ADRENAL CORTEX & ITS HORMONE

DR ABHAYA CHANDRA DAS 1ST YEAR PG STUDENT DEPT. OF PERIODONTICS Layers of cortex

CONTENTS
1. 2. 3. 4. 5. 6. a) b) c) d) Introduction Adrenal cortex Layers Steps of hormone synthesis Production of hormones & their actions Pathology : Adrenal insufficiency Cushing s syndrome Congenital adrenal hyperplasia Primary aldosteronism

Introduction
In mammals, the adrenal glands (also known as suprarenal glands) are the triangle-shaped endocrine glands that sit on top of the kidneys; Their name indicates that position (ad-, "near" or "at" + -renes, "kidneys"). They are chiefly responsible for regulating the stress response through the synthesis of corticosteroids and catecholamines, including cortisol and adrenaline.

Anatomy and function

Anatomically, the adrenal glands are located in the thoracic abdomen situated at top of the kidneys, specifically on their anterosuperior aspect. They are also surrounded by the adipose capsule and the renal fascia. In humans, the adrenal glands are found at the level of the 12th thoracic vertebra and receive their blood supply from the adrenal arteries.

Adrenal gland

 The adrenal gland is separated into two distinct structures:1. Adrenal medulla central core of the adrenal gland, surrounded by the adrenal cortex. The chromaffin cells of the medulla are the body's main source of the catecholamine hormones adrenaline(epinephrine) and noradrenaline (norepinephrine). These water-soluble hormones, derived from the amino acid tyrosine, are part of the fight-or-flight response initiated by the sympathetic nervous system. It is also the main source of dopamine,a catecholamine closely related to adrenaline and noradrenaline.

2. Adrenal cortex adrenal cortex is devoted to the synthesis of corticosteroid hormones from cholesterol. Some cells belong to the hypothalamic-pituitaryadrenal axis and are the source of cortisol synthesis. Other cortical cells produce androgens such as testosterone, while some regulate water and electrolyte concentrations by secreting aldosterone . In contrast to the direct innervation of the medulla, the cortex is regulated by neuroendocrine hormones secreted by the pituitary gland and hypothalamus, as well as by the renin-angiotensin system.

 Arteries and veins

Usually three arteries that supply each adrenal gland: 1. The superior suprarenal artery is provided by the inferior phrenic 2. The middle suprarenal artery is provided by the abdominal aorta 3. The inferior suprarenal artery is provided by the renal artery Venous drainage of the adrenal glands is achieved via the suprarenal veins: 1. The right suprarenal vein drains into the inferior vena cava 2. The left suprarenal vein drains into the left renal vein or the left inferior phrenic vein. 3. The suprarenal veins receive blood may form anastomoses with the inferior phrenic veins. The adrenal glands and the thyroid gland are the organs that have the greatest blood supply per gram of tissue. Up to 60 arterioles may enter each adrenal gland.

Adrenal cortex
Situated along the perimeter of the adrenal gland, The adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, including aldosterone and cortisol respectively. It is also a secondary site of androgen synthesis.

Layers of cortex

Cortical part of the adrenal gland (on the pointer).

Layers : The cortex can be divided into three distinct layers of tissue based on their organisation.
layer name Primary product

Most superficial cortical layer

zona glomerulosa

mineralocorticoids (eg, aldosterone)

Middle cortical layer

zona fasciculata

glucocorticoids (eg, cortisol , corticosterone)

Deepest cortical layer

zona reticularis

weak androgens (eg, dehydroepiandrosterone , androstenedione )

Steps of hormone synthesis : All adrenocortical hormones are synthesised from cholesterol. Cholesterol is transported into the inner mitochondrial membrane by steroidogenic acute regulatory protein (STAR), where it is converted into pregnenolone by the enzyme CYP11A1. Accordingly, production of hormones in all three layers of the adrenal cortex is limited by the transportation of cholesterol into the mitochondria and by its conversion into pregnenolone. Pregnenolone can be either dehydrogenated to progesterone, or hydroxylated to 17-alphahydroxypregnenolone.

 The steps up to this point occur in many steroidproducing tissues. Subsequent steps, however, only occur in the adrenal cortex: Progesterone (hydroxylation at C21) Deoxycorticosterone (two further hydroxylations) Aldosterone Progesterone (hydroxylation at C17) 17-alphahydroxyprogesterone (hydroxylation) Deoxycortisol (hydroxylation) Cortisol

Production : The adrenal cortex produces a number of different corticosteroid hormones: A. Mineralocorticoids:They are produced in the zona glomerulosa. The primary mineralocorticoid is aldosterone . Its secretion is regulated by the oligopeptide angiotensin II (angiotensin II is regulated by angiotensin I, which in turn is regulated by renin). Aldosterone is secreted in response to :1. high extracellular potassium levels, 2. low extracellular sodium levels, 3. low fluid levels and blood volume.

ACTION OF ALDOSTERONE

 Aldosterone affects metabolism in different ways:

It increases urinary excretion of potassium ions It increases interstitial levels of sodium ions It increases water retention and blood volume

B. Glucocorticoids: They are produced in the zona fasciculata.

The primary glucocorticoid released by the adrenal gland is cortisol. Its secretion is regulated by the hormone ACTH from the anterior pituitary.

 Upon binding to its target, cortisol enhances metabolism in several ways:

1. It stimulates the release of amino acids from the body 2. It stimulates lipolysis, the breakdown of fat 3. It stimulates gluconeogenesis, the production of glucose from newly-released amino acids and lipids 4. It increases blood glucose levels in response to stress, by inhibiting glucose uptake into muscle and fat cells 5. It strengthens cardiac muscle contractions 6. It increases water retention

7. It has anti-inflammatory and anti-allergic effects

C. Androgens:
They are produced in the zona reticularis. The most important androgens include:
1. Testosterone: a hormone with a wide variety of effects, ranging from enhancing muscle mass and stimulation of cell growth to the development of the secondary sex characteristics. 2. Dihydrotestosterone (DHT): a metabolite of testosterone, and a more potent androgen than testosterone in that it binds more strongly to androgen receptors. 3. Androstenedione (Andro): an androgenic steroid produced by the testes, adrenal cortex, and ovaries. While androstenediones are converted metabolically to testosterone and other androgens, they are also the parent structure of estrone. 4. Dehydroepiandrosterone (DHEA): It is the primary precursor of natural estrogens. DHEA is also called dehydroisoandrosterone or dehydroandrosterone.

Pathology Adrenal insufficiency (e.g. due to Addison's disease) Cushing's syndrome Congenital adrenal hyperplasia Conn's syndrome

Adrenal insufficiency
Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones primarily cortisol, but may also include impaired aldosterone production (a mineralcorticoid) which regulates sodium, potassium and water retention.

 Addison's disease is the worst degree of adrenal insufficiency, which if not treated, severe abdominal pains, profound weakness, extremely low blood pressure, kidney failure, and shock may occur (adrenal crisis). An adrenal crisis often occurs if the body is subjected to stress, such as an accident, injury, surgery, or severe infection. Death may quickly follow.

 Adrenal insufficiency can also occur when the hypothalamus or the pituitary gland, both located at the base of the skull cavity, doesn't make adequate amounts of the hormones that assist in regulating adrenal function. This is called secondary adrenal insufficiency and is caused by lack of production of ACTH in the pituitary or lack of CRH in the hypothalamus

Types of Adrenal Insufficiency : Adrenal impairment (primary adrenal insufficiency)

Addison's disease (autoimmune adrenalitis) Congenital adrenal hyperplasia

Pituitary or hypothalamus impairment (secondary adrenal insufficiency)

pituitary micro adenoma pituitary macro adenoma head injury Sheehan's syndrome (associated only with pituitary impairment) environmental genetics

Causes:1. Autoimmunue (may be part of a polyglandular autoimmune disorder which can include type I Diabetes Mellitus, autoimmune thyroid disease (also known as autoimmune thyroiditis, Hashimoto's thyroiditis and Hashimoto's disease) 2. Discontinuing corticosteroid therapy without tapering the dosage (severe adrenal suppression with ACTH suppression) 3. Surgery, illness or any other forms of stress 4. Injury 5. adrenoleukodystrophy

Method of diagnosis and treatment: Assessment of symptoms 1. The person may show symptoms of dehydration, weightloss and disorientation. 2. They may experiance weakness, tiredness, dizziness , Low blood pressure that falls further when standing (orthostatic hypotension), muscle aches, nausea, vomiting, and diarrhea. 3. These problems may develop gradually and insidiously. 4. Addison's can present with tanning of the skin which may be patchy or even all over the body and in some cases that a person with light skin can look so dark people can mistake them for being from another country. 5. Characteristic sites are skin creases (e.g. of the hands) and the inside of the cheek (buccal mucosa)j. goitre and vitiligo may also be present.

Testing : If the person is in adrenal crisis, the ACTH stimulation test may be given. If not in crisis, cortisol, ACTH, aldosterone, renin, potassium and sodium are tested from a blood sample before the decision is made if the ACTH stimulation test needs to be performed. X-rays or CT of the adrenals may also be done

Simple diagnostic chart

Sources of pathology hypothalam us (tertiary) CRH Low ACTH Low cortisol Low aldosterone Low renin Low Na Low K Low causes
tumor of the hypothalamus (adenoma), Antibodies environment, head injury tumor of the pituitary (adenoma), antibodies, environment, head injury, surgical removal, Sheehan's syndrome tumor of the adrenal (adenoma), stress, antibodies, environment, Addison's, injury,

pituitary (secondary)

High

Low

Low

Low

Low

Low

Low

adrenal glands (primary)

High

High

Low

Low

High

Low

High

Treatments
Adrenal crisis 1. Intravenous fluids 2. Intravenous steroid (Solu-Cortef of Solumedrol), later hydrocortisone, prednisone or methylpredisone tablets 3. rest Mineralcorticoid deficiency (low aldosterone) ludrocortisone (Florinef) (To balance sodium, potassium and increase water retention)

 Cortisol deficiency (primary and secondary) 1. Adrenal cortical extract (usually in the form of a supplement, non prescription) 2. Hydrocortisone (Cortef) (between 20 and 35 mg) 3. Prednisone (Deltasone) (7 1/2 mg) 4. Prednisolone (Delta-Cortef) (7 1/2 mg) 5. Methylprednisolone (Medrol) (6 mg) 6. Dexamethasone (Decadron) (1/4 mg, some doctors prescribe 1/2 to 1 mg, but those doses tend to cause side effects resembling Cushing's disease

Cushing's syndrome
Cushing's Syndrome (also called hypercortisolism or hyperadrenocorticism) is an endocrine disorder caused by high levels of cortisol in the blood from a variety of causes, including a pituitary adenoma (known as Cushing's disease), adrenal hyperplasia or neoplasia, ectopic adrenocorticotropic hormone (ACTH) production (e.g., from a small cell lung cancer), and iatrogenic (steroid use). Normally, cortisol is released from the adrenal gland in response to ACTH being released from the pituitary gland.

 Both Cushing's syndrome and Cushing's disease are characterized by elevated levels of cortisol in the blood, but the cause of elevated cortisol differs between the two disorders. Cushing's disease specifically refers to a tumour in the pituitary gland that stimulates excessive release of cortisol from the adrenal gland by releasing large amounts of ACTH. In Cushing's disease, the pituitary gland does not respond as it should with negative feedback to high levels of cortisol, and continues to produce ACTH.

 Exogenous Versus Endogenous There are two types of Cushing s syndrome: exogenous and endogenous. In endogenous disease, excess cortisol production within the body is the cause, whilst in exogenous disease the causal factor is typically steroid medication (i.e. it originates outside the body) mimicking cortisol's activity. The signs and symptoms are therefore virtually identical, aside from those induced by ACTH in pituitary-dependent disease and ectopic ACTHproducing tumours .

 The exogenous route is by far the most commonly taken in Cushing s syndrome (a fact that all too many seem to forget). Examples of such exogenous steroid medications are those used to treat inflammatory disorders such as asthma and rheumatoid arthritis, or to suppress the immune system after an organ transplant. This type of Cushing s is temporary and goes away after the patient has finished taking the cortisol-like medications. Endogenous Cushing s syndrome is unusual, it usually comes on slowly and can be difficult to diagnose.

Pathogenic pathways

Clinical manifestation of Cushing syndrome

METABOLIC EFFECT
Carbohydrate metabolism:
y y y y

SYMPTOM
polydypsia polyuria

SIGN
Diabetes Mellitus: impaired glucose use hyperglycaemia insulin resistance thin osteoporotic bone pathological fractures* poor wound healing abdominal striae* proximal muscle wasting and myopathy* moon face 'buffalo hump' . susceptibility to infection

increased glycogenesis increased glucogenesis

Increased protein catabolism

y y y

muscle weakness easily bruised thin skin* growth retardation

y y y y y

Increase and redistribution of body fat Reduced inflammatory response

central obesity

y y

METABOLIC EFFECT
Increased stomach acid production Mineralcorticoid effects
y

SYMPTOM

SIGN
predisposition to gastric ulcer y hypertension
y

sodium retention redistribution of fluids

y

oedema

Mood

depression psychosis

Sex hormones

acne hirtuism amenorrhoea/oligome norrhoea poor libido

Diagnosis : When Cushing's is suspected, either a dexamethasone suppression test (administration of dexamethasone and frequent determination of cortisol and ACTH level), or a 24-hour urinary measurement for cortisol offer equal detection rates. Dexamethasone is a glucocorticoid and simulates the effects of cortisol, including negative feedback on the pituitary gland. When dexamethasone is administered and a blood sample is tested, high cortisol would be indicative of Cushing's syndrome because there is an ectopic source of cortisol or ACTH (eg: adrenal adenoma) that is not inhibited by the dexamethasone.

 A novel approach, recently cleared by the US FDA, is sampling cortisol in saliva over 24 hours, which may be equally sensitive, as late night levels of salivary cortisol are high in Cushingoid patients. Performing a physical examination to determine any visual field defect may be necessary if a pituitary lesion is suspected, which may compress the optic chiasm causing typical bitemporal hemianopsia . When any of these tests are positive, CT scanning of the adrenal gland and MRI of the pituitary gland are performed to detect the presence of any adrenal or pituitary adenomas or incidentalomas (the incidental discovery of harmless lesions). Scintigraphy of the adrenal gland with iodocholesterol scan is occasionally necessary.

DIAGNOSIS :-

 Treatment: Cushing's Syndrome needs to be treated as it can be fatal due to hypertension, MI, heart failure or infection. General: control cortisol hypersecretion using METYRAPONE - a 11-hydroxylase antagonist
this needs to be done before any further specific treatment

monitor cortisol levels Specific: surgery radiotherapy with yttriom implants medical - reduce ACTH with bromocriptine

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands (steroidogenesis). Most of these conditions involve excessive or deficient production of sex steroids and can alter development of primary or secondary sex characteristics in some affected infants, children, or adults.

 Examples of conditions caused by various forms of CAH: 1. ambiguous genitalia, in some females, such that it can be initially difficult to determine sex 2. vomiting due to salt-wasting leading to dehydration and death 3. early pubic hair and rapid growth in childhood 4. precocious puberty or failure of puberty to occur (sexual infantilism: absent or delayed puberty) 5. excessive facial hair, virilization, and/or menstrual irregularity in adolescence 6. infertility due to anovulation 7. hypertension

Adrenal steroidogenesis in 21-hydroxylase deficiency congenital adrenal hyperplasia

 Treatment of all forms of CAH may include any of: 1. supplying enough glucocorticoid to reduce hyperplasia and overproduction of androgens or mineralocorticoids 2. providing replacement mineralocorticoid and extra salt if the person is deficient 3. providing replacement testosterone or estrogen at puberty if the person is deficient 4. additional treatments to optimize growth by delaying puberty or delaying bone maturation 5. genital reconstructive surgery to correct problems produced by abnormal genital structure

Primary aldosteronism
Primary aldosteronism, also known as primary hyperaldosteronism and Conn syndrome, is characterized by the overproduction of the mineralocorticoid hormone (aldosterone) by the adrenal glands. Aldosterone causes increase in sodium and water retention and potassium excretion in the kidneys. It is a rare but recognised cause of hypertension to arterial hypertension (high blood pressure).

Causes: The syndrome is due to: aldosterone-secreting adrenal adenoma (benign tumor, 50-60%) hyperplasia of the adrenal gland (40-50%)

Signs, symptoms and findings:high blood pressure , muscle cramps (due to hyperexcitability of neurons), muscle weakness (due to hypoexcitability of skeletal muscles) and headaches (due to the low potassium), metabolic alkalosis (due to increased secretion of H+ ions by the kidney). The high pH of the blood makes calcium less available to the tissues and causes symptoms of hypocalcemia (low calcium levels).

Diagnosis :Measuring aldosterone alone is not considered adequate to diagnose primary hyperaldosteronism. Rather, both renin and aldosterone are measured, and the ratio is diagnostic. Usually, renin levels are suppressed, leading to a very low renin-aldosterone ratio (<0.0005). This test is confounded by antihypertensive drugs, which have to be stopped up to 6 weeks. If plasma levels of renin and aldosterone suggest hyperaldosteronism, CT scanning can confirm the presence of an adrenal adenoma. If the clinical presentation primarily involves hypertension and elevated levels of catecholamines, CT or MRI scanning can confirm a tumor on the adrenal medulla, typically a pheochromocytoma

Therapy :The treatment for hyperaldosteronism depends on the underlying cause. In patients with a single benign tumor (adenoma), surgical removal (adrenalectomy) is curative. This is usually performed laparoscopically, through several very small incisions. For patients with hyperplasia of both glands, successful treatment is often achieved with spironolactone or eplerenone, drugs that block the effect of aldosterone. Note, in males one side effect of the drug therapy is gynecomastia. In the absence of proper treatment, individuals with hyperaldosteronism often suffer from poorly controlled high blood pressure, which may be associated with increased rates of stroke, heart disease, and kidney failure. With appropriate treatment, the prognosis is excellent.

REFERENCE
1. Text book of medical physiology(11th edition) by Guyton &Hall. 2. Ganong review of Medical physiology (22nd edition) . 3. Concise medical physiology (5th edition) by choudhuri. 4. Text book of Internal medicine (16th edition) by harrison. 5. Various internet sources.

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