Adrenal Gland Disorders

Adrenal Gland: Anatomy

Capsule
Zona glomerulosa Zona fasciculata
Glucocorticoid Cortisol 10 to 20 mg/day Mineralocorticoids Aldosterone 100 to 150 g/day

Cortex
Adrenal androgens Androgen&Estrogen 20 mg/day Catecholamine Norepinephrine (NE) Epinephrine (EPI) Bioactive amines

Zona reticularis

Medulla

Hormones of Adrenal Cortex

The adrenal cortex produces three major classes of steroids: (1) glucocorticoids (2) mineralocorticoids (3) adrenal androgens

Biosynthesis of Adrenal Steroids

Androgen Cholesterol
pathway pregnenolon

Glucocorticoid
pathway progesterone 17 OH progesterone

Mineralocorticoid
pathway deoxycorticosterone corticosterone

17 OH pregnenolone

dehydroepiandrosterone

deoxycortisol

18 OH corticosterone

androsterone

CORTISOL

ALDOSTERONE

ESTRADIOL

STEROID TRANSPORT

Cortisol circulates in the plasma as free cortisol, protein-bound cortisol, cortisol metabolites. Free cortisol is a physiologically active hormone, can act directly on tissue sites. Normally, <5% . Most synthetic glucocorticoid analogues bind less efficiently to CBG (~70% binding). This may explain the propensity of some synthetic analogues to produce cushingoid effects at low doses. Aldosterone is bound to proteins to a smaller extent than cortisol.

GLUCOCORTICOID PHYSIOLOGY

1.
2. 3. 4.

The principal glucocorticoid is cortisol (hydrocortisone). Maintain blood pressure & cardiovascular function Slow the immune system's inflammatory response Balance the effects of insulin in breaking down sugar for energy Regulate the metabolism of proteins, carbohydrates, and fats

There are 3 mechanism of neuroendocrine control : Episode secretion of the cicardian rhytm of ACTH Stress responsiveness of the hypothalamicpituitary adrenal axis Feed back inhibition by cortisol of ACTH secretion

1.

2.

3.

CICARDIAN REGULATION

The plasma level of ACTH varies during the days as a result of its pulsatile secretion.
It follows a cicardian pattern with a peak just prior to waking and nadir before retiring.

Glucocorticoids have been used for their anti-inflammatory & immunosupressive activity in treatment of a wide variety disorders. Because of their side effect, glucocorticoid should be used in the minimum effective dose for the shortest possible duration of therapy.

Side effects of glucocorticoids

Cardiovascular Arterial hypertension Congestive heart failure Esophagitis, gastritis, peptic ulcer, digestive hemorrhage

Gastrointestinal

Neuropsychiatric

Psychiatric disorders in general Intracranial hypertension

Glaucoma Cataracts Osteoporosis Aseptic bone necrosis Myopathies

Ophthalmic Musculoskeletal

Side effects

Endocrine/metabolic

Truncal obesity, supraclavicular & posterior cervical fat deposition, hirsutism, masculinization, menstrual disorders, growth failure in children & adolescents, hiperglycemia, dyslipidemia, negative nitrogen, potassium & calcium balance, sodium retention, hypokalemia, metabolic alkalosis Decrease in inflammatory response Higher susceptibility to infections

Immune

Cutaneous
Vascular

Striae,acne, delayed wound healing

Vasculitides, Thromboembolism Arteriosclerosis

CLINICAL USE OF ADRENAL STEROIDS

1. 2.

3. 4.

5. 6.

How serious is the disorder? How long will glucocorticoid therapy be required? Which preparation is the best? Evaluation of patients prior to initiating steroid therapy Alternate day steroid therapy Withdrawl of glucocorticoids following long-term use

Comparative steroid potencies

Name Hydrocortisone (Cortisol) Cortisone acetate Prednisone Prednisolone Methylprednisolone Glucocorticoid potency 1 0.8 4 4 5

Mineralocorticoid potency 1 0.8 0.25 0.25 <0.01

Duration of action (t1/2 in hours) 8 oral 8, i.m 18+ 16-36 16-36 18-40

Dexamethasone
Betamethasone Triamcinolone

30-40
25 5 8 puffs 4 x a day equals 14 mg oral

<0,01
<0,01 <0,01

36-54
36-54 Des-36

Beclometasone Fludrocortisone acetate Deoxycorticosterone acetate (DOCA) Aldosterone

prednisone once a day 15 0 0.3

200 20 200-1000

MINERALOCORTICOID PHYSIOLOGY

The principal steroid with mineralocorticoid activity is aldosterone Control of Aldosterone Secretion : 2 most significant regulators 1. Concentration of potassium ions in ECF 2. Angiotensin II

The major target of aldosterone is the distal tubule of the kidney, where it stimulates exchange of sodium and potassium.

Adrenocortical Diseases

Relatively rare If untreated:

Morbidity and mortality Availability of effective treatment

Classified on the basis of

1. Excess 2. Deficiency

Adrenocortical Diseases
Glucocorticoid Excess Cushings syndrome Pseudo-Cushings syndromes Glucocorticoid Resistance Glucocorticoid Deficiency Primary hypoadrenalism Secondary hypoadrenalism Post-chronic corticosteroid replacement therapy Mineralocorticoid Excess Mineralocorticoid Deficiency Defects in aldosterone synthesis Defects in aldosterone action Adenomas & Carcinomas

Congenital Adrenal Hyperplasia : enzymatic deffect 21-Hydroxylase,3-hydroxysteroid dehydrogenase, 17-hydroxylase, 11-hydroxylase

Hypofunction of The Adrenal Cortex

Can be divided into 2 general categories : Associated with primary inability of the adrenal to elaborated sufficient quantities of hormone Associated with a secondary failure due to inadequate ACTH formation or release

1.

2.

Primary adrenocortical insufficiency (Addisons Disease) Addison's disease occurs when the adrenal glands do not produce enough of the hormone cortisol and in some cases the hormone aldosterone.
Most cases are caused by the gradual destruction of the adrenal cortex, the outer layer of the adrenal glands, by the body's own immune system. Tuberculosis (TB), an infection which can destroy the adrenal glands, accounts for about 20% of cases of primary adrenal insufficiency in developed countries.

Clinical Features of Primary Adrenal Insufficiency

Symptom Weakness, tiredness, fatigue (100%) Anorexia (100%) Gastrointestinal symptoms (92%) Nausea (86%) Vomiting (75%) Constipation (33%) Abdominal pain (31%) Diarrhea (16%) Postural dizziness (12%) Muscle or joint pains (613%)

Sign

Laboratory Finding

Weight loss (100%) Hyperpigmentation (94%) Hypotension (<110 mm Hg systolic) (8894%) Vitiligo (1020%) Auricular calcification (5%) Electrolyte disturbances (92%) Hyponatremia (88%) Hyperkalemia (64%) Hypercalcemia (6%) Azotemia (55%) Anemia (40%) Eosinophilia (17%)

DIAGNOSIS
Sign and symptom Screening test Plasma cortisol 30-60 min after 250 g cosyntropin im/iv Subnormal (Normal cortisol level > 18g/dl) Plasma ACTH and/or plasma aldosterone increment 30 min after 250 g cosyntropin im/iv

High ACTH, subnormal Aldosterone increment Primary adrenal insufficiency

Low ACTH; normal Aldosterone increment Secondary adrenal insuficiency

 Addison's disease.

Without treatment by mineralocorticoid replacement therapy, a lack of aldosterone is lethal, due to electrolyte imbalances and resulting hypotension & cardiac failure

Therapy of Addisons disease general measures

Therapy of Addisons disease specific Hydrocortisone : 15-25 mg/d Prednisone 2-3 mg/morning 1-2 mg/early evening Fludrocortisone acetate, has a potent Na-retaining effect; 0.05-0.3 mg/d Dehydroepiandrosterone (DHEA) 50 mg/d for some women improvement of the sense of well being, mood, and sexuality

Treat all infections if occurred Increases the dose of hydrocortisone appropriately Maximal dose of hydrocortisone for severe stress is 50 mg IV or IM every 6 hours Advice patients to wear a medical alert bracelet or medal reading Adrenal insufficiencytakes hydrocortisone

Secondary Adrenocortical Insufficiency

Due to ACTH deficiency : 1. Prolonged administration of excess glucocorticoids : common 2. Deficiencies of multiple pituitary hormones Much more common than primary adrenal insufficiency

Secondary Adrenal Insufficiency

When a person who has been receiving a glucocorticoid hormone for a long time abruptly stops or interrupts taking the medication. Glucocorticoid hormones, which are often used to treat inflammatory illnesses block the release of both CRH and ACTH. If CRH levels drop, the pituitary is not stimulated to release ACTH, and the adrenals then fail to secrete sufficient levels of cortisol

Diagnosis

Low ACTH (< 5 pg/mL) and cortisol suggest secondary adrenal insufficiency Patients with confirmed secondary adrenal insufficiency should have CT/MRI of the brain to rule out pituitary tumor or atrophy.

Protocol for glucocorticoid dose reduction & withdrawal

Dose prednisone/ prednisolone

Protocol reduction

Interval

> 20mg 10-20 mg < 10 mg

25% 2.5 mg 2.5 mg

4 days 7 days 15 days

ACUTE ADRENOCORTICAL INSUFFICIENCY

1.Chronic adrenal insufficiency, usually precipitated by sepsis or surgical stress 2. Acute haemorrhagic destruction of both adrenal glands ( anticoagulant therapy / a coagulation disorder) 3. Rapid withdrawl of steroid from patients with adrenal atrophy owing to chronic steroid administration

Adrenal Crisis
Clinical feature :

Dehydration, hypotension, or shock out of proportion to current illness severity Nausea and vomiting with a history of weight loss and anorexia Abdominal pain so-called acute abdomen Unexplained hypoglycemia Unexplained fever EMERGENCY

TREATMENT

Primarily toward repletion of circulating glucocorticoids and replacement of the sodium and water deficits. Infusion of 5% glucose in normal saline solution should be started with a bolus intravenous infusion of 100 mg hydrocortisone followed by a continuous infusion of hydrocortisone at a rate of 10 mg/h. An alternative approach is to administer a 100-mg bolus of hydrocortisone intravenously every 6 h.

ADRENAL CORTICOL INSUFFICIENCY IN ACUTE ILL PATIENTS

HPA axis is dramatically altered during critical illnesses such as trauma, surgery, sepsis and shock. In such situations cortisol levels rise 4-6 fold, inadequate cortisol production during critical illness can result in hypotension, reduced systemic vascular resistance, shock and death. Treatment with supplementary cortisol

ALDOSTERONISM

Is a syndrome associated with hypersecretion of the mineralocorticoid aldosterone.

1.

2.

Primary aldosteronism the cause for the excessive aldosterone production resides within the adrenal gland Secondary aldosteronism the stimulus is extraadrenal.

Primary Aldosteronism

A generic term for a group of disorders; excessive aldosterone independently of normal Renin Angiotensin System Affects women > men; 3rd 5th decades of life. Hypertensive patients; 0.05 12% may have primary aldosteronism

Causes:

1.Solitary aldosteroneproducing adenoma (APA; Conns syndrome); 2.Bilateral hyperplasia 3.Primary adrenal hyperplasia, 4.Adrenal carcinoma

Clinical manifestations: Hypertension, metabolic alkalosis, hypokalemia; hypomagnesemia

...Primary Aldosteronism

Treatment
1.

Tumors should be removed laparoscopically. After removal of an adenoma, BP decreases in all patients; complete remission occurs in 50 to 70%.

2. With adrenal hyperplasia, 70% remain hypertensive after bilateral adrenalectomy; thus surgery is not recommended. Hyperaldosteronism in these patients can usually be controlled by spironolactone (aldosteron antagonist)

Secondary aldosteronism

An appropriately increased production of aldosterone in response to activation of the renin-angiotensin system

Usually occurs in association: 1. The accelerated phase of hypertension 2. An underlying edema disorder

Secondary aldosteronism in hypertensive states :

1. 2.

A primary overproduction of renin (primary reninism) An overproduction of renin secondary to a decrease in renal blood flow and/ perfusion pressure : due to a narrowing of one or both of the major renal arteries by atherosclerosis , fibromuscular hyperplasia, severe arteriolar nephrosclerosis (malignant hypertension), with profound renal vasoconstriction (the accelerated phase of hypertension).

Secondary aldosteronism is present in many forms of edema.

The rate of aldosterone secretion is usually increased in patients with edema caused by either cirrhosis or the nephrotic syndrome. In congestive heart failure, elevated aldosterone secretion varies depending on the severity of cardiac failure. The stimulus for aldosterone release in these conditions appears to be arterial hypovolemia and/hypotension. Thiazides and furosemide often exaggerate secondary aldosteronism via volume depletion

Glucocorticoid Excess
Cushing's syndrome Is a hormonal disorder caused by prolonged exposure of the body's tissues to high levels of the hormone cortisol.

Classification of Causes of Cushings Syndrome

ACTH-Dependent

ACTH-independent

Cushings disease (pituitarydependent) Ectopic ACTH syndrome Ectopic CRH syndrome Macronodular adrenal hyperplasia Iatrogenic (treatment with ACTH 124)

Adrenal adenoma and carcinoma Primary pigmented nodular adrenal hyperplasia and Carneys syndrome. Iatrogenic (e.g., pharmacologic doses of prednisolone, dexamethasone)

Pseudo-Cushings Syndromes Alcoholism Depression Obesity

Symptoms & Signs Cushing syndrome

Central obesity Moon face Buffallo hump Protuberant abdomen & thin extremities Oligo/amenorhea Weakness Headache Hypertension Purple striae Hyperglycemia Hypokalemia
etc.

Brain/CNS: Excess : initially euphoria, prolonged exposure a variety of physiologic abnormalities : irritability, emotional lability & depression

Adipose tissue distribution Glucocorticoids excess increase fat deposition promotes visceral obesity, the reason for abdominal fat deposition & distribution in states of cortisol excess is unknown.

Endocrine system: Female : supress LH responsiveness to GnRH, resulting in supression of estrogens & progestin w/ inhibition of ovulation & amenorhea.

Cardiovascular/renal:
Glucocorticoids cardiac out put and peripheral vascular tone, regulate the expression of adrenergic receptors In excess, the may cause hypertension. They affect water and electrolyte balance (sodium retention, hypokalemia, hypertension, increased GFR)

Skin/muscle/connective tissue: In excess inhibit fibroblasts, lead to loss of collagen and connective tissue resulting in thinning of the skin (easy bruising, stria formation, poor wound healing).

Bone & calcium metabolism: Intestinal calcium absorption. Glucocorticoids in excess leads to osteoporosis

In the liver: increased glycogen deposition; increased gluconeogenesis Muscle & Fat: inhibits glucose uptake & utilization; increased lipolysis FFA increased cholesterol & triglycerides; decreased HDL-cholesterol Permissive effect of other hormones

increase blood glucose; protein & lipid catabolism

2. Definitive test ACTH : Normal 20-100 pgr/ml Pituitary dependent : 80-250 Adrenal tumor : 0-40 Ectopic ACTH : > 250

How Is Cushing's Syndrome Treated?

Treatment depends on the specific reason for cortisol excess and may include
1. 2. 3.

4.

surgery radiation chemotherapy or the use of cortisol-inhibiting drugs.

How Is Cushing's Syndrome Treated?

If the cause is long-term use of glucocorticoid hormones to treat another disorder, the doctor will gradually reduce the dosage to the lowest dose adequate for control of that disorder. Once control is established, the daily dose of glucocorticoid hormones may be given on alternate days to lessen side effects.

Hormones of Adrenal Medulla

Secretes 2 hormones, epinephrine & norepinephrine. Secreted in response to stimulation by sympathetic nerve, particularly during stressful situations. Hypersecretion, usually from a tumor, causes prolonged or continual sympathetic responses.

Major effects mediated by epinephrine and norepinephrine

Common stimuli for secretion of adrenomedullary hormones include exercise, hypoglycemia, hemorrhage, emotional distress. Increased rate and force of contraction of the heart muscle : predominantly epinephrine acting through beta receptors Constriction of blood vessels: norepinephrine Dilation of bronchioles
Stimulation of lipolysis in fat cells Increased metabolic rate: in response to epinephrine. Dilation of the pupils Inhibition of certain "nonessential" processes: an example is inhibition of gastrointestinal secretion and motor activity.

Pheochromocytoma
Is an adrenal medullary tumor composed of chromaffin cells ,which secretes excessive amounts of catecholamines, usually epinephrine and norepinephrine Occurs at all ages but is most common in young - midadult. Most patients come to medical attention as a result of hypertensive crisis, paroxysmal symptoms suggestive of seizure disorder/anxiety attacks/hypertension that responds poorly to conventional treatment.

Clinical Manifestations
Hypertension is the most common clinical manifestation of pheochromocytoma and is present in 90% to 100% of patients. Sustained hypertension is seen in approximately half, paroxysmal hypertension in a third, and normal blood pressure in less than a fifth of patients.

Clinical Manifestations

Paroxysmal episodes that include the classic triad of severe headaches, palpitations, diaphoresis. These episodes may occur daily or as frequently as every few months. More than 90% of patients present with at least two of the three symptoms in the classic triad

...Pheochromocytoma

Hypertension, episodic severe of headaches, diaphoresis, and palpitations (sensitivity 91%, specificity 94%) The rule of 10s for pheochromos: 10% extra-adrenal, 10% bilateral; 10% familial, and 10% malignant