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Corticotropin releasing hormone (CRH) is produced in the hypothalamus.  This is released via the hypothalmic-hypophyseal portal sytem into the anterior pituitary.  It then interacts with its target cells, the corticotrohps, in the ant. pit.  This interaction stimulater the production of ACTH (Adrenocorticotropic hormone), which stimulates cells in the adrenal cortex to synthesize the glucocorticids and the adrenal androgens.  

Outer Zone (zona glomerulosa) makes up 15% and synthesizes the mineralocorticoids; the major mieralocorticoid is ALDOSTERONE

Middle zone (zona fasciculata) makes up 75% and synthesizes glucocorticoids; the major glucocorticoid is CORTISOL

Inner zone (zona reticularis) makes up 10% ans sythesizes the adrenal androgens

ACTH regulates zona fasciculata and reticularis.  So, excess of ACTH increases the production of glucocorticoids and adrenal androgens. It will also cause growth in theses areas, while a deficiency in ACTH will cause atrophy in these areas.

A synthetic cortisol, prednisone, is used to prevent inflammation in intact tissues in inflammatory disorders such as Rheumatoid arthritis and Systemic Lupus Erythmatosis.  

Prednisone:

-Inhibits the enzyme phospholipase A so that the inflammatory mediator prostaglandins are not synthesized

-Inhibits capillary permeability

-Inhibits diapedesis = leukocyte movement from blood into tissue

-Inhibits degranulation and the release of inflammatory mediators such as histamine

-Stimulates vasoconstriction; inhibits vasodilation

It is used after tissue/organ transplant to reduce the chance of tissue/organ rejection 

It:

-Inhibits leukocyte movement and function

-Apoptosis of leujocytes = decrease leukocyte number

-Stimulates involution (atrophy/shrinking) of the thymus 

Primary hypercortisolism: High levels of cortsol produced by two zonae fasciculata due to tumor of the adrenal glands (associated with low levels of ACTH)

Secondary hypercortisolism: High levels of ACTH produced by the corticotrophs due to tumor in the ant. pit., which stimulates the zonae fasciculata and the reticularis to produce high levels of both cortisol and the adrenal androgens; excessive growth of these two zones = increase in adrenal size. (refferred to as Cushing's disease - the most common form of hypercortisolism (70%))

Tertiary hypercorticsolism: Hypothalmic tumor releasing high level of CRH --> high ACTH --> high cortisol and adrenal androgens

Ectopic CRH or ACTH or cortisol hypersecretion from nonpituitary tumors

Exogeneous intake of synthetic cortisol as an anti-inflammatory drug or as an immunosuppressive drug to control an inflammatory disease or to prevent tissue/organ rejection.

ACTH-dependent hypercortisolism due to high levels of ACTH from an anterior pituitary tumor 

It's the most common form of hypercortisolism (70%)

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Also,

-Glucocorticoid induced osteoporosis

-hypercalciuria (excessive calcium in urine)

-Renal calculi

-Hirsutism (hairy)

-Inability to fight infections

-High blood sugar

-High blood pressure

-Vertigo (lightheadedness/dizziness)

-Blurry vision

-Water retention

-Menstrual irregularities

-Severe depression

-Cognitive disabilities

-Emotional instability

-Sleep disorders

-Fatigue

1) Low dose Dexamethasone Suppression Test:

This test screens for Cushing's syndrome when it's suspected. The cortisol agonist, dexamethasone (Dex) is given to suppress cortisol release.  1 mg of Dex is given at bedtime (11pm) and the blood cortisol levels are measured at 8am the following morning.

Results: Normal = cortisol levels will be suppressed (below 1.8 ug/dl).  Levels of cortisol above 1.8 ug/dl is suggestive of Cushing's syndrome. High blood or urine levels establish Cushing's syndrome

2) Measurement of blood ACTH levels (Petrosal Venous Sinus Sampling):

If blood cortisol levels are high but ACTH levels are low (<5pg/ml) => primary hypercortisolism; MRI of adrenal glands

If blood cortisol levels are high and ACTH levels are also high => secondary and tertiary hypercortisolism; MRI of pituitary gland to locate tumor

If the cortisol and ACTH levels are low and the patient has Cushing's =>due to exgenous intake of synthetic cortisol

3) High dose Dexamethasone Suppression Test:

This tests differentiates between Cushing's disease and all other forms of Cushing's syndrome. Give pt 8mg overnight and measure blood cortisol levels at 8am the following morning.  Results: levels of cortisol fall 50% in Cushing's disease and the cortisol levels remain high as in the low dose test in all other forms

1) Surgical removal of adrenal tumor in primary hypercortisolism

2) Transsphenoidal microsurgery to remove pituitary tumor in Cushing's disease

3) Drugs to manage excess cortisol after surgery or if surgery is not an option

1) Drugs that inhibit SCCE (which converts cholesterol to pregnenolone): Aminoglutethimide and Ketoconazole (antifungal drug)

2) Drugs that inhibit 11 hydroxylase that converts 11 deoxycortisol to cortisol: Metyrapone

3) Cytotoxic drug that selectively destroys cells in the adrenal cortex: Mitotane

1) What is hypofunction of the adrenal cortex refferred to as?

2) What are three types of hypofunction of the adrenal cortex?

1) Adrenal (Adrenocortical) Insufficiency (AI)

2) Primary AI (also known as Addison's disease): cortisol, adrenal androgens and aldosterone levels are low; ACTH levels are high

Secondary AI: ACTH levels are low and therefore cortisol and adrenal androgen levels are low; aldosterone function is preserved 

3) Partial resistance to cortisol: associated with hypercortisolism without the clinical features of Cushing's syndrome

1) Primary AI:

i) Autoimmune adrenalitis (Schmidt's syndrome)

ii) Adrenal hemorrage (Waterhouse-Friderichsen syndrome (WFS)) due to infections such as HIV, TB, and CMV (fungal infection) 

iii) Congenital Adrenal Hyperplasia (CAH)

iv) Aggressive treatment of Cushing's disease

2) Secondary AI: 

i) Exogenous intake of synthetic cortisol - suppresses the HPA axis

ii) Pituitary tumors that compress the corticotrophs resulting in low ACTH release