Lect. 5 of 6_Corticosteroids & Adrenocortical Dysfunction

Photo: Colorized transmission electron micrograph of an endocrine cell from the anterior pituitary gland. The secretory vesicles (brown) contain hormones.

From: Seeley’s Anatomy & Physiology 10th ed New York, NY: McGraw-Hill 2010.

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Learning Objectives 4. Adrenocorticosteroids 1. The role of ACTH and the HPA axis in the regulation of corticosteroid synthesis 2. The principal physiological responses to both glucocorticoids and mineralocorticoids, especially the role of cortisol and exogenous glucocorticoids in the negative feedback suppression of the HPA axis.

3. The use of synthetic glucocorticoids and mineralocorticoids drugs in the treatment of adrenal deficiency diseases such as Adrenal insufficiency and Congenital Adrenal Hyperplasia 4. The mechanism of action of glucocorticoid drugs and their pharmacological use in the treatment of non-endocrine diseases e.g. Rheumatoid Arthritis, Asthma, Inflammation and Cancer.

Marc Imhotep Cray, MD

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Learning Objectives Adrenocorticosteroids cont.

5. The major adverse effects associated with the clinical use of glucocorticoids 6. The concept that abrupt withdrawal of chronic glucocorticoid therapy can lead to acute adrenal crisis due to atrophy of the adrenal cortex and subsequent deficiency in endogenous cortisol production 7.The use of cortical synthesis inhibitors such as ketoconazole, metyrapone, aminoglutethimide and mitotane in the treatment of Cushing’s disease.

Marc Imhotep Cray, MD

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Summary of adrenal corticosteroids CORTICOSTEROIDS

Betamethasone Cortisone Dexamethasone Fludrocortisone Hydrocortisone Methylprednisolone Prednisolone Prednisone Triamcinolone INHIBITORS OF ADRENOCORTICOID BIOSYNTHESIS OR FUNCTION

Eplerenone Ketoconazole Spironolactone Marc Imhotep Cray, MD

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Corticosteroids & Adrenocortical Dysfunction

Marc Imhotep Cray, MD

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Marc Imhotep Cray, MD

Baron SJ and Lee CI. Lange Pathology Flash Cards. New York: McGraw-Hill, 2009

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Case 41 Adrenal Cortex A 45-year-old man presents for the evaluation of weight gain. He has noticed a 20-lb weight gain in the past few months without any change in his diet or activity level. He has started developing “stretch marks” on his abdomen as well. His wife has noted that even his face seems to be “growing fatter.” Review of systems is significant for complaints of fatigue, multiple recent upper respiratory infections, and the development of facial acne. He has no significant medical history and takes no medications. There is a family history of diabetes and hypertension.

On examination, his blood pressure is elevated at 165/95 mm Hg, but his other vital signs are normal. His face is plethoric, and he has a small fatty hump developing on his upper back. His abdomen is obese but soft and nontender without masses or fluid. Skin examination is notable for moderate facial acne and multiple violaceous striae on the abdomen. Blood tests show an elevated glucose level of 150 mg/dL, normal electrolytes, and renal function. His thyroid function tests are normal. You suspect idiopathic Cushing disease and order a dexamethasone suppression test to assist with confirming the diagnosis. _ Which pituitary hormone stimulates the release of adrenocortical steroids? _ What is the major glucocorticoid produced in the adrenal glands? _ What is the major mineralocorticoid produced in the adrenal glands? _ What is the major effect of mineralocorticoids?

Marc Imhotep Cray, MD

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Regulation of Adrenal Hormones  The 2 adrenal glands in human body are responsible for producing  mineralocorticoids (eg, aldosterone) regulate fluid and electrolyte balance  glucocorticoids (eg, cortisol) which are essential for carbohydrate metabolism  Aldosterone production is mediated primarily by renin-angiotensin system  Cortisol production is regulated by a feedback mechanism involving hypothalamic-pituitary-adrenal (HPA) axis

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Regulation of Adrenal Hormones Cortisol production cont.

First, hypothalamus releases CRH in response to various stimuli including neurotransmitters, vasopressin, and catecholamines CRH stimulates anterior pituitary to release ACTH which then stimulates adrenal cortex to produce cortisol as serum cortisol levels increase, synthesis and secretion of CRH and ACTH decrease via a negative feedback loop

Marc Imhotep Cray, MD

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Mineralocorticoids and Glucocorticoids  Mineralocorticoids enhance reabsorption of sodium and water from distal tubule of kidney and increase urinary potassium and hydrogen ion excretion

 Principal function of glucocorticoids involves regulation of carbohydrate metabolism  They are also involved in other physiologic actions, including: o gluconeogenesis o glucose utilization o lipid and bone metabolism o fluid and electrolyte homeostasis o alteration of levels of various immune cells o alleviation of inflammatory response, and o participation in neuropsychiatric functions Marc Imhotep Cray, MD

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Glucocorticoid functions cont.  As a result of these functions—most notably immunosuppressive and antiinflammatory actions (a direct result of immunosuppressive effects)— glucocorticoids are widely used in treatment of  cancer  autoimmune disorders  inflammatory disorders such as  asthma  inflammatory bowel disease  arthritis, and  allergies

Marc Imhotep Cray, MD

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Corticosteroids  Therapeutic corticosteroids (eg, hydrocortisone, prednisone, dexamethasone), with different mineralocorticoid and glucocorticoid activities, are antiinflammatory and immunosuppressive via inhibiting immune cells  This reduces formation, release, and activity of inflammation mediators (eg, cytokines, histamine, prostaglandins, leukotrienes)

 Short-term therapy adverse effects include  Insomnia  euphoria, and increased appetite  Long term therapy effects include  osteoporosis  hypertension  edema  hyperglycemia, and  cushing-like syndrome Marc Imhotep Cray, MD

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Corticosteroids cont.  Long-term drug use can suppress the HPA axis and abrupt stopping of therapy can cause possibly fatal acute adrenal insufficiency syndrome “adrenal crisis”  Slow dosage tapering allows HPA axis to begin functioning  To reduce systemic absorption and side effects, drugs can be given topically or by inhalation or nasal spray, intraarticular injection, or rectal suppository  Alternate-day and lowest effective dosing may limit side effects and adrenal atrophy Marc Imhotep Cray, MD

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Question A 37-year-old kidney transplant recipient presents to her primary care physician for follow-up. Among other immunosuppressant drugs, she has been taking daily prednisone for the past 2 months since her transplant. With only a few doses of prednisone left, she gets snowed into her house and cannot refill her prescription (but she has enough of the other medications to last a few more weeks). If she runs out of prednisone and cannot get it refilled, what is she most at risk for developing?

(A) Cardiovascular collapse (B) Osteoporosis (C) Increased risk of infection (D) Insomnia (short-term oral/parenteral) (E) Nausea/vomiting (short-term oral/parenteral)

Marc Imhotep Cray, MD

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The answer is A: Cardiovascular collapse (adrenal crisis) Chronic use of glucocorticoids (such as prednisone) will lead to adrenal atrophy because the exogenous steroid suppresses the hypothalamic-pituitary-adrenal (HPA) axis. If the exogenous steroid is abruptly withdrawn, the atrophied adrenal gland is unable to compensate by producing endogenous steroids quickly enough. The sudden loss of adrenal steroids is termed “adrenal crisis� and can result in cardiovascular collapse and death.

(B) Osteoporosis is a possible result of continued chronic glucocorticoid therapy, not abrupt cessation.

(C) Increased risk of infection is a result of continued chronic glucocorticoid therapy, not abrupt cessation.

(D) Insomnia is a possible side effect from short-term oral or parenteral glucocorticoid therapy.

(E) Nausea/vomiting are possible side effects from short-term oral or parenteral glucocorticoid therapy.

Marc Imhotep Cray, MD

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Pathophysiology of acute adrenal crisis  Patients with acute adrenal crisis have symptoms of fever, weakness, apathy, and confusion.  Anorexia, nausea, and vomiting may lead to volume depletion and dehydration.  Abdominal pain may mimic that of an acute abdominal process.  Evidence suggests that symptoms of acute glucocorticoid deficiency are mediated by significantly elevated plasma levels of cytokines, particularly IL-6 and, to a lesser extent, IL-1 and TNF.  Hyponatremia, hyperkalemia, lymphocytosis, eosinophilia, and hypoglycemia occur frequently.  Acute adrenal crisis can occur in patients with undiagnosed ACTH deficiency, in patients receiving corticosteroids and who are not given increased steroid dosage during periods of stress Precipitants include infection, trauma, surgery, and dehydration. o Gastrointestinal infections are particularly challenging because of the associated inability to ingest or absorb oral hydrocortisone replacement, which can lead to adrenal crisis despite other treatments.

If unrecognized and untreated, coma, severe hypotension, or shock unresponsive to vasopressors may rapidly lead to death.

Hammer GD, McPhee SJ, eds. Pathophysiology of Disease: An Introduction to Clinical Medicine, 7th Edn. New York: McGraw-Hill, 2014

Adrenal steroids and congenital adrenal hyperplasia

Marc Imhotep Cray, MD

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

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Adrenal steroids and congenital adrenal hyperplasia (2)

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

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Question Regarding the release of ACTH from the anterior pituitary in a 24-year-old man who is a marathon runner, which of the following is the next step in the process?

(A) Activation of protein S (B) Increase of cGMP (C) Stimulation of conversion of cholesterol to pregnenolone (D) Release of adrenocorticosteroids (E) Synthesis of pulmonary ACTH

Marc Imhotep Cray, MD

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The answer is C: Stimulation of conversion of cholesterol to pregnenolone.

The target organ of ACTH is the adrenal cortex, where it binds to specific receptors on the cell surfaces. The occupied receptors activate G protein– coupled processes to increase cyclic adenosine monophosphate (cAMP), which in turn stimulates the rate-limiting step in the adrenocorticosteroid synthetic pathway (cholesterol to pregnenolone). This pathway ends with the synthesis and release of the adrenocorticosteroids and the adrenal androgens.

(A) The occupied receptors activate G protein–coupled processes.

(B) The activated G protein complex increases cyclic AMP. (D) Release of adrenocorticosteroids occurs after they are synthesized.

(E) Pulmonary ACTH is produced in disease states such as oat cell carcinoma.

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Cushing Syndrome  Cushing syndrome is a group of clinical symptoms that result from prolonged exposure to excess glucocorticoids  May be caused by exogenous factors, such as long-term corticosteroid use, or  May be of endogenous origin due to either  excess ACTH secretion (ACTH dependent) or  autonomous cortisol hypersecretion (ACTH independent)

 Conditions such as adrenocortical adenomas and carcinomas as well as ectopic ACTH and CRH syndromes are responsible for endogenous syndrome Marc Imhotep Cray, MD

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Increase cortisol due to a variety of causes: 1. Exogenous corticosteroids—result in (Most common cause)

ACTH, bilateral adrenal atrophy

2. Primary adrenal adenoma, hyperplasia, or carcinoma—result in atrophy of uninvolved adrenal gland.

ACTH,

3. ACTH-secreting pituitary adenoma (Cushing disease); paraneoplastic ACTH secretion (eg, small cell lung cancer, bronchial carcinoids)—result in ACTH, bilateral adrenal hyperplasia.

Note: Cushing disease is responsible for majority of endogenous cases of Cushing syndrome.

Marc Imhotep Cray, MD

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Cushing Syndrome cont.  Clinical manifestations affect multiple organ systems and depend on degree and duration of hypercortisolism  Most common sign is progressive obesity seen in face, neck, trunk, and abdomen  Facial fat accumulation produces a moon-face appearance, and an enlarged dorsocervical fat pad produces a buffalo hump  Other symptoms include o weakness o muscle wasting o reduced arm muscle mass o osteoporosis, o cardiovascular and o metabolic complications

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Ketoconazole  Therapy for exogenous Cushing syndrome consists of minimizing exposure to glucocorticoids or ACTH  For the endogenous syndrome, therapy aims to reduce cortisol production in preparing patients for surgery or to maintain normal plasma cortisol levels until full effects of surgery or radiation are felt  Ketoconazole (an antifungal agent) is used to treat paraneoplastic Cushing syndrome secondary to ectopic ACTH production  The agent is highly effective in decreasing cortisol by inhibiting adrenocortical cytochrome P-450–dependent enzymes o These enzymes normally catalyze formation of cortisol precursors such as pregnenolone as well as metabolizing drugs (see NIP Figure 5-21 steroidogenesis schematic) Marc Imhotep Cray, MD

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Ketoconazole cont.  Drug-Drug Interactions Because ketoconazole is a cytochrome P-450–enzyme inhibitor , it can increase levels of many hepatically metabolized agents, such as    

cyclosporine warfarin digoxin, and phenytoin

 Side effects of ketoconazole include       

blood dyscrasias headache dizziness fatigue gynecomastia GI symptoms, and rash

 Patients respond to therapy after 4 to 6 weeks Marc Imhotep Cray, MD

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Metyrapone  Metyrapone is used to treat Cushing syndrome when dose limiting side effects occur with ketoconazole  and it can be used in combination with other agents

 Metyrapone is also used as a test for adrenal function  MOA It reduces cortisol production by inhibiting 11-β-hydroxylation final step in glucocorticoid synthesis process leads to accumulation of adrenal androgens and 11-deoxycorticosterone (the potent mineralocorticoid)  Resultant adverse effects include  water retention  hirsutism  GI disturbances, and  dizziness

o Dose reduction can limit these adverse effects  Metyrapone may take up to 4 months to produce a response Marc Imhotep Cray, MD

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Aminoglutethimide  Aminoglutethimide is used primarily for  Cushing syndrome secondary to adrenal hyperplasia  ectopic ACTH production, or  adrenal carcinoma o most useful when given after pituitary irradiation or in combination with metyrapone  MOA Aminoglutethimide partially inhibits conversion of cholesterol to pregnenolone in adrenal glands and blocks conversion of androstenedione (prehormone produced in adrenals) to estrone and estradiol in peripheral tissues

Marc Imhotep Cray, MD

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Aminoglutethimide cont.  Inhibition interrupts production of cortisol, aldosterone, and estrogens  A reflex increase in ACTH results, which partly or completely overcomes blockade this reflex can be prevented by replacement amounts of hydrocortisone (but not dexamethasone) given concomitantly

 Adverse effects include         

headache sedation dizziness nausea anorexia rash blood dyscrasias tachycardia, and hypertension

 This drug may take up to 4 months to produce a response Marc Imhotep Cray, MD

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Addison Disease or Primary Adrenal Insufficiency  Addison disease is due to  autoimmune-mediated destruction of adrenal cortex  mycobacterial infection  adrenal metastases, or  use of certain drugs

 Symptoms, caused by reduced production of  glucocorticoids  mineralocorticoids, and  sex hormones range from vague feelings of illness to acute syncope and mental status changes Biochemical abnormalities (eg, hyponatremia, hyperkalemia) usually exist Marc Imhotep Cray, MD

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Adrenal Insufficiency cont.  life-threatening adrenal crisis, which occurs in cases of undiagnosed adrenal insufficiency & untreated stress, mimics septic shock presents with  severe anorexia  dehydration, and  hypotension  Treatment: IV fluids and high-dose IV glucocorticoids  Chronic disease is managed with a glucocorticoid (hydrocortisone) plus a mineralocorticoid (fludrocortisone) with dosage tailored to avoid Cushing syndrome or inadequate therapy  Patients should be monitored for fludrocortisone side effects (eg, electrolyte changes, hypertension, edema, and hyperglycemia) Marc Imhotep Cray, MD

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Case 41 Answers Adrenal Cortex Summary: A 45-year-old man has Cushing disease.

• Pituitary hormonal stimulus of adrenocortical steroid production: ACTH. • Primary adrenal glucocorticoid: Cortisol.

• Primary adrenal mineralocorticoid: Aldosterone.

• Major mineralocorticoid effects: Regulation of salt and water balance in the kidney, promote sodium retention, and potassium loss.

CLINICAL CORRELATION Cushing disease is caused by ACTH-secreting tumors in the pituitary gland. The continuous production of ACTH disrupts the normal circadian production of ACTH and overrides the feedback of adrenal steroids on the hypothalamus and pituitary, resulting in excessive adrenocortical steroid production. Glucocorticoids affect most organs and tissues in the body.

Marc Imhotep Cray, MD

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Case 41 Answers Adrenal Cortex cont.

Their effects are mediated by specific intracellular glucocorticoid receptors that modulate the transcription rates of specific genes and results in increases or decreases of specific proteins.

The major glucocorticoid produced in the adrenal glands is cortisol (hydrocortisone). Glucocorticoids have numerous physiologic effects, including the stimulation of gluconeogenesis, increasing lipolysis, decreasing glucose uptake into fat cells, and redistributing body fat. These effects cause some of the symptoms and signs of Cushing disease, which include glucose intolerance or overt diabetes, weight gain, and increasing truncal obesity. Glucocorticoids also have anti-immune effects, which include decreasing circulating lymphocytes, monocytes, eosinophils, and basophils, increases in circulating neutrophils and atrophy of lymphoid tissue. The excess production of glucocorticoids can therefore lead to immune system suppression and recurrent infections.

Marc Imhotep Cray, MD

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Case 41 Answers Adrenal Cortex cont.

Under normal physiologic conditions, adrenocortical steroids will exert a negative feedback of ACTH release from the pituitary gland. ACTH release, and subsequent cortisol production, can be suppressed even more by the administration of synthetic steroids such as dexamethasone. ACTH, which is continuously produced by a tumor, will not be suppressed by this feedback mechanism. This formulates the basis for the dexamethasone suppression test, in which a dose of dexamethasone is administered and subsequent cortisol production is measured. Normally dexamethasone administration would cause a reduction of circulating cortisol. In Cushing disease the measurement of cortisol will remain at normal, or even elevated, levels.

Marc Imhotep Cray, MD

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THE END

See next slide for further study.

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Sources and further study: eLearning Endocrine cloud folder tools and resources MedPharm Guidebook: Unit 5 Drugs Used In Disorders of Endocrine System Endocrine and Reproductive System Pharmacology eNotes Clinical Pharmacology Cases 39 to 44 (Learning Triggers) Textbooks Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill, 2011 Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill, 2012 Mulroney SE. and Myers AK. Netter's Essential Physiology. Philadelphia: Saunders, 2009 Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition.

Philadelphia: Sanders, 2014 Toy E C. et.al. Case Files-Pharmacology Lange 3rd ed. New York: McGraw-Hill 2014.

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