Adrenocortical hormones

Adrenocortical HormonesChapter 77 Textbook of Medical PhysiologyGuyton 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 GlucocorticoidsAffect the electrolytes “minerals” Affects the blood

glucose of the extracellular fluids sodium & concentrationpotassium; protein and fat

metabolism;Aldosterone Cortisol

• And a small amounts of sex hormones , especially:Androgenic Hormones .

Synthesis and Secretion of Adrenocortical 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)


(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).


(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 glucocorticoidsand 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 andthe 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



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


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 Deficiency2. Glucocorticoid Deficiency3. 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

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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 SyndromeHypersecretion 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 cortex5. 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 associatedwith 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:3. Hypokalemia ( occasional muscle paralysis)4. Slight increase in extracellular fluid volume5. Slight increase in blood volume6. Very slight increase in plasma Na+ concentration7. 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.

Abnormalities in Adrenocortical SecretionAdrenogenital Syndrome

An occasional adrenocortical tumor secretes excessive quantities of androgensthat 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… masculinecharacteristics.

In a prepubertal male, rapid development of the male sexual organs.

In the adult male, the virilizing characteristics of the syndrome are usuallyobscured by the normal virilizing characteristics of the testosterone secretedby the testes; as a result diagnosis could be difficult, but in this syndrome, theexcretion of 17-ketosteroids in the urine may be 10-15 times normal, this canbe used in the diagnosis of the disease.

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Adrenocortical hormones