
• Only about 60 per cent of circulating aldosterone combines with the
plasma proteins, so that about 40 per cent is in the free form; as a
result, aldosterone has a relatively short half-life of about 20
minutes.

Adrenocortical Hormones Are Metabolized in the
Liver
• The adrenal steroids are degraded mainly in the liver and
conjugated especially to glucuronic acid and, to a lesser extent,
sulfates.
• About 25 per cent of these conjugates are excreted in the bile and
then in the feces. The remaining conjugates formed by the liver
enter the circulation but are not bound to plasma proteins, are
highly soluble in the plasma, and are therefore filtered readily by the
kidneys and excreted in the urine.

The normal concentration
• Of aldosterone in blood is about 6 nanograms (6
billionths of a gram) per 100 ml, and the average
secretory rate is approximately 150 µg/day (0.15
mg/day).
• Of cortisol in the blood averages 12 µg/100 ml,
and the secretory rate averages 15 to 20 mg/day.

Functions of the Mineralocorticoids-Aldosterone
1. Renal Na+ reabsorption ( action on the principal cells
of the late distal tubule and collecting duct).
2. Renal K+ secretion ( action on the principal cells of
the late distal tubule and collecting duct).
3. Renal H+ secretion ( action on the alpha-intercalated
cells of the late distal tubule and collecting duct).

ALDOSTERONE
• Excess aldosterone increases extracellular fluid volume and arterial
pressure but has only a small effect on plasma sodium
concentration.(osmotic reabsorption)
• Even though aldosterone is one of the body’s most powerful sodium
retaining hormones, only transient sodium retention occurs when
excess amounts are secreted.
• Arterial pressure kidney excretion of salt (pressure natriuresis)
and water (pressure diuresis).

ALDOSTERONE
• Excess aldosterone causes hypokalemia and muscle weakness; this is
caused by alteration of the electrical excitability of the nerve and muscle
fiber membranes.
• Excess aldosterone increase tubular hydrogen ion secretion and
causes mild alkalosis.

ALDOSTERONE
• Too little aldosterone causes hyperkalemia and cardiac toxicity;
when it rises to 60 to 100 per cent above normal, serious cardiac toxicity,
including weakness of heart contraction and development of arrhythmia,
becomes evident; progressively higher concentrations of potassium lead
inevitably to heart failure.
Mineralocorticoid deficiency causes severe
renal sodium chloride wasting and
hyperkalemia

ALDOSTERONE
Aldosterone stimulates sodium and Potassium transport in sweat
glands, salivary glands and intestinal epithelial cells;
aldosterone greatly increases the reabsorption of sodium chloride and
the secretion of potassium by the ducts.
The effect on the sweat glands is important to conserve body salt in
hot environments, and the effect on the salivary glands is necessary to
conserve salt when excessive quantities of saliva are lost.

Regulation of Aldosterone
• The regulation of aldosterone secretion by the zona glomerulosa
cells is almost entirely independent of the regulation of cortisol and
androgens by the zona fasiculata and zona reticularis
• Factors that increase aldosterone secretion :
1. Increased Potassium ion concentration (hyperkalemia)
2. Increased activity of the renin-angiotensin system (increased
angiotensin II)
3. ACTH from the anterior pituitary gland (little effect on the rate of
secretion)
• Increased sodium ion concentration very slightly decreases
aldosterone secretion

• At least 95% of the glucocorticoid activity of the
adrenocortical secretions results from the secretion of
cortisol, known as hydrocortisone.
• In addition to this, a small but significant amount of
glucocorticoid activity is provided by corticosterone.
Functions of the Glucocorticoids

Effects of Glucocorticoids
1. Promote gluconeogenesis; They work in tandem with insulin from
the pancreas to maintain blood glucose levels in the proper
balance;
(a) Cortisol increases the enzymes required to convert amino acids into
glucose in the liver cells.
(b) Cortisol causes mobilization of amino acids from the extrahepatic tissues
mainly from muscle.
2. On protein and nucleic acid metabolism; by promoting transcription and
protein synthesis in liver. They also cause catabolic effects in extra-
hepatic tissues results in enhanced degradation of protein

3. On lipid metabolism; by increasing lipolysis in adipose tissue and
reducing synthesis of triglyceride.
4. On water and electrolyte metabolism: Deficiency causes increased
production of ADH which can decrease GFR causing water retention in
the body.
5. 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; corticosteroids (prednisone, prednisolone, etc.)
are used with all diseases involving inflammatory processes, including
auto-immune diseases.

6. On cardiovascular system: Cortisol could control the contraction
of the walls of the mid-sized arteries in increasing blood pressure.
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. 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.

• AdrenoCorticoTropic Hormone (ACTH) stimulates cortisol
secretion
• No stimuli has direct control effects on the adrenal cells that secrete
cortisol; instead it’s almost entirely controlled by ACTH (ant.
pituitary gland)
• = Corticotropin = Adrenocorticotropin
• It’s a large polypeptide (39 a.a)
• ACTH secretion is controlled by Corticotropin-Realising
Factor (CRF) from the hypothalamus
• CRF is a peptide (41 a.a)
Regulation of Cortisol Secretion by ACTH

Primary capillary plexus of the
hypopheseal portal system in the
median eminence of the
hypothalamus
CRF
Ant.
Pituitary
CRF; in the
paraventricular
nucleus of the
hypothalamus
This nucleus
receives many
nervous
connections from
the limbic system
and lower brain
stem

• ACTH activates adrenocortical cells to produce steroids by
increasing Cyclic Adenosine Monophosphate (cAMP)
• The principal effect of ACTH on the cells to activate adenylyl
cyclase in the cell membrane
• Then this induces the formation of (cAMP) in the cell cytoplasm
(max. effect in 3 mins.)
• cAMP activates the intracellular enzymes; that cause formation of
the hormones. (second messenger signal system)

• Most imp. step is activation of the enzyme protein kinase A; causes
initial conversion of cholestrol to pregnenolone (rate limiting step
for all the adrenocortical hormones)
• Long-term stimulation of the adrenal cortex by the ACTH increases
secretory activity and causes hypertrophy and proliferation of the
adrenocortical cells (zona fasiculata and zona reticularis)

• Almost any type of physical or mental stress can lead within mins.
to greatly enhance ACTH and consequently cortisol secretion (20-
fold)

• Mental stress = physical stress (rapid increase in ACTH secretion);
this is believed to result from increased activity in the
limbic system, especially in the amygdala and hippocampus
region ` transmit signals to the post. Med. hypothalamus

• Inhibitory effect of cortisol on the hypothalamus and on the
anterior pituitary to decrease ACTH secretion
• Cortisol has a direct negative feedback on:
1. Hypothalamus ( to decrease CRF)
2. Ant. Pituitary (to decrease ACTH)
All this to help regulate the plasma concentration of cortisol

• The secretory rates of CRF, ACTH and cortisol are high in the early morning
but low in the late evening
• This effect results from a 24-hour cyclical alteration in the signals from the
hypothalamus that cause cortisol secretion
Circadian Rhythm of glucocorticoid
secretion

Circadian Rhythm of glucocorticoid
secretion

Synthesis and secretion of ACTH in association with
Melanocyte-Stimulating Hormone, Lipotropin and
Endorphin
• When ACTH is secreted from the ant. Pituitary, other hormones that have
similar chemical structures are secreted simultaneously.
• Why? It’s because the gene that is transcribed to form the RNA molecule that
causes ACTH synthesis initially causes the formation of a considerably larger
protein, a prehormone called proopiomelanocortin (POMC); its a precursor for ’
ACTH , melonocyte-stimulating hormone (MSH), beta-lipotropin, beta-
endorphin and few others.
• Under normal conditions, none of these hormones is secreted in enough
quantity to have a significant effect on the human body, but when the secretion
rate of ACTH is high, formation of these hormones increases as well.
• ACTH is more important than MSH in determining the amount of melanin in
the skin.

Adrenal Androgens
• Several moderately active male sex hormones, most important:
dehydroepiandrosterone. ( mainly secreted during fetal life)
• Also progesterone and estrogen (female sex hormones), are secreted in
minute quantities.
• Weak effects in humans; part of the early development of the male sex
organs. Mild effects in the female throughout life (pubic and axillary hair)
• In extra-adrenal tissue, some of these hormones are converted into
testosterone; the primary male sex hormone.

Abnormalities in Adrenocortical
Secretion

Abnormalities in Adrenocortical Secretion
Hypoadrenalism-Addison’s Disease
Failure of the adrenal cortices to produce adrenocortical hormones; most
frequently caused by primary atrophy of the adrenal cortices
• This atrophy is caused by:
1. 80% of the cases, it’s caused by autoimmunity against the cortices.
2. Tuberculous destruction of the adrenal glands.
3. Invasion of the adrenal cortices by cancer.
• The disturbances in Addison’s disease are:
1. Mineralocorticoid Deficiency
2. Glucocorticoid Deficiency
3. Melanin pigmentation

Mineralocorticoid Deficiency
• Lack of aldosterone secretion Na+ reabsorption Na+, Cl- and
water lost into urine extracellular fluid volume.
• Hyponatremia, hyperkalemia and mild acidosis.
• Extracellular fluid volume depleted, plasma volume falls, red blood cell
concentration rises markedly, cardiac output decreases and the patient dies
in shock (4 days – 2 weeks)

Glucocorticoid Deficiency
• Unable to maintain normal blood glucose concentration between meals (no
gluconeogenesis)
• Many of the metabolic functions of the body will be depressed (no mobilization of fats
and proteins form the tissues)
• Muscles are weak .
• Susceptibility to deteriorating effects of different types of stress.

Melanin pigmentation
• Of the mucous membranes and skin.
• Not evenly deposited, rather deposited in blotches, especially in thin skin such as the
mucous membranes of the lips .

Treatment
A person can live to years if small quantities of mineralocorticoids and glucocorticoids
are administered daily.
Addisonian Crisis : the critical need for extra glucocorticoids and the associated
severe debility in times of stress.
Different types of trauma, disease or other stresses, such as surgical operations, a person is
likely to have an acute need for excessive amounts of glucocorticoids and often must be given
10 or more times the normal quantities to prevent death

Symptoms By Mayo Clinic Staff
Addison's disease symptoms usually develop slowly, often over several months,
and may include:
•Muscle weakness and fatigue
•Weight loss and decreased appetite
•Darkening of your skin (hyperpigmentation)
•Low blood pressure, even fainting
•Salt craving
•Low blood sugar (hypoglycemia)
•Nausea, diarrhea or vomiting
•Muscle or joint pains
•Irritability
•Depression
•Body hair loss or sexual dysfunction in women

Acute adrenal failure (addisonian crisis)
Sometimes, the signs and symptoms of Addison's disease may appear suddenly.
In acute adrenal failure (addisonian crisis),
The signs and symptoms may also include:
•Pain in your lower back, abdomen or legs
•Severe vomiting and diarrhea, leading to dehydration
•Low blood pressure
•Loss of consciousness
•High potassium (hyperkalemia)

• United States President John
F. Kennedy was one of the
best-known people with
Addison's disease and was
possibly one of the first to
survive major surgery.
Substantial secrecy
surrounded his health during
his years as president.

Hyperadrenalism-Cushing’s Syndrome
Hypersecretion by the adrenal cortex causes a complex cascade of hormone effects.
• Cortisol as well as androgens may causes imp. Effects.
• Hypercorticolism can occur from multiple causes:
1. Adenomas of the ant. Pituitary that secrete large amounts of ACTH; then causes
adrenal hyperplasia and excess cortisol secretion
2. Abnormal function of the hypothalamus that causes high levels of Corticotropin-
Releasing Hormone (CRH); which stimulates excess ACTH release
3. Ectopic secretion of ACTH by a tumor elsewhere in the body; such as an
abdominal carcinoma
4. Adenomas of the adrenal cortex
5. When large amounts of glucocorticoids are administered over a prolonged
periods for therapeutic purposes; for example rheumatoid arthritis

• When Cushing’s syndrome is secondary to excess secretion of ACTH by
the anterior pituitary gland, this is referred to as Cushing’s disease
• Excess ACTH secretion is the most common causes of Cushing’s
syndrome, and is characterized by high plasma levels of ACTH as well as
cortisol.
• Primary overproduction of cortisol
• Acounts for about 20-25% of the
clinical cases, and is usually associated
with reduced ACTH

To distinguish between ACTH-dependent and ACTH-independent
Cushing’s syndrome (first step in differential diagnosis):
Administration of large doses of dexamethasone (synthetic glucocorticoid)
• In patients who have overproduction of ACTH due to an ACTH-secreting
pituitary adenoma or to hypothalamic-pituitary dysfunction, even large doses of
dexamethasone usually do not suppress ACTH secretion
• Patients with primary adrenal overproduction of cortisol (ACTH-independent)
usually have low or undetectable levels of ACTH

•Extra deposition of fat in
the thoracic and upper
abdominal regions part
“buffalo torso”
•Androgenic potency
causes acne and hirsuitism.
•Hypertension due to slight
mineralocorticoid effects of
the cortisol.

Treatment
• Removing an adrenal tumor if this is the cause or decreasing the secretion of
ACTH, if this is possible.
• Hypertrophied pituitary glands or even small tumors, 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 GABA-transaminase inhibitors, can also be used when surgery is not feasible.
• Sometimes the only satisfactory treatment is usually bilateral partial (or even
total) adrenalectomy, followed by administration of adrenal steroids.

Primary Aldosteronism (Conn’s Syndrome)
Causes:
1. Small tumor of the zona glomerulosa cells occurs and secretes large amounts of
aldosterone.
2. In few instances hyperplastic adrenal cortices secrete aldosterone rather than
cortisol.
The effects as mentioned before:
1. Hypokalemia ( occasional muscle paralysis)
2. Slight increase in extracellular fluid volume
3. Slight increase in blood volume
4. Very slight increase in plasma Na+ concentration
5. Almost always hypertention
Diagnostic criteria: Decreased plasma renin concentration (feedback suppression)
Treatment: Surgical removal of the tumor or of most of the adrenal tissue when
hyperplasia is the cause.

Adrenogenital Syndrome
An occasional adrenocortical tumor secretes excessive quantities of androgens
that cause intense masculinizing effects throughout the body
In females, virile characteristics; growth of beard, a much deeper voice,
occasionally baldness, masculine distribution of hair on the body… masculine
characteristics.
In a prepubertal male, rapid development of the male sexual organs.
In the adult male, the virilizing characteristics of the syndrome are usually
obscured by the normal virilizing characteristics of the testosterone secreted
by the testes; as a result diagnosis could be difficult, but in this syndrome, the
excretion of 17-ketosteroids in the urine may be 10-15 times normal, this can
be used in the diagnosis of the disease.

Adrenocortical Hormones Regulation and Functions

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